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Ann Thorac Surg 2000;70:1832-1838
© 2000 The Society of Thoracic Surgeons

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Original article: general thoracic

Biological features and preoperative evaluation of mediastinal nodal status in non–small cell lung cancer

^a Department of Thoracic Surgery, Kyoto University, Kyoto, Japan
^b Department of Radiology, Fukui Medical University, Fukui, Japan

Address reprint requests to Dr Wada, Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto, 606-8507, Japan
e-mail: wadah{at}kuhp.kyoto-u.ac.jp

Presented at the Poster Session of the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Background. To examine whether biological features of primary tumor can help preoperative evaluation of mediastinal nodal status in non-small cell lung cancer.

Methods. A total of 450 patients who underwent tumor resection and mediastinal dissection were reviewed. p53 status and proliferative fraction (PI) were evaluated immunohistochemically.

Results. The accuracy of preoperative evaluation of mediastinal nodal status with computed tomography (CT) was 72.2%; mediastinal nodal metastases had not been revealed until operation in 59 patients (13.1%) (false-negative), and no metastasis was revealed in 66 patients (14.7%) although mediastinal nodal enlargement had been demonstrated by CT (false-positive). The number of false-negative patients was significantly larger when p53 aberrant expression was positive or when PI was higher. Combined with p53 status and PI, there were 27 false-negatives (24.1%) among patients with aberrant p53 expression and higher PI, whereas only two false-negatives (1.5%) among those with negative p53 expression and lower PI.

Conclusions. Mediastinoscopy may be recommended for tumor showing aberrant p53 expression and higher PI, even when CT demonstrates no mediastinal nodal enlargement.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

 
Postoperative survival of non–small cell lung cancer (NSCLC) remains to be poor [1, 2]. The most important factor to determine the postoperative survival is lymph node metastases (pN factor) as well as distant metastases (pM factor). When metastases to mediastinal lymph nodes are proved pathologically (pN2), 5-year survival rates after surgery have been reported to be around 20% [1–3]. Although postoperative adjuvant therapy has been introduced to improve the survival, the efficacy has not been established [1, 4]. Therefore, induction (or neo-adjuvant) therapy prior to operation has been conducted to improve the survival of pN2 patients, and the efficacy has been demonstrated in prospective randomized studies [5–7]. As a result, when mediastinal lymph nodal metastases are demonstrated preoperatively, induction chemotherapy or chemo-radiotherapy prior to operation is recommended [1]. That is, preoperative evaluation of mediastinal nodal status is important in decision-making of therapy for patients with NSCLC.

Computed tomography (CT) is a useful diagnostic modality in evaluation of intrathoracic diseases, and become a routine examination for patients with lung cancer. Recent improvement of postoperative survival of lung cancer patients is apparently caused by accurate preoperative evaluation and by increased cases of early detection of lung cancer, both of which can be realized by use of CT [1, 3, 8]. That is, CT is useful not only for detection and evaluation of primary tumor (T factor), but also for detection of enlarged lymph nodes. Usually, mediastinal lymph nodes are considered to be "abnormal" when the short-axis diameter is more than 1.0 cm; subcarinal lymph nodes are sometimes considered "abnormal" when the short-axis diameter is more than 1.5 cm [9]. However, "abnormal," that is enlarged, lymph nodes demonstrated by CT do not always mean metastases to mediastinal lymph nodes, because CT can not distinguish nodal enlargement caused by cancer metastases from non-metastasis nodal enlargement [9]. In addition, cancer metastases are sometimes proved pathologically even in non-enlarged lymph nodes, and nodal metastases can not be revealed until operation in such cases. Therefore, the sensitivity and specificity of CT for detection of mediastinal nodal metastases have been reported to be unsatisfactory [9–11]. Thus, accurate preoperative evaluation of mediastinal nodal status is sometimes difficult, whereas it is critical in decision-making of therapy for lung cancer patients.

