Eur J Cardiothorac Surg 2004;25:1114-1120
© 2004 Elsevier Science NL
Skip mediastinal nodal metastases in non-small cell lung cancer
Fumihiro Tanakaa*,
Kazumasa Takenakaa,
Hiroki Oyanagia,
Takuji Fujinagaa,
Yosuke Otakec,
Kazuhiro Yanagiharaa,b,
Harumi Itod,
Hiromi Wadaa
a Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Shogoin-kawahara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan
b Department of Translational Clinical Oncology, Kyoto University, Kyoto, Japan
c Department of Thoracic Surgery, Seishin-iryo Center Hospital, Kobe, Japan
d Department of Radiology, Fukui Medical University, Fukui, Japan
Received 6 October 2003;
received in revised form 25 February 2004;
accepted 1 March 2004.
* Corresponding author. Tel.: +81-75-751-4975; fax: +81-75-751-4974
e-mail: ftanaka{at}kuhp.kyoto-u.ac.jp
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Abstract
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Objective: To reveal the incidence and clinical significance of mediastinal nodal metastases without N1-station nodal metastases (‘skip-N2 metastases’) in non-small cell lung cancer (NSCLC). Methods: A total of 450 NSCLC patients who underwent tumor resection with a systemic mediastinal nodal dissection were retrospectively reviewed. p53 status and proliferative activity represented as proliferative index (PI) were also examined immunohistochemically. Results: Skip-N2 metastases were documented in 49 (13%) patients of all 450 patients; among 334 patients without N1-nodal involvement, 18% patients had skip-N2 metastases. The postoperative survival of skip-N2 patients was almost same as that for patients with metastases to both N1 and N2 nodes. Skip-N2 metastases were significantly more frequent in male patients and squamous cell carcinoma patients. In addition, the mean PI for tumor with skip-N2 metastases was significantly higher than that for any other pathologic nodal (pN)-status diseases. Combined with histologic type and PI, the incidences of skip-N2 metastases for adenocarcinoma showing lower PI were only 5% (7/137) of all patients and 7% (7/94) of patients without N1-nodal involvement. Conclusions: N1 nodal status is not a useful predictor of N2 nodal status in NSCLC, because skip-N2 metastases were documented in 18% patients showing no N1-nodal involvement. However, N1 node-guided dissection might be performed in patients with adenocarcinoma showing lower PI, because the incidence of skip-N2 metastases was extremely low.
Key Words: Non-small cell lung cancer • Mediastinal nodal metastases • N2 • Skip metastases • Prognosis • Biomarker
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1. Introduction
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Non-small cell lung cancer (NSCLC) accounts for approximately 75–80% of primary lung cancer that is the leading cause of cancer deaths in most industrialized countries, and the survival after surgery remains poor [1–3]. The most important prognostic factor in operable NSCLC is lymph node metastases (pathologic nodal (pN)-factor), and 5-year survival rates after operation were only 20% when mediastinal nodal metastases were documented (pN2 disease) [2,3]. Thus, a systemic mediastinal nodal dissection of N2 nodes as well as N1 nodes during thoracotomy is essential for accurate evaluation of pN-factor.
Skip mediastinal nodal metastases (skip-N2 metastases) are mediastinal nodal metastases without any N1-nodal involvement [4–6]. It has been reported that the incidences of skip-N2 metastases are 20–40% of all N2 diseases [4–6], but the nature and clinical significance of skip-N2 metastases remains unclear. We have already revealed that biomarkers such as p53 status and proliferative activity of the tumor can influence on mediastinal nodal metastases in NSCLC [7]. Thus, the aims of this study are to reveal the nature and clinical significance of skip-N2 metastases, especially in correlation with biomarkers, and to assess the validity of N1-status guided nodal dissection.
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2. Patients and methods
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A total of 450 consecutive patients with pathologic (p-) stage IA–IV NSCLC who underwent thoracotomy with a systemic 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) [7]. No systemic N3 nodal dissection was performed. Video-assisted thoracoscopic surgery (VATS) was not performed in any patient. Preoperative clinical staging (c-stage) and postoperative p-stage were re-evaluated 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. Performance status (PS) was determined according to the eastern cooperative oncology group (ECOG) scale as follows: grade 0, fully active, 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 house work or office work; grade 2, ambulatory and capable of all self-care but unable to carry work activities, up and about >50% of waking hours; grade 3, capable of only limited self-care, confirmed to bed or chair 
50% of waking hours; grade 4, completely disabled, cannot carry on any self-care, totally confirmed to bed or chair [8]. For all these patients, the inpatient medical records, chest roentgenogram films, whole-body computed tomography (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. Among all 450 patients, preoperative CT did not show mediastinal nodal enlargement (cN0-1) in 317 patients (70.4%), and did show (cN2-3) in 133 patients (29.6%). Mediastinoscopy was not performed routinely, and was actually performed in only a few selected cN2-3 patients.
