Interact CardioVasc Thorac Surg 2007;6:474-478. doi:10.1510/icvts.2007.154641
© 2007 European Association of Cardio-Thoracic Surgery
Institutional report - Thoracic general |
Retrospective study of patients with pathologic N1-stage II non-small cell lung cancer
Tatsuo Nakagawa*,
Norihito Okumura,
Yujiro Kokado,
Kentaroh Miyoshi,
Tomoaki Matsuoka and
Kotaro Kameyama
Department of Thoracic Surgery, Kurashiki Central Hospital, 1-1-1 Miwa, Kurashiki, Okayama, 710-8602, Japan
Received 22 February 2007;
received in revised form 30 April 2007;
accepted 3 May 2007
*Corresponding author. Tel.: +81-86-422-0210; fax: +81-86-421-3424.
E-mail address: tn8336{at}kchnet.or.jp (T. Nakagawa).
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Abstract
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The population of patients with N1-stage II disease is small among non-small cell lung cancer patients and there have been relatively few studies regarding prognostic factors for the disease. We retrospectively evaluated the clinicopathological features of the disease to identify prognostic factors. The clinical records of 85 patients with N1-stage II non-small cell lung cancer who underwent lobectomy or pneumonectomy with systematic lymph node dissection or sampling were retrospectively reviewed. The study population comprised 64 men and 21 women, among whom 49 had adenocarcinoma, six had squamous cell carcinoma and two had large cell carcinoma. The prognosis was significantly better for p0 vs. p2–3 disease (P=0.029), pneumonectomy vs. lobectomy (P=0.027) and direct extension vs. metastasis to N1 lymph nodes (P=0.015). On the other hand, there was no significant difference in survival regarding the number or level of the involved lymph node stations. A multivariate analysis for prognostic factors revealed that status of lymph node involvement as well as gender and pleural factor was a significant independent prognostic factor (P=0.026). Our results have revealed that direct extension to N1 lymph nodes is an independent favorable prognostic factor as opposed to metastasis for surgically-treated patients with N1-stage II disease.
Key Words: Lung cancer; Lymph nodes; Statistics; Survival analysis
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1. Introduction
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Surgical resection is a standard procedure for the treatment of stage I–II non-small cell lung cancer (NSCLC). However, the postoperative prognosis is much worse for patients with N1 disease than for those with N0 disease. The 5-year survival rates of patients with N1-stage II disease varies from 33% to 65% for stage IIA and from 27% to 56% for stage IIB [1], suggesting that patients with N1-stage II disease can be classified into heterogeneous subgroups based on their clinical outcome. In addition, the proportion of patients with stage II disease is quite small and there have been relatively few studies of N1-stage II disease. The therapeutic strategy for N1-stage II disease is basically surgical resection, and the efficacy of postoperative adjuvant therapy has not been proven to date. On the other hand, recently conducted large randomized clinical trials revealed that adjuvant chemotherapy improved the 5-year survival rates by 10–15% in patients with completely resected stage IB or II NSCLC [2, 3]. In this respect, this group of patients with N1-stage II draws an increasing attention in the clinical research of lung cancer. In the present study, we retrospectively reviewed the clinicopathological records of patients with resected N1-stage II NSCLC and analyzed prognostic factors for the disease.
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2. Patients and methods
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From January 1989 to December 2005, thoracotomy was performed in a total of 1239 patients with NSCLC at Kurashiki Central Hospital, Okayama, Japan. Among these patients, 90 were diagnozed as having N1-stage II disease. Of these 90 patients, five patients who underwent segmentectomy were excluded from the study and a final total of 85 (6.9%) patients who underwent lobectomy or pneumonectomy with complete dissection or systematic sampling of hilar and mediastinal lymph nodes were retrospectively reviewed. The clinical findings for each patient were obtained and reviewed from the medical records. The pathological typing and staging were determined according to the current General Rules for Clinical and Pathological Record of Lung Cancer (6th edition) [4], which are identical to the International System for Staging Lung Cancer [5]. The anatomical location of each N1 station was defined as follows: the lymph nodes located adjacent to the main bronchus, between the lobar bronchus and adjacent to the lobar bronchus were No. 10 (hilar), No. 11 (interlobar) and No. 12 (lobar), respectively. Regarding the status of lymph node involvement, direct extension was defined as fixation or infiltration of a primary tumor into adjacent lymph nodes, whereas metastasis was not fixed or had not infiltrated into adjacent lymph nodes. The categorized group of patients with direct extension to N1 lymph nodes was limited to direct extension only without metastasis to other lymph nodes. The presence or absence of direct extension to N1 lymph nodes was evaluated according to the pathological results and operation records and confirmed by the findings of preoperative computed tomography. The patient outcomes were confirmed from the medical records or by telephone interviews. The median follow-up time was 46.0 months (range: 3.6–196.5 months). Of the 85 patients, 70 (82.4%) patients were completely followed up until their death or for more than 5 years after the operation.