Recent progress in molecular biology has revealed a variety of biological and genetic disorders involved in development and progress of malignant tumors. Among them, mutations of p53 gene, a tumor suppressor gene, are the most common genetic disorder shown in a variety of malignant tumors including NSCLC [12, 13]. p53 status has been reported to be clinically important in that abnormal p53 status may serve not only as a significant factor to predict poor prognosis [14] but also as a factor to determine sensitivity to radiation therapy and/or chemotherapy [15]. However, clinical significance of biological features of tumor tissues including p53 status has not been established in NSCLC, and decision-making in therapy for NSCLC patients based on these biological factors is not recommended [16]. The purpose of the article is to examine whether or not biological features including p53 status and proliferative properties of tumor cells can contribute to improvement of accuracy of preoperative mediastinal nodalevaluation.

	Patients and methods

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Patients
A total of 450 consecutive patients with pathologic stage (p-stage) IA–IV NSCLC who underwent thoracotomy with a complete mediastinal lymph node dissection without any preoperative therapy at the Department of Thoracic Surgery, Kyoto University, from January 1985 through December 1992, 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 [2]. Histologic type and cell differentiation were determined using the classification by the World Health Organization. With regard to tumor differentiation, well-differentiated squamous cell carcinoma (Sq) and adenocarcinoma (Ad) were both classified as well-differentiated tumor. Moderately differentiated Sq and Ad were classified as moderately differentiated tumor. Large cell carcinoma (La) as well as poorly differentiated Sq and Ad were classified as poorly differentiated tumor. The other histologic types were excluded in analysis according to cell differentiation. p53 status was determined by immunohistochemical staining (IHS) [16]. Cell proliferation was also evaluated by immunohistochemical detection of proliferating cell nuclear antigen (PCNA) that was expressed in the cell nucleus during late G1 and S stages of cell cycle [17]. All the biologic features were evaluated in histologic sections taken from the primary tumor. For all these patients, the inpatient medical records, chest roentgenogram films, whole-body CT films, bone and gallium scanning data, and operation records were reviewed. CT scans were performed using a CT/T8800 model scanner (General Electrical, Milwaukee, WI) with a 10-mm slice thickness. Mediastinal lymph nodal status was evaluated by a thoracic radiologist (H.I.). Mediastinal lymph nodes were considered to be enlarged when the short-axis diameter was more than 1.0 cm, and subcarinal lymph nodes were considered to be enlarged when the short-axis diameter was more than 1.5 cm. Accuracy, sensitivity, and specificity of CT of mediastinal nodal status were calculated on a per-patient basis.

Statistical methods
The numbers of true-positive, false-negative, false-positive, and true-negative cases for preoperative mediastinal nodal evaluation with CT were defined as TP, FN, FP, and TN, respectively. The sensitivity and specificity were estimated by TP/(TP + FN) and TN/(FP + TN), respectively. In addition, the positive and negative predictive values were estimated by TP/(TP + FN) and TN/(FP + TN), respectively. Counts were compared by the ² test, and trends in counts were analyzed by the ² test for trends. Continuous data were compared using Student’s t test if the distribution of samples was normal, or using the Wilcoxon test if the sample distribution was asymmetric. In addition to univariate analysis, multiple logistic regression models were used to evaluate the covariate-adjusted significance of several factors in determining mediastinal nodal status. A multiple logistic regression analysis was used to determine whether each variable was an independent predictor. Differences were considered significant when the p value was less than 0.05. All statistical manipulations were performed using the SPSS for Windows software system (SPSS Inc., Chicago, IL).