No patient received chemotherapy or radiotherapy during operation. As postoperative therapy, systemic chemotherapy was subscribed to 159 patients (35.5%); cisplatin (CDDP)-based chemotherapy were prescribed to 81 patients (18.0%) and oral 5-fluorouracil (5-FU) derivatives (tegafur or tegafur and uracil [UFT]) to 78 patients (17.3%). Seventy-four patients (16.4%) received radiotherapy postoperatively; 43 patients (9.5%) received radiotherapy alone, 13 patients (2.8%) received radiotherapy and CDDP-based chemotherapy, and 18 patients (4.0%) received radiotherapy and oral 5-FU treatment. No postoperative treatment was performed in 217 patients (48.2%).
2.1. Skip-N2 metastases
Skip-N2 metastases are defined as N2-nodes metastases without involvement of any N1-node. Intra N2-nodes skip metastases, i.e. metastases to highest mediastinal nodes (#1) without any other N2-nodal involvement in patients with N1-nodal metastases, were not judged to be skip-N2 metastases.
2.2. Biomarkers
As this study was performed retrospectively, biomarker analyses were performed using formalin-fixed and paraffin-embedded tumor samples that had been resected during operation and had been stored in our institute. Status of p53 was determined by immunohistochemical staining (IHS) [9–11]. 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 [12]. All the biologic features were evaluated in histologic sections taken from the primary tumor. Procedure of IHS using streptoavidin–biotinylated horseradish peroxidase complex method (LSAB kit; DAKO Japan, Kyoto, Japan) was described in the previous paper [13,14]. Mouse anti-human p53 monoclonal antibody (MoAb) DO-7 (mouse IgG2b, kappa, 250 µg/ml, DAKO Japan, Kyoto, Japan) diluted at 1:50 and mouse anti-human PCNA, MoAb PC-10 (mouse IgG2a, kappa, 400 µg/ml, DAKO Japan, Kyoto, Japan) diluted at 1:50 were used as the primary antibody. Aberrant p53 expression was judged, 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).
2.3. Statistical methods
Counts were compared by the 
2 test. Continuous data were compared using unpaired t-test if the distribution of samples was normal, or using Mann–Whitney 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 using Cox's regression model. Variables that achieved statistical significance (P<0.05) in the univariate analysis were sequentially included in a multivariate analysis using a stepwise forward Cox's regression model [15]. All statistical manipulations were performed using the SPSS for Windows software system (SPSS Inc., Chicago, IL, USA, 1993).
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3. Results
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3.1. Nodal involvement in NSCLC
Among all 450 patients, 119 (26.4%) had pN2 disease, and eight (1.8%) had pN3 disease. Because all pN3 patients had N2-nodal metastases, pN2 and pN3 patients were included in pN2-3 patients (n=127) in the present study (Table 1). Mediastinal metastases were more frequently documented in higher PS patients (P=0.039) (Table 1). There was no significant difference in nodal metastases according to the histologic types or the grade of tumor differentiation (Table 1).
3.2. N1 status as a predictor of N2 status
For all patients, 274 (82.0%) of 334 patients showing no N1 involvement had no N2 involvement. The negative predictive value (NPV) of N1 status for N2 status (82.0%) was almost same as that of preoperative CT evaluation (79.5%, 256/317). For Sq patients, NPVs of N1 status and preoperative CT evaluation were 77.9 (95/122) and 79.3% (81/102), respectively, for Ad patients, NPVs were 83.1% (143/172) and 79.7% (141/177), respectively.
For all patients, 67 (57.8%) of 116 patients showing N1 involvement had also N2 involvement. The positive predictive value (PPV) of N1 status for N2 status was almost same as that of preoperative CT evaluation (49.6%, 66/133). For Sq patients, PPVs of N1 status and preoperative CT evaluation were 37.0 (10/27) and 34.0% (16/47), respectively, for Ad patients, PPVs were 66.7 (52/78) and 61.6% (45/73), respectively.
3.3. Incidences of skip-N2 metastases
Skip-N2 metastases were documented in 60 patients, which accounted for 13.3% of all NSCLC patients, and for 47.2% of pN2-3 patients (Table 2). Even when N1 nodal metastasis was not documented, N2 nodal metastases were positive in 18.0% of patients (60/334). In addition, even when preoperative CT did not show mediastinal nodal enlargement (cN0-1), 33 (10.4%) of 317 cN0-1 patients showed skip-N2 metastases, and 28 (8.8%) showed N2 metastases along with N1 metastases (continuous N2 metastases).
