Reconsidering N component of cancer staging for T1-2N0-2M0 small-cell lung cancer: a retrospective study based on multicenter cohort

Lung cancer is the first-rank cause of cancer-related mortality worldwide, and it mainly includes two histological types, non-small cell lung cancer and small cell lung cancer (SCLC) [1]. Most lung cancer is non-small cell lung cancer, which accounts for over 83.0%, and its 5-year overall survival rate reaches about 23% [2]. SCLC has a much worse survival than non-small cell lung cancer, of which the 5-year overall survival rate is approximately 6%, although it is only a small part of lung cancer (about 15%) [2]. As an important treatment approach, surgery provides survival benefits for limited-stage SCLC patients, confirmed by previous studies and recommended for patients with clinical classification T1-2N0M0 [3‐5]. Thus, limited-stage SCLC patients with lung resection have better survival outcomes than those without surgery [3, 4, 6]. However, the prognosis of those patients remains heterogeneous [1, 7]. Differences in patient prognosis may imply different treatment strategies; therefore, it is important to assess the patient’s prognosis accurately. The tumor, nodal, and metastasis (TNM) classification system is the leading evaluation approach to predicting the prognosis [8]. The current 8th edition TNM category system was launched in 2017, which had a more accurate predictive ability to assess the patient prognosis than the previous edition [9]. However, the pathological nodal (pN) classification is still the same in those two editions [10]. The status of lymph nodes indicates whether SCLC patients with a clinical classification of T1-2N0M0 receive adjuvant radiotherapy [5]. Accordingly, accurate lymph node status estimates are the key to providing prognostic information and determining the appropriate therapy strategies.

However, the current pN classification still has some drawbacks and is limited by the level of lymph node dissection. Some studies suggested that the number of examined lymph nodes (ELNs) could affect patient survival [11, 12]. In addition, the status of pN classification does not reflect the tumor burden in the lymph node enough. Some researchers confirmed that lymph node ratio (LNR) might be a more accurate tool than the current pT classification to predict prognosis and guide the plan for adjuvant therapy [13‐15]. As a consequence, ELNs and LNR may play important roles in the modification of pN classification.

Previous studies have assessed patient prognosis by ELN or LNR; however, the ELN or LNR usually appears alone [16‐18]. For example, in one report, the LNR was primarily evaluated as an indication of patient prognosis, but the harm caused by insufficient lymph node dissections was not reflected. Although another study evaluated both ELN and LNR, this study included an analysis of patients with metastases of lymph nodes and did not include SCLC [15]. Also, most studies utilized publicly available data sets and did not validate each other with data from their hospitals [15‐17].

Moreover, there is a lack of studies including ELNs and LNR in SCLC patients with pathological classification T1-2N0-2. Therefore, in the present study, we analyzed the cutoff points for the number of ELNs and LNR in SCLC patients with pathological classification T1-2N0-2M0 using data from the multicenter database (MCDB) in China (included four hospitals) and Surveillance, Epidemiology, and End Results (SEER) database. In addition, we further compared predictive ability between the current pN classification and a new pN classification that combined ELNs with LNR in patient prognosis. This study aimed to elucidate which pathological nodal classification is the best: the current pN classification or the new pN classification that combined ELNs with LNR.

SCLC is a small part of lung cancer that has received less attention from investigators than non-small cell lung cancer. In thoracic surgical oncology, surgeons seem more inclined to discuss which combined stages of the disease are appropriate to undergo surgical resection. The National Comprehensive Cancer Network guidelines recommend that SCLC patients with clinical stage I-IIA (classification T1-2N0M0) perform a surgical operation [5]. Thus, recent studies on the surgical treatment of SCLC have explored the role of surgery in stage III patients [3, 6, 22, 23]. Based on their results, surgery was considered a potential treatment for stage III SCLC patients, which provided patients with an optional therapeutic approach, though their research results were not consistent enough. However, there are few studies on lymph node dissection and pN classification in the limited-stage SCLC patients. The current pN classification was based on the idea that lymph node metastasis follows the direction of lymphatic drainage from intrapulmonary lymph nodes (pN1) to mediastinal lymph nodes (pN2) and then to distant lymph nodes (pN3). However, in some studies and our clinical practice, it has been found that lymph node metastases can skip the N1 station and jump directly to the N2 station (skip-N2). Moreover, patients with the N1 station and N2 station metastases are also classified as N2. However, although both are N2, the prognosis of patients with skip-N2 metastases is much better than those with N2 metastases that include N1 stations [24‐26]. In other words, the current pN classification is likely to have some flaws in evaluating the prognosis of SCLC patients after surgery. Accordingly, some researchers used LNR and the number of positive lymph nodes to supplement the pN classification in order to strengthen the predictive ability [15, 27]. Regrettably, both of their studies only collected non-small cell lung cancer patients. Therefore, to the best of our knowledge, there is still information lacking regarding improving pN classification in SCLC.