	Results

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p53 status and PI according to patients’ characteristics
Aberrant p53 expression was observed in 201 (44.7%) of the 450 patients. The mean and median PIs for all patients were 48.1% and 49.0%, respectively. p53 status and PI for each patient group stratified according to patients’ characteristics are shown in Table 1. Percentage of patients with aberrant p53 expression was significantly lower in well-differentiated tumor (50 of 146 patients, 34.2%) than in moderately (82 of 157 patients, 52.2%) or poorly differentiated tumor (69 of 147 patients, 46.9%). Aberrant p53 expression was seen more frequently in Sq patients (84 of 149 patients, 56.4%) than in Ad patients (94 of 250 patients, 37.6%), which may be related to the fact that ratio of well-differentiated tumor was significantly lower in Sq than in Ad. Aberrant p53 expression was seen more frequently in male patients (165 of 342 patients, 48.2%) than in female patients (36 of 108 patients, 33.3%), which may be related to the fact that ratio of Sq patients was significantly higher in male than in female patients. Increased aberrant p53 expression was seen in higher p-stage patients. PIs were significantly correlated with histologic type, cell differentiation, and tumor progression (p-stage). That is, PIs were significantly higher in Sq than in Ad, lower in well-differentiated tumor than in moderately to poorly differentiated tumor, and higher in higher p-stages.

Accuracy of preoperative evaluation of mediastinal nodal status
In 128 (28.4%) of all 450 patients, mediastinal nodal metastases were proved in histologic sections postoperatively (pN2 to pN3). Mediastinal nodal enlargement had been demonstrated by preoperative CT in 67 patients (true positive, TP), and not in 61 patients (false negative, FN). Among 322 patients with negative mediastinal nodal metastasis (pN0 to pN1), 256 patients had been diagnosed correctly with preoperative CT (true negative, TN), and 66 patients incorrectly (false positive, FP). Therefore, the positive and the negative predictive values in mediastinal nodal metastasis were 52.3% (67/128) and 79.5% (256/322), respectively. The accuracy, sensitivity, and specificity for preoperative evaluation of mediastinal nodal status were 71.8%, 53.2%, and 79.6%, respectively.

The accuracy of CT for each patient group stratified according to various patient characteristics and biologic features of the primary tumor is shown in Table 2. In evaluating the role of PI, patients were grouped into lower-PI patients (PI less than 49.0%) and higher-PI patients (PI 49.0% or higher), based on the median PI value. Among all the factors studied, p53 status and PI of the primary tumor were the most significant factors to affect the accuracy. When aberrant p53 was demonstrated in the primary tumor, 44 (67.7%) of 67 patients with pN2 to pN3 disease were diagnosed incorrectly with preoperative CT and the correct predictive value for positive mediastinal nodal metastasis was only 32.3%; 46 (73.0%) of 63 patients without aberrant p53 expression were diagnosed correctly as having mediastinal enlargement with preoperative CT (p < 0.001). Similarly, there were 42 (56.8%) false-negative results among pN2 to pN3 patients with higher PI, whereas only 19 (35.2%) false-negative results among pN2 to pN3 patients with lower PI, showing a significantly higher percentage of the incorrect prediction in higher-PI patients (p = 0.020). Moreover, the percentage of patients with false-positive results was significantly lower for higher-PI patients (19 of 152 pN0 to pN1 patients, 12.5%) than for lower-PI patients (47 of 170 pN0 to pN1 patients, 27.6%) (p = 0.001). Although grade of tumor differentiation or histologic type might influence the accuracy of CT evaluation, the influence was weak as compared with p53 status or PI of the tumor.

View larger version (25K): [in this window] [in a new window]   Fig 1. Biologic features (p53 status, proliferative index) of primary tumor and the accuracy of computed tomography (CT) for preoperative nodal evaluation (per-patient basis).

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments References

Several biologic features including p53 status and PI have been reported to be a prognostic factor after operation for NSCLC [14, 15, 18]. In addition, p53 status has been reported to predict the efficacy of postoperative adjuvant chemotherapy for NSCLC and to be an important factor in decisions regarding therapy [14]. In the present study, p53 and PI proved to be important factors to predict mediastinal nodal metastases. For patients with tumor showing normal p53 status and lower PI, there was little chance of false-negative CT evaluation for mediastinal nodal metastases (cN0 to cN1/pN2 to pN3). For patients with tumor showing aberrant p53 expression and higher PI, however, there was an increased chance of false-negative evaluation. When biologic features of the primary tumor, that is p53 status and PI, are taken into consideration in combination with CT diagnosis, the accuracy of preoperative mediastinal evaluation may be increased. Thus, a strategy of preoperative mediastinal nodal evaluation and therapy for operable NSCLC may be suggested based on p53 status and PI value.