Skip-N2 metastases seemed less frequent in Ad patients than in Sq patients, although the difference did not reach a statistical significance (Fig. 1)
. The most common mode of N2 metastases in Ad patients was continuous N2 metastases (Fig. 1). Among pN2 patients, the incidence of skip-N2 metastases was significantly higher in Sq patients than in Ad patients (Table 2). There was no significant difference in the incidence of skip-N2 metastases according to the grade of tumor differentiation. Skip-N2 metastases were more frequent in male patients than in female patients (Table 2). Patients with PS0 showed lower incidence of skip-N2 metastases than in PS1–3 patients (Table 2).
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Fig. 1. Pathologic nodal (pN) status according to the histologic types. Among 149 squamous cell patients, 95 (63.8%) had pN0, 17 (11.4%) had pN1, 27 (18.1%) had skip-N2 metastases, and 10 (6.7%) had N2 metastases along with N1 metastases (continuous N2 metastases); among 250 adenocarcinoma patients, 143 (57.2%), 26 (10.4%), 29 (11.6%), and 52 (20.8%) showed each pN-status, respectively. Continuous N2 metastases were more frequent in adenocarcinoma patients than in squamous cell carcinoma patients (P<0.001). Skip-N2 metastases were seemed less frequent in adenocarcinoma patients than in squamous cell carcinoma patients, but the difference did not reach a statistical significance (P=0.075).
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3.4. Biomarkers and skip-N2 metastases
The mean PIs for pN0, pN1, and pN2-3 diseases were 45.2, 46.4, and 54.9, respectively, showing a significant increase along with mediastinal nodal involvement (Table 1). Among pN2-3 disease, tumor showing skip-N2 metastases showed a significantly higher PI value than any other tumor, and tumor showing continuous N2 metastases showed an almost same PI value as pN0 and pN1 tumors (Fig. 2)
. These results suggested that higher PI value was characteristic in skip-N2 metastases. There was no significant difference in p53 status according to nodal status (Tables 1 and 2). When PI status and histologic types were combined, the incidence of skip-N2 metastases for Ad showing lower PI was only 5.1%, which was significantly lower than any other tumor (Fig. 3)
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Fig. 2. Proliferative index (PI) according to pathologic nodal (pN) status. Each column shows the mean PI value and error-bar shows the 95% confidence interval. The mean PI for pN0 disease, pN1 disease, skip-N2 metastases disease, and continuous N2 metastases disease were 45.2, 46.4, 62.8, and 47.9, respectively. The mean PI for skip-N2 metastases was highest (P<0.001), and there was no significant difference among the other three groups.
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Fig. 3. Pathologic nodal (pN) status according to the histologic type (Sq or Ad) in combination with the proliferative index (PI, lower or higher). The incidence of skip-N2 metastases for Sq showing lower PI, Sq showing higher PI, Ad showing lower PI, and Ad showing higher PI were 16.1 (10/62), 19.5 (17/87), 5.1 (7/137), and 19.5% (22/113), respectively. The incidence of skip-N2 metastases for Ad showing lower PI was significantly lower than that of any other tumor (P=0.002).
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3.5. Postoperative survival
Five-year survival rates of pN0, pN1, and pN2-3 patients were 68.1, 63.5, and 30.3%, respectively (P<0.001) (Table 1 and Fig. 4a)
. A multivariate analysis confirmed that nodal involvement was the significant and independent factor to predict a poor postoperative survival (relative risk [RR] and the 95% confident interval [CI], 1.683 [1.371–2.065]; P<0.001). A multivariate analysis demonstrated that higher pT-factors (RR, 1.392 [1.182–1.640]; P=0.001) and presence of distant metastases (M1) (RR, 2.893 [1.672–5.005]; P<0.001) were also significant factors to predict a poor survival, but did not demonstrate that any postoperative therapy, radiotherapy, CDDP-based chemotherapy, or oral 5-FU derivative treatment, significantly improved the survival.
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Fig. 4. (a) Postoperative survival of resected non-small cell lung cancer (NSCLC) according to the pathologic nodal (pN) status. (b) Postoperative survival of resected non-small cell lung cancer (NSCLC) with mediastinal nodal metastases (pN2-3). Comparison between pN2-3 disease without N1 metastasis (skip-N2 metastases) and that with N1 metastases (continuous N2 metastases).
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Among N2 patients, there was no difference in the survival between skip-N2 patients and continuous N2 patients (Table 2 and Fig. 4b), which was confirmed by a multivariate analysis (RR [95% CI], 0.645 [0.357–1.166], P=0.146). These results showed that N2 metastases itself, regardless of the mode of N2 metastases, was the most significant prognostic factor.
