In the treatment of NSCLC patients, accurate node staging is important for predicting prognosis and selecting an appropriate treatment strategy. Clinical N staging based solely on CT and positron emission tomography (PET) is not accurate enough for early NSCLC. (15) Thorough postoperative pathological N examination is optimal for N staging. The number of LNs examined is an intuitive indicator of examination thoroughness. In this study, we found that the number of N1 LNs examined was an 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 LNs examined. An increasing number of N1 LNs examined would lead to a greater probability of discovering metastasized LNs in the hilum and lung, leading to stage migration, which is considered to be the main factor for the improvement of OS and DFS in patients with a large number of N1 LNs examined. Inadequate LN examination may result in some metastatic LNs not being detected and patients would be wrongly staged as IA or IB when they should be staged as IIB and receive adjuvant therapy. The resection of micrometastases and the effect of the immunologic microenvironment may also be related to the survival advantage brought by the larger number of N1 LNs examined.(16-19) In this study, patients who underwent sublobectomy were excluded which means all intrapulmonary lymph nodes are removed along with the lobes. The resection of micrometastases did not have a significant impact on the survival advantage brought by the larger number of N1 LNs 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 LNs on survival.
In our pilot study, the number of LNs examined was 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. The patients in this study underwent a high-quality mediastinal LN 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 the American College of Surgeons Oncology Group (ACOSOG) Z0030 trial which had a superb quality of N2 LN examination. (21) There is no apparent difference in the 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 decreases when the quality of N2 LN examination increases to a high level. The number of N2 LNs examined lost statistical significance in the Cox regression model. However, this result cannot deny the vital role of N2 LN examination in node staging. Both N1 and N2 LN examinations are important for accurate node staging.
Some researchers have focused on the importance of the number of N1 LNs examined. Mert Saynak et al, reported that T1N0 patients with inadequate N1 LNs 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 LNs examined, the better the patient survival outcomes.(23) John Varlotto et al, demonstrated that a minimum of 11 to 16 LNs should be examined when examining only N1 lymph nodes(24). Similar to the finding of the above study, patients with more than 11 N1 LNs examined had the lowest HR values in the multivariate analyses of OS and DFS, signifying that at least 12 N1 LNs should be examined in to achieve optimal OS and DFS. However, it is difficult to accomplish this goal in clinical practice. Only 26.2% of patients accepted the examination of more than 11 N1 LNs in this study. Patients with 6-8 N1 LNs examined had the second lowest HR values in the multivariate analysis of OS. The median number of N1 LNs examined in this study was 8, which means that more than half of the patients did not have at least 9 N1 LNs examined. As a comparison, the median number of N1 LNs examined was 5 in the ACOSOG Z0030 trial and 5 in Saynak’s study. It is not easy to examine at least 9 N1 LNs for each patient. The clinical decision should be feasible and at least 6 N1 LNs examined is 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 LNs has not received enough attention. One of the phenomenons was that the quality of LN examination exhibits noteworthy variability during surgical and pathological management.(25, 26) Another phenomenons is that incomplete intrapulmonary LNs were retrieved 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 N2 LN examinations were of superb quality, 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 in which N1 LNs were dissected by surgeons and reconfirmed by pathologists contributed to this result.
In addition to insufficient attention to N1 LN examination possibly affecting the number of N1 LNs examined, the surgical approach may also affect the number of N1 LNs examined. Melanie Subramanian et al, reviewed 1,687 patients with stage IA NSCLC from National Cancer Data Base, and included 1,354 patients who underwent lobectomy, and 333 patients who underwent sublobar resections. They found that sublobar resection had an inadequate LNs examined and was associated with a 39% increased risk of recurrence. The majority of patients were treated with sublobar resection. (28) For both sublobar resection and lobectomy, the procedure of mediastinal LN dissection does not have apparent differences. However, sublobar resection, especially wedge resection might lose some N1 LNs, which is associated with poor outcomes. In addition, when we dissected intrapulmonary LNs, we found a phenomenon in which patients whose primary tumor was near a segmental bronchus were prone to segmental LN metastases. Therefore, we suggest that patients whose primary tumor is near a segmental bronchus need a careful intrapulmonary LNs dissection. Furthermore, intrapulmonary LNs are dissected extracorporeally, if 6 lymph nodes were not dissected in the first operation, it is safe to dissect the lung specimens again to take an LN sample for accurate staging.
There are some limitations to 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, the data of this study did not find a 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, the findings from this study should be cautiously interpreted.