Abstract
OBJECTIVE To analyze the number and the metastatic status of lymph nodes resected during NSCLC surgery, and to determine the relationship of the lymph node status to the prognosis.
METHODS Clinical data from 1,575 inpatient NSCLC cases were retrospectively reviewed, and the number and the different metastatic status of the LNs resected analyzed. The Kaplan–Meier method was used for survival analysis.
RESULTS Stage N0 patients with 7 to 12 LNs resected during surgery had a significant increase in survival (P=0.001, 0.021),compared to patients with less than 6 LNs or more than 12 LNs. Stage N1 or N2 patients with more than 12 LNs resected had a significant increase in survival(P=0.000, 0.003), compared with cases who had less than 6 LNs or 7 to 12 LNs resected. The 5-year survival rate of Stage N0 patients was superior to Stage N1 and N2 patients (P =0.000,0.000), and the 5-year survival rates of Stage N0 and skip N2 patients were superior to the continue N2 patients. Patients with a single station of LNs metastasis had a significant increase in survival (P=0.000), compared with those with multiple stations of LNs metastasis. Patients with 1 to 2 metastatic LNs had a significant increase in survival(P=0.000), compared with patients having more than 2 metastatic LNs. The metastatic LN ratio(percentage of metastatic lymph nodes resected) was divided into four subgroups: <25%, 25%~50%, 51%~75%,> 75%. The 5-year survival rate gradually decreased with an increase in the metastatic ratio.
CONCLUSION For patients with NSCLC the number of LNs resected during surgery should be 7 to 12; the range and number of LN metastasis and the metastatic LN ratio significantly affect the prognosis of patients with NSCLC.
keywords
In China, non—small cell lung cancer(NSCLC) is one of most common malignant tumors, with a poor prognosis and high mortality. For curative treatment, surgical resection remains the most effective therapy. Among the prognostic factors, regional lymph node metastasis are an important factor for patients with operable NSCLC[1].But some studies have indicated that the 5-year survival rates of patients with NSCLC were different even when at the same N stage. The reason maybe due to a different number or location of the regional lymph node metastasis, but the actual reason has not been established.
We retrospectively analyzed the clinical data, especially lymph node related features, of NSCLC patients who underwent an operation in our hospital. Our purpose was to study whether these features, such as the different number of lymph node metastasis, affected the prognosis.
DATA AND METHODS
Clinical data
A total of 1,575 patients with NSCLC who received an operation between 1995 and 2000 were identified at the Cancer Hospital & Institute, Tianjin Medical University. All patients were postoperatively staged according to the 1997-TNM classification of NSCLC [2]. Lymph node levels were classified according to the American Thoracic Society system. Characteristics of the 1,575 patients with NSCLC are listed in Table 1.
Clinical characteristics of 1,575 patients with NSCLC.
Statistical analysis
All data were managed and analyzed by SPSS 13.0 statistical software. The probability of survival was calculated according to the Kaplan–Meier method. Univariate analysis of survival was performed using the log-rank test. A probability value < 0.05 was considered statistically significant. The follow-up was conducted until January 2006.
RESULTS
The results of univariate analysis of prognostic factors for NSCLC
The following clinical and pathologic parameters were studied for each case: age, sex, smoking history, histologic type, clinical stage and N Stage. The results of univariate analysis are reported in Table 2.
Results of univariate analysis of 1,575 patients with NSCLC.
The prognostic significance of the number of lymph nodes resected
The mean number of lymph nodes (LNs) resected was 10. Patients with more than 6 LNs resected compared with those having less than 6 LNs had a significant increase in survival (P=0.017) (Fig.1). The same results were obtained for stage N0 (P=0.027, 5-year survival rates were 39.1% and 35.2%) and stage N1-2(P=0.001,5-year survival rates were 15.0% and 6.7%).
Survival curves for patients with more and less than 6 LNs resected. The 5-year survival rates were 29.4% and 24.8%.