In the present study, we used a large cohort from the SEER and the multicenter database in China to develop and validate a new pathological nodal classification. ELNs and LNR reflected the status of lymph node dissection and lymph node metastasis and reached optimal cutoff points by X-tile software. We develop a new pN classification. The new pN classification had a better predictive ability than the current pN classification. Therefore, we propose that the new pN classification that combines LNR and ELNs has a better performance than the current pN classification in predicting SCLC patients’ prognoses.

A sufficient lymph node dissection is key to categorizing the pathological nodal classification and evaluating the prognosis precisely. Previous studies confirmed that an insufficient lymph node dissection was associated with a poor prognosis in the field of non-small cell lung cancer [12, 16]. Besides, the survival benefit of lobectomy was unable to be accurately assessed because of lack of lymph node dissection information compared with sub-lobectomy, according to a recent report [28]. The studies mentioned above show that adequate lymph node dissection plays a vital role in thoracic surgical oncology. Nevertheless, the current guidelines about SCLC do not indicate a consistent number of lymph nodes necessary [5]. Analysis of data from 1051 limited-stage SCLC patients indicated that survival was improved s when the ELNs were over 7 [29]. The threshold for the number of ELNs from their study was more extensive than ours. The reason might be that they excluded patients with sub-lobectomy; however, we did not. We found that patients with sub-lobectomy also performed lymph node dissection when we processed the data; therefore, we decided to reserve this part of the data. Besides, another study performed the same operation of data as the present study [17]. Regardless of the difference in the number of ELNs, all demonstrated similar results that inadequate lymph node dissections decreased the survival time of limited-stage SCLC patients after surgery.

LNR is a simple and effective tool for postoperative prognostic assessment for SCLC patients with classifications T1-2N0-2M0. However, it is undeniable that the calculation of LNR is still based on lymph node dissection. The present study showed that patients with N0-#ELNs ≤ 3 had similar survival to those with N1-2-#LNR ≤ 0.14. Those results might suggest that patients with inadequate lymph node dissection were accompanied by the diseases of lymph node metastasis. The low number of ELNs masked the actual metastatic status of the lymph nodes. Accordingly, the N modification that combined ELNs and LNR might reflect the actual nodal situation, which showed a better predictive ability than the current pN classification in the present study. Similarly, the study from Li F at el. also demonstrated that the pN classification combined with the number of metastatic lymph nodes or LNR had a more accurate performance than the current pN classification alone in the non-small cell lung cancer patients with pN1-2 classification [15]. On the one hand, these results illustrated the shortcomings of the current pN classification and, on the other hand, suggested that the combination of LNR improved the prognostic, predictive accuracy of the pN classification. Thus, we suggest that the next 9th edition TNM staging system should consider the information about lymph nodes except the anatomical location of lymph nodes, such as ELNs, LNR, and the number of metastatic lymph nodes.

There were still some limitations in this study. First, the present research was a retrospective study; therefore, some confounders were not included in the study; selection bias was still possible. Second, the treatment sequence of chemotherapy and radiotherapy in the SEER database was unknown. Thus, the cases with neoadjuvant therapy were not excluded from the SEER database. However, we excluded cases with neoadjuvant therapy in the multicenter database from China and reached similar results after analyses for the MCDB to validate the performance of the N modification. Third, the distribution of baseline characteristics still had some differences between the MCDB and SEER databases, though the sample size of MCDB was large. Finally, the N modification was confirmed to have a better performance than the current pN classification, but this does not mean it could replace the traditional TNM staging system. We need more studies to confirm our findings.

In this multicenter cohort we developed and validated a new nodal classification for SCLC patients with pathological category T1-2N0-2M0 after surgery. Besides, we propose that an adequate lymph node dissection is essential; surgeons should perform and consider the situation of ELNs and LNR when they evaluate postoperative prognoses of SCLC patients.