Comparisons between two groups were performed by Pearson's  2 test for counts data and Student's t-test for continuous data if the sample distribution was normal, or by the Mann–Whitney U-test if the sample distribution was not normal. For univariate analyses, all the cumulative survival rates after the operation were calculated by the Kaplan–Meier method and any differences were evaluated by the log-rank test. A multivariate analysis of independent prognostic factors was conducted by Cox's proportional hazards regression model. Differences were considered significant when the P-value was <0.05. All statistical analyses were performed using the SPSS statistical software program package (SPSS ver. 13.0 for Windows; SPSS Inc., Chicago, IL).
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3. Results
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3.1. Patient backgrounds
The study population comprised 64 men and 21 women who ranged in age from 48 to 83 years (mean age: 66.5±8.3 years). Regarding the pathological types, 49 (57.6%) patients had adenocarcinoma, 34 (40.0%) patients had squamous cell carcinoma and 2 (2.4%) patients had large cell carcinoma. The maximum tumor length was  30 mm in 40 (47.1%) patients and >30 mm in 45 (42.9%) patients. The grade of pleural invasion was p0 in 54 (63.5%) patients, p1 in 19 (22.4%) patients and p2 or p3 in 12 (14.1%) patients. All the patients with p3 were cases of tumor invasion into the neighboring lobe of the lung. A total of 53 (62.4%) patients received adjuvant therapy: chemotherapy for 42 patients, radiotherapy for four patients and chemo-radiotherapy for seven patients (Table 1).
3.2. Status of lymph node metastasis
Lymph node involvement was detected at a single station in 58 patients, 2 stations in 19 and >3 stations in 8 patients. The highest levels of lymph node involvement were No. 10 in 27 patients, No. 11 in 26 patients and No. 12 or more in 32 patients. Direct extension to N1 lymph nodes was complicated in 11 patients (Table 1).
3.3. Prognostic analysis
The 5-year survival rate of all the patients was 54.1%. Univariate analyses of postoperative survival stratified according to clinicopathologic factors are shown in Table 1. There was a significant difference for the pleural factor (P=0.029). Specifically, the 5-year survival rates were 61.7% for p0 disease, 45.5% for p1 disease and 33.3% for p2 or p3 disease, with a significant difference between p0 and p2 or p3 (P=0.008). Only nine patients underwent pneumonectomy and their 5-year survival rate was 100%, showing a significant difference from that of the patients who underwent lobectomy (P=0.027). Regarding the status of lymph node involvement, patients with direct extension to N1 lymph nodes had a significantly better prognosis than those with metastasis (P=0.015) (Fig. 1). On the other hand, there was no significant difference in survival regarding the number or level of the involved lymph node stations (Table 1).
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Fig. 1. Comparison of the postoperative survival curves according to the status of lymph node involvement (direct extension vs. metastasis).
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3.4. Multivariate analysis
To elucidate independent prognostic factors, all the clinicopathologic factors shown in Table 1 were analyzed by multivariate analysis using Wald's stepwise method in Cox's proportional hazards regression model. Gender, pleural factor and direct extension to N1 lymph nodes as opposed to metastasis were found to be significant independent prognostic factors (P=0.027, P=0.023 and P=0.026, respectively) (Table 2).