We divided these patients into three groups based on the LNs resected, as follows:1 to 6 LNs(group A),7 to 12 LNs(group B), >12 LNs(group C).The 5-year survival rate of group B was superior to group A(P =0.025), and group C had a tendency toward better survival than group A(P=0.060), but there was no significant survival difference between groups B and C (P=0.983). For Stage N0 patients, the 5-year survival rate of group B was superior to groups A and C(P=0.001,0.021), there was no significant survival difference between groups A and C (P=0.472). For stage N1 or N2 patients, the 5-year survival rate of group C was superior to groups A and B(P=0.000,0.003), but there was no significant survival difference between groups A and B(P=0.527).
The prognostic significance of location of lymph node metastasis
The 5-year survival rates of Stage N0,N1 and N2 patients were 37.3%, 11.7% and 11.2%, respectively. Stage N0 patients compared with stage N1 and N2 patients had a significant increase in survival(P=0.000, 0.000), but there was no significant survival difference between Stage N1 and Stage N2 cases(P=0.196). In a subset analysis, the 5-year survival rate of Stage N1 patients and skip N2 patients showed no significant difference(P=0.451), but all were superior to continue N2 patients(P=0.003,0.002)(Fig.2); The mean stations of lymph node metastasis were 1.64. Patients with a single station of lymph node metastasis compared with patients having multiple stations had a significant increase in survival(P=0.000), as 5-year survival rates were 13.9% and 7.3%) (Fig.3).
Survival curves of patients with metastatic LNs in different regions. The 5-year survival rates of N1, skip N2 and continue N2 patients were 12.4%, 14.7% and 7.0%.
Survival curves of patients with single-station metastatic LNs and multiple-station metastatic LNs. The 5-year survival rates were 13.9% and 7.3%.
The prognostic significance of the number of lymph node metastasis
The mean number of lymph node metastasis was 3.52. Patients with 1 or 2 lymph node metastasis compared with those having more than 2 had a significant increase in survival(P=0.000), (Fig.4). There was no significant survival difference for patients with 1 versus 2 lymph node metastasis(P= 0.611). But among Stage N1,continue N2 and skip N2 patients, only skip N2 patients with 1 or 2 lymph node metastasis compared with patients having more than 2 lymph node metastasis had a significant increase in survival(P=0.004, 5-year survival rates were 22.0%and 8.7%).
Survival curves of patients with a different number of metastatic LNs. The 5-year survival rates of 1~2 LNs and more than 2 LNs were 12.4% and 8.3%.
The prognostic significance of the metastatic lymph node ratio
The metastatic lymph node ratio was defined as the percentage of the total number of lymph nodes resected which were metastatic. We divided them into the following four groups: <25%,25%~50%, 50%~75%, >75%. The 5-year survival rates were 16.7%, 13.5%, 6.8%, 2.0%, respectively. The group with <25% metastatic nodes compared with the other 3 groups had a significant increase in survival (P values were 0.004, 0.000, 0.000, respectively).The 5-year survival rates of groups 25%~50% and 50% ~75% were not significantly different(P= 0.209), but they both were superior to the group with >75% metastatic nodes.(P=0.000, 0.013)(Fig.5).
Survival curves of patients with a different metastatic ratio of LNs. The 5-year survival rate were 16.7%, 13.5%, 6.8% and 2.0%, respectively.
DISCUSSION
NSCLCs are malignant tumors which have a world wide impact on human health and life. It is known that many factors affect the prognosis of NSCLC patients. Birim et al.[3] summarized and analyzed numerous reports, showing that a number of factors have a negative influence on the prognosis of NSCLC patients, such as serious lung functions, cardiovascular disease, gender, age, TNM stage, non-squamous cell carcinoma, pneumonectomy, and lack of clinical experience. Apart from the TNM stage and the extent of surgical resection, controversies still exist with regard to other factors. By analyzing the clinical data from 1,575 NSCLC cases, we found those with advanced age, non-squamous cell carcinoma, an advanced clinical stage and lymph node metastasis had a worse prognosis. Of course, the definitive conclusions need to be confirmed by prospective randomized control studies.