As reported previously, when CT (cN2 to cN3) demonstrates mediastinal nodal enlargement, mediastinoscopy should be performed to examine nodal status pathologically. If mediastinal nodal metastases are pathologically proved by mediastinoscopy, induction therapy before operation should be performed; if not, operation without induction therapy is justified. When mediastinal nodal enlargement is not demonstrated by CT (cN0 to cN1), mediastinoscopy for all patients is questionable. According to a prospective randomized study, mediastinoscopy for all patients has no advantage over CT because of lower cost effectiveness [20]. Therefore, mediastinoscopy is not commonly performed when preoperative CT does not demonstrate mediastinal nodal enlargement. In some cN0 to cN1 cases, however, mediastinal nodal metastases may be revealed postoperatively (cN0 to cN1/pN2 to pN3, false-negative cases). When p53 status and PI of the primary tumor are taken into consideration in selection of candidates for mediastinoscopy, the chance for false-negative evaluation can be diminished. That is, if mediastinal nodal enlargement is not demonstrated with CT in patients with tumor showing normal p53 status and lower PI, thoracotomy without pathologic examination of mediastinal nodal status by mediastinoscopy can be justified, because there is little chance of finding mediastinal nodal metastases in such cases. However, mediastinoscopy should be performed in patients with tumor showing aberrant p53 and higher PI, even when CT does not demonstrate mediastinal nodal enlargement, because mediastinal nodal metastases that cannot be revealed by CT are sometimes proved pathologically.

In the present study, p53 status and PI were examined in a large tumor sample obtained during thoracotomy. However, when biologic features of a tumor are actually taken into consideration in preoperative evaluation, usually only a small specimen can be obtained preoperatively. Because the proliferative nature of each tumor cell is usually heterogeneous, the exact evaluation of PI of the entire tumor can be judged only when a large specimen is examined carefully. In addition, it is known that the cut-off value for the lower and higher PI can be changed depending on the distribution. For these reasons, PI may not be used as a useful marker in preoperative evaluation of nodal status. With respect to p53 status, aberrant p53 can be detected even in a small specimen, when it is warranted that tumor cells are contained in the specimen. However, polymerase chain reaction-based analysis of mutations in p53 gene is a more accurate and sensitive method to determine p53 status. Because the amount of specimen obtained preoperatively for biopsy is usually small and because the tumor cells in the specimen are sometimes morphologically crushed, p53 status determined by polymerase chain reaction-based analysis should be used for preoperative evaluation.

Recently, 2-[fluorine¹⁸fluoro-2-deoxy-D-glucose positron emission tomography (PET) has been proved to be useful in preoperative mediastinal nodal evaluation. In a meta-analysis study on preoperative nodal evaluation, PET proved to be significantly more accurate than CT; the sensitivities and specificities were 79% and 91% for PET and 60% and 77% for CT, respectively [11]. As a preoperative diagnostic modality, PET was not used in the present study and has not been used routinely until now, because PET has not been covered by the health-care system in Japan. However, because of the superiority of PET over CT, whether or not biologic features including p53 status and PI can improve the accuracy of PET for preoperative mediastinal nodal evaluation should be examined in future. Additional points to study would be whether postoperative recurrence, survival, or cost effectiveness can be improved when these biologic features are introduced and used as clinical markers.

	Acknowledgments

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We thank Miss Tomoko Yamada for excellent preparation of tumor tissues. We also thank Drs Yozo Kawano, Tatsuo Nakagawa, Tetsuya Takata, Hiroki Oyanagi, and Hiromichi Katakura for technical assistance with this work.

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