In the treatment of NSCLC patients, accurate node staging is important for prognostic prediction and treatment strategy. Clinical N staging based solely on CT and PET is not accurate enough for early NSCLC.(15) Postoperative thorough pathological N examination is optimal N staging. The number of LN examined is an intuitive indicator of examination thoroughness. In this study, we found that the number of N1 LNs examined was the independent prognostic factor of OS and DFS for stage IA-IIA patients.
There are some potential explanations for the survival advantage brought by the larger number of N1 LN examined. An increasing number of N1 LNs examined would lead to a greater probability of discovering metastasized LNs in the hilar and lung, leading to stage migration; considered to be the main role in the improvement of OS and DFS in patients with large number of N1 LNs examined. Inadequate LNs examination may result in some metastatic lymph nodes not being detected and patients would be wrongly staged as IA or IB. Actually, this part of patients should be staged as IIB and received adjuvant therapy. Resecting micrometastases and the effect of immunologic microenvironment may be also related with survival advantage brought by the larger number of N1 LN examined.(16–19) In this study, patients received sublobectomy were excluded which means all intrapulmonary lymph nodes are removed along with the lobes. Resecting micrometastases did not have significant impact on survival advantage brought by the larger number of N1 LN examined.
Several researchers have emphasized that a larger number of LNs examined could increase the accuracy of N staging and enhance prognosis. Pezzi et al retrospectively analyzed 98,970 patients from The National Cancer Data Base (NCDB) and found that the amounts of LNs examination apparently affect the long-term survival and at least 10 LNs should be examined in surgical management.(17) Ou SH et al, retrospectively investigated the data of 2545 patients and confirmed that the number of LN examination was the favorable prognostic factor for stage IA patients and suggested that the removal of 11–15 LNs could improve the patients prognosis.(20) However, the above two studies did not separately analyze the effects of N1 and N2 lymph nodes on survival.
In our pilot study, the number of LNs examination has been identified as an independent prognostic factor for OS(P = 0.005). In this study, the survival advantage from the increase in the number of LNs examined should be attributed to the increase in the number of N1 LNs examined, which might be associated with the following reason. Patients in this study received a high-quality mediastinal lymph node dissection. The number of patients with at least 1,2 and 3 N2 stations dissected was 2044 (98.2%), 1916 (91.5%) and 1509 (71.8%), respectively and the median number of N2 LNs examined was 11 in this study. The median number of N2 LNs examined was 12 in American College of Surgeons Oncology Group (ACOSOG) Z0030 Trial which had a superb quality of N2 LNs examination.(21) There is no apparent difference in median number of N2 LNs examined between this study and the ACOSOG Z0030 Trial. As the number of N2 LNs examined increases, the survival advantage would decrease when the quality of N2 LNs examination increasing to high level. The number of N2 LNs examined lost statistical significance in Cox regression model. But this result cannot deny the vital role of N2 LNs examination in the node staging. Both N1 and N2 LNs examination are important for accurate node staging.
Some researchers have focused on the importance of the N1 lymph node examined. Mert Saynak et al, reported that T1N0 patients with inadequate N1 LN examined had similar local recurrence-free survival compared with T1N1 patients.(22) The ACOSOG Z0030 trial also found a tendency that the greater the number of intrapulmonary LN examined, the better the patients survival outcomes would be.(23) John Varlotto et al, demonstrated that a minimum of 11 to 16 lymph nodes should be examined when only examining N1 lymph nodes(24). Similar to the above study, patients with more than 11 N1 LNs examined had the lowest HR value in multivariate analysis of OS and DFS, signifying that at least 12 N1 LNs should be examined in order to achieve an optimal OS and DFS. However, it is difficult to accomplish this goal in clinical practice. Only 26.2% of patients accepted more than 11 N1 LNs examined in this study. Patients with 6–8 N1 LNs examined had the second lowest HR value in multivariate analysis of OS. At least 6 N1 LNs examined was a realistic goal in clinical practice. Therefore, we recommend at least 6 N1 LNs examined in surgical and pathological management.
However, the examination of N1 lymph node has not received enough attention. One of the manifestations was that that the quality of LN examination exists noteworthy variability during surgical and pathological management.(25, 26) Another manifestations is that incomplete intrapulmonary lymph node retrieval in pathological examination. One previous study revealed that a median of six additional LNs were discovered after rechecking remnant lung specimens and the median number of N1 LNs examined was only 3 in the community-based Memphis Metropolitan Area Quality of Surgical Resection cohort.(27) Although with superb quality of N2 LNs examination, the median number of N1 LNs examined was 5 in the ACOSOG Z0030 trial.(21) In this study, the median number of resected N1 LNs was eight. The pattern of LN examination that N1 LNs were dissected by the surgeons and reconfirmed by pathologists contributed to this result.
There are some limitations exist in this study. First, this was a single-center retrospective study and associated biases may have been inevitable. Second, external validation was not performed to validate the findings. In addition, data of this study did not find the survival advantage from the increase in the number of N2 LNs examined and cannot answer how many N2 LNs should be examined in surgical and pathological management. Therefore, further validation from multicenter database is needed and meanwhile, the findings from this study should be cautiously interpreted.