To date, surgical resection remains the most effective therapy for NSCLC patients. Resection of suspected metastatic lymph nodes during surgery, or to do a systematic nodal dissection is considered to be routine. It is well known that the number of lymph nodes resected during surgery affects the prognosis of NSCLC patients [4]. For Stage N0 patients, our results were similar to that reported by Ludwig et al.[5,6]They analyzed data from 16,800 patients with Stage I NSCLC. Patients with 5 to 8 LNs resected during surgery had a modest but statistically significant increase in survival, similar results for 9 to 12 LNs and 13 to 16 LNs resected further increased survival. There appeared to be no incremental improvement after evaluating more than 16 LNs.
Theoretically, Stage N0 patients should not have metastatic lymph nodes, and the number of lymph nodes resected should not affect the survival. But we believe that stage N0 patients have micrometastatic lymph nodes which can not be found by current pathological examinations. So the optimal number of lymph nodes resected may improve survival. For Stage N1 or N2 patients, only patients with more than 12 LNs resected had survival advantage. So we conclude that more than 12 LNs should be resected if lymph node metastasis are suspected by preoperative examinations or during surgery. Otherwise 7 to 12 LNs should be resected. The optimal number of lymph nodes resected may remove micrometastatic lymph nodes and, in turn, increase the proportion of complete R0 resections, leaving no residual disease. It may reduce the staging error and exactly guide postoperative adjuvant therapy.
Lymph node metastases were the important prognostic factor for postoperative long term survival of NSCLC patients [2].But we found the 5-year survival rates were not significantly different between Stage N1 and Stage N2 patients. So we conducted this subset analysis for patients with lymph node metastasis.
Our data showed that the 5-year survival rate for Stage N1 patients and skip N2 patients were not significantly different, and both superior to that of continue N2 patients. But Casali et al.[8] showed 5-year survival rates were not significantly different between skip N2 and continue N2 patients. Patients with a single station of lymph node metastasis compared with those having multiple stations had a significant increase in survival. Similar results have been reported [7,8,9]. But patients with multiple N1 stations of lymph node metastasis had similar survival with single N2 station patients with lymph node metastasis[7]. So multiple stations of lymph node metastasis must affect the prognosis of NSCLC patients. The prognosis of skip N2 patients was controversial and should be studied in the future.
The number of lymph node metastasis affected the postoperative survival of NSCLC patients [4]. Our data demonstrated that patients with more than 2 lymph node metastasis had a significant decrease in survival, especially for patients with skip N2 metastasis. But the number of lymph node metastasis didn’t affect the prognosis of Stage N1 and continue N2 patients. Perhaps the number of lymph node metastasis mainly affected the prognosis of skip N1 patients, for patients with extensive and continue lymph node metastasis, the number of lymph node metastasis was not a important prognostic factor. Suzuki et al. [9] retrospectively analyze data from Stage N2 patients. Those with more than 1 lymph node metastasis had significant decrease in survival.
A randomized trial of systematic nodal dissection conducted by Wu et al.[4] demonstrated that the metastatic lymph node ratio affected the prognosis of operable NSCLC patients. For Stage N2 patients, patients with less than a 50% metastatic lymph node ratio compared to patients with more than 50% metastatic lymph node ratio had a significant increase in survival(P=0.0001)[10]. Our data showed that patients with less than a 25% metastatic lymph node ratio had the best survival, and with an increase in the metastatic lymph node ratio, the survival gradually decreased. So the metastatic lymph node ratio may be used to evaluate the prognosis of NSCLC patients.
In conclusion, the metastatic status of lymph nodes is an important prognostic factor for NSCLC patients. For NSCLC patients the optimal number of lymph nodes should be resected during surgery. The range, numbers of LNs metastasis and the metastatic lymph node ratio significantly affect the prognosis of NSCLC patients.
- Received February 26, 2007.
- Accepted March 10, 2007.
- Copyright © 2007 by Tianjin Medical University Cancer Institute & Hospital and Springer
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