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Nodal Involvement Pattern in Clinical Stage IA Non-Small Cell Lung Cancer According to Tumor Location

Purpose The purpose of this study was to investigate lymph node involvement pattern in clinical stage IA non-small cell lung cancer (NSCLC). Patients and Methods Clinical stage ⅠA NSCLC patients who underwent lobectomy and lymph node resection were included in this retrospective study. Mediastinal lymph node involvement was distinguished by different lobes and tumor size. Results From 2000 to 2015, a total of 759 patients were identified: 282 (37.2%) with tumors in the right upper lobe (RUL), 183 (24.1%) in the left upper lobe (LUL), 124 (16.3%) in the right lower lobe (RLL), 103 (13.6%) in the left lower lobe (LLL), and 67 (8.8%) in the right middle lobe (RML). Patients with tumor size ≤1 cm accounted for 19.6%, >1 and ≤2 cm for 47.8%, >2 and ≤3 cm for 32.5%. Patients with pN1 accounted for 8.2%, and pN2 for 12.5%. Among patients with pN2, the inferior mediastinum was involved in 9.7% of RULs and 17.4% of LULs; the superior mediastinum was involved in 52.2% of RLLs and 36.4% of LLLs. Mediastinal lymph node metastasis was found in 13.2% of patients with size >1 and ≤2 cm, and 19.0% of >2 and ≤3 cm. Patients with tumors ≤1 cm had no N2 lymph node involved. Conclusion Selective lymph node dissection based on tumor location is not recommended in clinical stage ⅠA NSCLC, and systemic lymph node dissection should be performed for NSCLC with size >1 cm.


Introduction
Lung cancer is the leading cause of cancer death among both men and women. 1 The overall 5-year survival rate of non-small cell lung cancer (NSCLC) ranges from 83.9% in ⅠA to 29.6% in IIIB. 2 Lymph node involvement pattern is crucial for accurate staging of NSCLC. 3 However, there is still controversy over whether to dissect the mediastinal lymph nodes in early lung cancer. From the perspective of skip N2 metastasis and occult mediastinal metastasis in lymph node involvement pattern, some authors consider systemic lymph node dissection to be the only acceptable procedure. 4,5 Others have suggested that selective lymph node dissection can be performed according to the primary tumor site in patients with no apparent nodal metastases preoperatively. [6][7][8] In this study, we aimed to examine mediastinal lymph node involvement pattern of clinical stage ⅠA NSCLC patients.

Patients and Methods Patients
Lung cancer patients who underwent surgery in Peking University People's Hospital between January 2000 and December 2015 were reviewed. The clinical records included disease history, medication information, surgical records, and pathological results. Preoperative chest computed tomography (CT) was performed in all patients. If the short-axis dimension of lymph nodes was ≥1 cm, positron emission tomography-computed tomography (PET-CT) scan or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed. We focused on primary NSCLC patients with clinical stage ⅠA who underwent lobectomy and lymph node resection. Cases with positive lymph nodes and multiple tumor lesions were excluded.

Ethics Statement
The study protocol was approved by the Ethics Committee of Peking University People's Hospital (approval number: 2018PHB144-01). Written informed consent was obtained from each participant and the study was conducted in accordance with the guidelines in the Declaration of Helsinki.

Statistical Analysis
Continuous variables were described as mean ± S.D. and categorical variables were described as number and proportion.
The involvement of lymph nodes in different tumor sizes is shown in Table 3. No pN2 was found in the T1a group, which meant that no mediastinal lymph node metastasis occurred in NSCLC with the ≤1 cm size. In the T1b and T1c groups, the proportion of pN2 was13.2% (n = 48) and 19.9% (n = 47), respectively.
The distribution of pN2 in each lobe is shown in detail in Supplementary Tables 1-5.
In the RUL, 31 of 282 cases (11.0%) were N2 involved. A total of 12 (4.3%) were skip metastases, and their pN2 status only existed in SM. Nineteen patients (6.7%) had both N1 and N2 involved. Three of 31patients (9.7%) had pN2 status both in the SM and the IM, and their subcarinal lymph nodes (Station 7)  In the RLL, 23 of 124 cases (18.5%) were N2 involved. A total of 6 (4.8%) were skip metastases, and their subcarinal lymph nodes (Station 7) were all involved. Seventeen patients (13.7%) had both N1 and N2 involved. Twelve of 23 patients (52.2%) had pN2 status found both in the SM and IM, while the other 11 only in the IM (47.8%). Moreover, 66 patients in the RLL were classified into the T1b group, of whom 10 (15.2%) had N2 involved. Thirty-eight patients were classified into the T1c group, and 13 (34.2%) had N2 involved.
In the LUL, 23 of 183 cases (12.6%) were N2 involved. A total of 7 (3.8%) were skip metastases, all of which were only the SM involved. Sixteen patients (8.7%) had both N1 and N2 involved. Two of 23 patients (8.7%) had pN2 status found both in the SM and IM, while 19 only in the SM (82.6%) and 2 only in the IM (8.7%). Moreover, 85 patients in the LUL were classified into the T1b group, of whom 12 (14.1%) had N2 involved. Sixtynine patients were classified into the T1c group, and 11 (15.9%) had N2 involved.
In the LLL, 11 of 103 cases (10.7%) were N2 involved. A total of 4 (3.9%) were skip metastases, all of which were only the IM involved. Seven patients (6.8%) had both N1 and N2 involved. Three of 11 patients (27.3%) had pN2 status found both in the SM and IM, while 7 only in the IM (63.6%) and 1 only in the SM (9.1%). Moreover, 44 patients in the LLL were classified into the T1b group, of whom 4 (9.1%) had N2 involved. Thirty-four patients were classified into the T1c group, and 7 (20.6%) had N2 involved.

Discussion
The current common surgical options for lung cancer are VATS and systemic lymph node dissection, 9,10 which was reflected in our study. In recent studies, 11,12 the incidence of pN1 and pN2 in clinical stage IA NSCLC patients was about 5.9-7.8% and 7.1-10.6%, respectively. The proportions in our study were similar, 8.2% for pN1 and 12.5% forvpN2.
The prognosis of single-station N2 (N2a) is generally considered good. 13 In our study, patients with N2a (n = 53) accounted for 55.8% of pN2 cases, which was consistent with previous studies. In the RUL group, Station 4 was the most common single-station metastasis (17/18, 94.4%), while Station 5 was the most frequent in LUL (9/16, 56.3%). Station 7 was the most common single-station metastasis both in RLL and LLL (10/11, 90.9% and 5/6, 83.3%, respectively). This may be related to the different lymphatic anatomy between the sides. 14 Skip metastases (n = 32) occurred in 4.2% of patients with clinical stageⅠA NSCLC, which was similar to previous studies. 15,16 There were 24 pN2a1 cases in total (3.2%). Some studies have suggested that overall survival and recurrence-free survival rates of pN2a1 cases are similar to pN1, and have significantly better survival rates than pN1N2. 17 No pN2 status occurred in NSCLC with tumor size ≤1 cm, which indicates that mediastinal lymph node dissection may not be necessary for NSCLC ≤1cm. The pN2 status accounted for a considerable proportion in the T1b and T1c (13.2% and 19.0%, respectively), and even reached 15.2% and 34.2% in RLL, which suggests that mediastinal lymph node dissection should be performed for NSCLC with size >1 cm. Among patients with pN2, 9.7% of RUL and 17.4% of LUL had the IM involved; as for the SM involved, 52.2% of RLL and 36.4% of LLL were found. This suggests that selective lymph node dissection based on tumor location is not convincing.
There were 3 of 31 cases in RUL that had Station 7 involved (9.7%), and 3 of 23 in LUL also (13.0%). Upper lobe tumor with only the IM involved was found in 2 of 54 cases (3.7%). Lower lobe tumor with only the SM involved was found in 1 of 34 case (2.9%). These findings were similar to previous studies. [18][19][20] It has been suggested that Station 7 dissection is unnecessary if there is no IM involved in the LUL cases. 20 However, in our study, 2 of 23 LUL cases (8.7%) showed Station 7 metastasis without the SM involved. Given the results in our study, we cannot agree with the previous opinion. All cases that the SM involved in LLL had pN1, but 3 cases in RLL were the SM involved without pN1 (3/12, 25.0%). All cases with the SM involved in RLL had Station 7 metastasis. This suggests that the SM metastases of RLL NSCLC may require the involvement of Station 7. Similarly, the IM metastases of RUL NSCLC were also related to Station 7. There was no such involvement of Station 7 in left lobes.
We believe that systemic lymph node dissection should be performed for NSCLC with size >1cm.
Several studies had investigated recurrence and survival outcomes related to systemic lymph node dissection and selective dissection. A meta-analysis of six cohort studies concluded that there was no significant difference in overall survival and disease-free survival between the two dissection methods. 21 Selective lymph node dissection had significant benefits in relation to operating time and blood loss. 21,22 Some studies have shown that lobe-specific selective dissection and systemic dissection were similar in local, regional, or distant recurrence. 7,8 However, it has also been found that selective dissection caused by patient-related factors has a higher recurrence rate. 22 There were some limitations in our study. First, there was only one patient with T1N3 (1/759, 0.1%), which may be different from the real world situation but it did not affect our main conclusion about mediastinal lymph nodes. Second, our conclusions were based on a single-center retrospective study. Additionally, considering that the postoperative follow-up time of some patients was <5 years, our study only described the nodal involvement pattern, without evaluation of prognosis. However, lymph node involvement pattern directly affects the staging and adjuvant treatment of patients, so it is still of some importance.

Conclusion
We conclude that selective lymph node dissection based on tumor location is not recommended in clinical stage ⅠA NSCLC, and systemic lymph node dissection should be performed for NSCLC with size >1cm.