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4. Discussion
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In the present study, we revealed that the skip-N2 metastases occurred in 13.3% of all NSCLC patients and in 47.2% of pN2-3 patients. In addition, when the N1 metastases were not documented, the chance of N2-metastases (skip-N2 metastases) was as high as 18.0%. These results clearly showed that N1 nodes status could not be a predictor of N2 status. The incidences of skip-N2 metastases in previously reported studies were 5–10% in all NSCLC patients and 20–40% of pN2 patients [4–6], which seemed to be lower than those documented in the present study. The reason why the higher incidence of skip-N2 metastases was unclear, but one possible reason may be an extensive nodal dissection performed in our institute. Even when preoperative CT did not reveal mediastinal nodal enlargement, the incidence of skip-N2 metastases was 10.4% in the present study. Thus, an accurate evaluation of mediastinal nodal status should be achieved only after a systemic nodal dissection during thoracotomy. Whether mediastinoscopy should be performed for cN0-1 patients and whether VATS can achieve an accurate nodal status should be examined in further prospective studies.
We revealed, in the present study, a higher incidence of skip-N2 metastases in Sq patients than in Ad patients. The incidence of N2 metastases seemed to be lower in Sq patients (37/149, 24.8%) than in Ad patients (81/250, 32.4%; P=0.277) (Table 1). These results showed that the common mode of N2 involvement in Ad patients was ‘continuous nodal metastases’, i.e. N2 metastases along with N1 metastases. We also revealed a lower incidence of skip-N2 metastases in female patients than in male patients, which might be caused by a higher incidence of Ad in female patients.
We first examined the incidence of skip-N2 metastases in correlation with biomarkers such as p53 status and proliferative activity. We had already revealed that p53 status and proliferative activity could influence on the chance of N2 metastases [7]; tumor showing aberrant expression of p53 and higher PI had an increased chance of N2 metastases even when preoperative CT did not reveal a nodal enlargement. In the present study, we revealed that tumor with skip-N2 metastases showed a significantly higher PI, although no correlation with incidence of skip-N2 metastases and p53 status was documented. We should note some issues in applying the PI as a predictor of the need for N2 nodal dissection. First, we can know PI values in tumor tissues after thoracotomy, which means that we cannot determine the need for N2 nodal dissection before operation. Preoperative bronchoscopic or CT-guided needle biopsy of primary tumors may provide specimens available for IHS, but the validity of IHS results obtained from small biopsied specimens should be checked. Second, the cut-off value of PI to determine the need for N2 nodal dissection should be determined, and the validity should also be examined in a prospective study.
We demonstrated, in the present study, that N2 involvement was a critical prognostic factor, which was consistent with results reported in other studies [1–3]. In regard to postoperative prognosis of skip-N2 patients, some studies revealed that pN2 patients with skip-N2 metastases had a favorable prognosis as compared with pN2 patients with continuous N2 metastases [4,6]. In the present study, however, there was no difference in the postoperative survival between skip-N2 metastases and continuous N2 metastases. Thus, the prognostic significance of skip-N2 metastases remains controversial. Recently, the concept of sentinel node-guided nodal dissection has been established in some malignant tumors including breast carcinoma [16]. In NSCLC, some studies on sentinel node-guided nodal dissection have been reported [17,18], but the validity has not been established. As suggested in the present study, N1-status can be a predictor of N2 status in case of Ad showing lower PI where skip-N2 metastases may rarely occur; N1 status-guided nodal dissection in such patients may be validated, which should be examined in prospective clinical trials. In conclusion, a systemic nodal dissection for accurate evaluation of N2 status should be required to predict the prognosis properly.
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Acknowledgments
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We thank Miss Tomoko Yamada for excellent technical assistance of this work. We also thank Miss Seiko Sakai for helpful assistance of preparation of the manuscript. This work was supported by Grants-in-aid 14370410 (to F.T.) for Scientific Research (B) and 15390411 (to H.W. and F.T.) 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 (JFMC).
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Footnotes
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Presented at the joint 17th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 11th Annual Meeting of the European Society of Thoracic Surgeons, Vienna, Austria, October 12–15, 2003.
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Appendix A. Conference discussion
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Dr P. De Leyn (Leuven, Belgium): You didn't mention it here, but in your abstract you stated that due to the problem of skip metastases, you think that the technique of sentinel nodes would not be valid in lung surgery. I don't agree with this, because in studies using in sentinel technique in lung cancer, the sentinel nodes are located in the mediastinum in about 20% of the patients. Could you comment on this, please?
Dr Tanaka: Actually I have no comment on your question, because we do have no data on the validity of sentinel technique in lung cancer surgery.
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Abstract
1. Introduction
