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Prognostic impact of lymphadenectomy on outcomes of sublobar resection for non-small cell lung cancer ≤1 or >1 to 2 cm

Background Lymphadenectomy is an important part of surgical treatment for non-small cell lung cancer (NSCLC). However, the prognostic impact of lymph node (LN) dissection for patients with NSCLC ≤1 and >1 to 2 cm who underwent sublobar resection is still unclear. Methods A group of patients numbering 7,627 with NSCLC 2 cm or less who underwent sublobar resection were identified from the Surveillance, Epidemiology, and End Results (SEER) database between January 2010 and November 2015. The overall survival (OS) and lung cancer-specific survival (LCSS) were evaluated among patients who had undergone dissection of ≥4 LNs, 1 to 3 LNs or who had no-LN dissection; log-rank and Cox proportional-hazards regression analyses were used for the evaluation. Results Patients with NSCLC ≤2 cm who underwent ≥4 LNs dissection had better OS and LCSS compared with those who underwent dissection of 1 to 3 LNs or who had no-LN dissection after sublobar resection. Subgroup analysis showed that dissection of ≥4 LNs had better OS and LCSS than those of 1 to 3 LNs dissection in NSCLC >1 to 2 cm, whereas had similar OS and LCSS in NSCLC ≤1 cm. Multivariate Cox analysis showed that dissection of 1 to 3 LNs was not an independent risk factor of OS and LCSS than dissection of ