In this meta-analysis, we evaluated the patients in pN1 NSCLC have different survival according to different N1 lymph node zones involvement: patients with N1p metastasis have a better prognosis than those with N1h metastasis. In our ten studies included, we found an excellent homogeneity, so we use the fixed effect model. In these included studies, we found different lymph node map definitions. It did not cause significant heterogeneity. Nevertheless, we still explored the heterogeneity it might cause. The differences between lymph nodes map definition are minor, and HR as a comparison variable is hard to understand what causes the differences (Supplementary Figure. 3).
The first lymph node map, developed by Naruke during the 1960s22,23, was initially widely used worldwide. Subsequently, to improve the anatomical description of the Naruke map, the American Thoracic Society (ATS) 24 map was developed. Then the Mountain-Dresler modification of the ATS map (MD-ATS) 25 was worked out. The main difference between these two lymph node maps is that the Naruke map treats the subchondral lymph nodes along the lower border of the main bronchus as station 10(N1), and the MD-ATS map treats them as the station 7(N2). In 2009, the new international lymph node map (IASLC map) was promulgated by the IASLC4. Furthermore, it defined the border of #10 Hilar Nodes: "the upper border is the lower rim of the azygos vein on the right and the pulmonary artery on the left; the lower border is interlobar region bilaterally."
The scientific study of lymphatic drainage patterns can be traced back to the early 1900s26. The lymph fluid produced by the lung tissue drains into the lymph nodes around the segmental bronchi and then flows into Hilar/Interlobar lymph nodes. Considering the drainage patterns of lymph nodes, the patients of the peripheral zone involved will have an earlier stage than the hilar zone involved, so it will also have better survival. IASLC presented IASLC Map and proposed lymph node stations together into "zones", which was also proposed for future survival analyses4. Before the TNM of the 7th edition, IASLC analyzed the survival difference between patients with #10–11(N1p) and patients with only 12+ (N1p) (n = 522). The results showed no statistical difference, but it could be observed that the median survival time was reduced in N1h. At the same time, IASLC carried out statistical analysis of N1h and N1p, and it was observed that the median survival time of N1p was 52 months and that of N1h was 40 months. However, the survival difference was not statistically significant. We attempted to explore whether there was a real difference in survival between N1h and N1p patients under "the trend of statistical differences" 27. To our knowledge, this is among the first systematic review and meta-analyses assessing the different prognoses for N1 lymph node involvement in different zones. Now, this meta-analysis revealed the different survival between N1p and N1h.
Compared with the frequently changed and improved T descriptors, there were has been little change in the N classification of lymph nodes. However, we know that as an essential part of TNM classification, N classification is also crucial for patients' prognosis and subsequent treatment after surgery.
In terms of the lymph node division, mang doctors are continually trying to improve and refine its descriptors (Such as statistical analysis of the single or multiple lymph nodes stations, statistics of LNR, the total number of metastatic lymph nodes). In the latest TNM Classification edition, the N1 group is divided into the N1a (single station) and N1b (multiple stations). However, we believe that only in a single station and station to distinguish between heterogeneity is still insufficient to explain within the N1 patients. Based on the zone N1 in installment, we put forward the N1p and N1h classification of advice.
It is well known that, to some extent, T staging is about high, and it is easy to find higher levels of N classifications. In the eighth edition of TNM classification, T1-2N1M0 was classified as IIb and T3-4N1M0 as IIIa, with a 5-year OS of 41% and 56%, respectively3. In this meta-analysis, we conducted a meta-summary of the individual rates of N1p and N1h. Surprisingly, the 5-year OS obtained by the meta-summary was precisely close to those of stage IIb and IIIa (40%, 56%). While this may be a statistical coincidence, it does give us a reminder as to whether the different survival of those patients between T3-4N1M0 and T1-2N1M0 is due to a higher T stage or the presence of more "N1h" patients in T3-4N1M0.
Our study's main limitation is that this meta-analysis is based on a medium sample of retrospective cohort studies. For N1 lymph node groups, especially the peripheral zone, it is not easy to assess the lymph nodes in the peripheral zone without prospective studies. One previous study reported that the median number of intrapulmonary lymph nodes (peripheral zone) retrieved increased from 2 to 5 after a novel pathology gross dissection protocol28. In the ten articles included in the analysis, none of the total number of N1 lymph nodes tested was reported, which may cause the lack of relevant information. Due to the different publication times of the articles, the included articles used different lymph node maps. Because of controversy in the definition of #10 Hilar Nodes, in the Naruke map, some lymph nodes should now be included as N2 (#7 station) are underestimated as hilar lymph nodes resulting in differences in survival. However, this difference is not reflected in the IASLC map group4. In the retrospective study, perhaps to explore the influence of various factors on survival, few articles independently explored the survival difference between N1p and N1h, which led to difficulties in gathering information and a lack of baseline information. This meta-analysis underlines a need for more extensive and well-conducted prospective studies evaluating patients' survival in the pN1 stage. Future prospective studies should re-dissect the lymph nodes after lobectomy and determine a standardized anatomical protocol. Plenty of studies are needed to explore adjuvant therapy's benefits in different N1 zones and formulate guidelines for different zones of N1 lymph nodes.
From the perspective of lymph node drainage, because the survival of the peripheral zone is better than that of the hilar zone, it can be verified laterally that tumors in the peripheral areas can be gradually transferred from the peripheral zone to the hilar zone when lymph node metastasis occurred. When performing intentional wedge resection, full consideration should be given. The anatomical segmental resection can remove the lymph nodes in the peripheral zone to determine the lymph node staging's accuracy. It is maybe a better choice than the wedge resection.