Background
Lung cancer is the leading cause of malignancy-related deaths in males and is second among female cancer patients worldwide [
1,
2]. Non-small cell cancer (NSCLC) makes up approximately 85% of all lung cancers [
3,
4]. The tumor-node-metastasis (TNM) staging system is an essential prognostic assessment tool for decision-making about the most appropriate stage-specific therapeutic strategy for NSCLC patients [
5].
An accurate assessment of lymph node involvement is essential for the diagnosis and treatment of NSCLC, including the location of the metastatic lymph nodes and the number of positive lymph nodes. Some studies [
6,
7] have demonstrated that the number of positive lymph nodes is an important prognostic factor for resected NSCLC. Nwogu CE et al. [
8] demonstrated that both the resection of more lymph nodes (LNs) and low ratios of positive LNs to total examined LNs are associated with superior patient survival after NSCLC resection independent of age, sex, grade, tumor size and disease stage. Wei S et al. [
9] demonstrated that the nN category was a better prognostic determinant than location-based pN stage classification.
The number of positive lymph nodes is considered as part of the TNM staging system in breast, gastric, and colorectal cancer [
10,
11]. However, the seventh edition [
12] and the revised eighth edition [
13] TNM staging system defined nodal status depending only on the location of the metastatic lymph nodes and does not involve the number of positive lymph nodes. To the best of our knowledge, the number of positive lymph nodes has not been tested as the one criterion of TNM staging.
Accurate staging at the time of initial diagnosis is very important for patients with NSCLC to determine prognosis and guide treatment [
14,
15]. The current seventh edition TNM staging system was published in 2009
12 and the revised eighth edition TNM staging system was published in 2015 [
13]. TNM stages include three components: primary tumor (T), nodal status for metastasis (N), and metastasis at the distant organs (M). The eighth TNM staging system included notable changes in the T and M descriptors and in nodal map, while the N descriptor remained the same as in the previous version.
Nodal status is a significant factor in staging, including the location of the metastatic LNs and the number of metastatic LNs, and should predict survival of NCSLC patients after surgery. The nodal status of the current TNM staging assesses tumor burden in the regional hilar and mediastinal nodes [
16] and is defined as N0 (no nodal involvement), N1 (peribronchial, interlobar, hilar node involvement), N2 (ipsilateral nodal involvement), N3 (contralateral mediastinal, contralateral hilar or supraclavicular nodal involvement), depending on the location of the metastatic lymph nodes. The number of PLNs has been shown to be a prognostic factor for resected NSCLC [
9,
17‐
19]. An accurate PLN metastasis assessment is crucial in determining treatment, as the prognosis of lung cancer is directly proportional to the PLN.
Saji H et al. [
17] demonstrated that resection of ≥10 LNs influenced survival and that the number of involved LNs (four and more) was a strong independent prognostic factor in NSCLC. In another relevant study [
18], they showed that a combined anatomically based pN stage classification and numerically based nN stage classification was a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Similarly, other research [
19‐
22] also showed that the number of lymph nodes and lymph node ratio were important in TNM classification for NSCLC. Furthermore, Asamura H and his colleagues [
23] recommended that physicians recorded the number of metastatic lymph nodes (or stations) to further classify N category using new descriptors, such as N1a, N1b, N2a, N2b, and N3, for further testing in the other study.
In NSCLC, similar to colorectal, breast and bladder cancer [
24‐
26], the number of positive lymph nodes has been proven to be a prognostic factor and impacts disease survival [
21,
27,
28]. In solid tumors, the number of metastatic lymph nodes has been included in the TNM staging system, such as breast, gastric, and colorectal tumors. However, current pN staging of NSCLC depends only on the location of the metastatic lymph nodes.
In this study, we retrospectively evaluated the association between the number of PLN and the prognosis of patients with resected stage IA-IIIB NSCLC and compared this hypothesized TNM staging system with the current TNM stage classification in terms of prognostic accuracy.
Discussion
In the present study, 1-, 2-, 5-year OS rate were the endpoints. Using the X-tile models, we classified involved the number of PLN into the three nN categories as follows: nN0, no PLN metastasis; nN1–3, metastasis in one to three PLNs; and nN4-, metastasis in four or more PLNs. The outcomes of multivariable analysis had shown that 1 ≤ No. of PLN ≤ 3 and No. of PLN ≥ 4 were independent factors associated with OS (all P < 0.001) in patients with stage IA - IIIB NSCLC after surgery. We compared the 1-, 2-, 5-year OS rate for different substages of the current TNM stages, respectively. From this comparison, we found that the current TNM staging system was irrational to guide clinical treatment.
In this study, there were only 20 cases with stage pN3 which accounted for 0.2% of the total patient population. So, we ignored this population and only examined those with stage pN1 and pN2 as the focus of our research. According to nN category and 5-year OS rate, we re-divided the TNM stages and obtained the hypothesized TNM stages. The main changes compared with the current TNM stages included the reclassification of T2aN1M0 to stage IIB from stage IIA, T1 N2(1–3)M0 and T2aN2(1–3)M0 to stage IIB from IIIA, T4 N2(1–3)M0 to stage IIIA from stage IIIB and reclassification of T2bN1(4-)M0 to stage IIIB from stage IIIA and T3 N1(4-)M0, T3N2M0, T4 N1(4-)M0 to stage IIIB from stage IIIA. Survival curves were drawn for both staging system. A comparison showed that the patients with the hypothesized TNM stages had better OS than those with classic TNM staging, although both of P < 0.001.
For patients with stage IA-IIIA NSCLC, the first choice treatment is curative tumor resection via surgery [
30,
31]. Postoperative chemotherapy and radiotherapy have improved outcomes for these patients and decreased the risk of locoregional recurrence [
32‐
34]. However, Andre F et al. [
35] have reported that many patients who have N2+ disease are a heterogeneous group. And the treatment should be individualized for these patients. Surgery alone may be a more limited for patients with stage IIIA-N2 NSCLC [
36]. Chemotherapy and radiation are main treatment methods for these patients. In this study, patients with pN2 NSCLC who account for 14.9% were treated with surgery from SEER database. We analyzed the impact of these patients on staging and we did not analyze those patients who did not undergo surgical treatment. This may have an impact on staging system. So, we need to validate this result in future studies.
In addition, Scagliotti GV et al. [
37] have reported that patients with stage IIA-IIIB NSCLC could be benifit from neoadjuvant treatment including preoperative chemotherapy, preoperative radiotherapy and targeted treatment. Among stage IIIA-IIIB patients, we screened from the database, neoadjuvant therapy may or may not be accepted. However, due to the limitation of the database, we could not obtain information on neoadjuvant therapy for stage IIIA and IIIB patients and these data may have an impact on clinical prognosis. Even if this information is not available, we could reflect some problems by incorporating the number of lymph nodes into the revised staging compared with conventional staging.
However, this study has any other limitations that should be noted. First, this was a retrospective study. Moreover, it was difficult for physicians to evaluate the number of positive lymph nodes at the time of diagnosed NSCLC. Some other variables, including smoking history, type of surgery, other treatment affecting the prognosis were not included in the analysis. In addition, all data originated from SEER database according to the seventh edition TNM staging system rather than the eighth edition TNM staging system. This may have some influence on the final results. So, the results require further large-scale prospective clinical study to confirm these recommendations.
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