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Table 2 Multivariate analysis of prognostic factors (Cox's proportional hazards regression model; Wald's stepwise method)
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4. Discussion
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In the present study, we have revealed that pleural factor and status of lymph node involvement defined as direct extension or metastasis to N1 lymph nodes had significant impacts on the postoperative prognosis of pN1-stage II NSCLC patients in mulivariate analysis as well as univariate analysis. The extent of pleural invasion is reflected in the current TNM staging as the T factor and our result that patients with p0 or p1 disease had a significantly better prognosis than those with p2 or p3 disease is fairly acceptable. It is rather interesting that direct extension to N1 lymph nodes had a better impact on the postoperative prognosis than metastasis. In the current international TNM staging [5], regional lymph node metastasis of N1 is designated as metastasis to ipsilateral peribronchial or ipsilateral hilar lymph nodes, or intrapulmonary nodes including involvement by direct extension of the primary tumor. Metastasis to regional lymph nodes is thought to occur via the initial lymphatic spread of tumor cells. On the other hand, tumors that extend directly to lymph nodes are situated in the central area and commonly progress along the bronchus. Cotton [6] studied direct extension along the bronchus and noted that submucosal lymphatic spread only occurred in 6% of the tumors examined. It is possible that there are some biological differences in tumor behavior between direct extension and metastasis, which may represent the reason for the prognostic difference between these two types of lymph node involvement. In our study, however, there was no significant difference between the two groups regarding the ratio of the presence of lymphatic invasion in up to 80% of the cases evaluated (data not shown). Thus, the precise reason for the prognostic difference between the two types of lymph node involvement remains uncertain.
A few previous studies have assessed the prognostic significance of direct extension to N1 lymph nodes. Marra et al. studied T1-4N1M0 disease and reported that the prognosis of patients with direct extension to N1 lymph nodes was significantly better than that of patients with metastases to hilar, interlobar or both hilar and interlobar lymph nodes [7]. van Velzen et al. reported that the survival of patients with direct extension to N1 lymph nodes was superior to that of patients with metastasis to hilar lymph nodes, but did not differ from that of patients with metastasis to lobar lymph nodes in T1N1M0 disease [8] and T2N1M0 disease [9]. In a study of patients with T1-T4N1M0 disease, Fujimoto et al. demonstrated that metastasis to N1 lymph nodes as opposed to direct extension was an independent factor for locoregional and distant metastasis, but failed to show any significance for survival [10]. On the other hand, there is a contradictory study that showed no significant difference in survival between N1 involvement by direct extension and metastasis [11].
The nature of the N1 lymph node involvement in stage II is important. The number of involved lymph node nodules or stations as well as the involved station level have been reported to be decisive factors for postoperative survival. Some studies have reported that hilar lymph node involvement is a poor prognostic indicator compared with interlobar or lobar lymph node involvement [7, 8, 11, 12], whereas no significant difference was found in other studies [13, 14]. Our study did not find any significant difference in survival among the three categorized groups according to the level of N1 involvement. The reason for the differences among the results of these studies may be partly due to the difficulties associated with determining the borders between the anatomic locations of the lymph node stations, especially for the hilar lymph nodes. The hilar lymph nodes are contiguous with the lobar lymph nodes distally and also with the mediastinal lymph nodes proximally. Watanabe et al. studied the inter-observer variability in systematic lymph node dissection and reported that the concordance rate for N1 stations was only 72.3% between two observers from Japan and the UK [15]. On the other hand, multiple lymph node nodule or station involvement was reported to be a poor prognostic factor compared with single involvement [7, 13], whereas other studies did not identify any significance for the number of involved lymph node nodules or stations [11, 12]. Our study also did not find any significant difference in survival between single and multiple lymph node involvement, and, therefore, the clinical implication of lymph node involvement in N1 disease remains unclear.
The survival of the patients who underwent pneumonectomy was significantly better than that of pneumonectomy in univariate analysis. The number of the patients with squamous cell carcinoma was 5 out of 9 (55.6%) in the pneumonectomy group and 29 out of 76 (38.2%) in the lobectomy group. The survival of the patients with squamous cell carcinoma was better than the other histological groups although there was no statistic difference. The difference of the histological type may contribute to the better survival of the pneumonectomy group. In addition, 3 out of 9 (33.3%) patients in the pneumonectomy group had direct extension to N1 lymph node, whereas only 8 out of 76 (10.5%) patients in the lobectomy group had direct extension to N1 lymph node. The difference of the status of lymph node involvement may be another reason for the better prognosis of the pneumonectomy group because the direct extension to N1 lymph node was shown to be a favorable prognostic factor in our study. However, the superiority of pneumonectomy over lobectomy was not confirmed in the multivariate analysis, which means pneumonectomy in itself was not an independent prognostic factor.
In conclusion, our results have revealed that direct extension to N1 lymph nodes as opposed to metastasis is independent prognostic factor for surgically-treated patients with N1-stage II disease. However, our study was performed retrospectively and some controversy still remains. Specifically, the clinical implication of direct extension to N1 lymph nodes needs to be confirmed in a large prospective study in the future.
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Abstract
1. Introduction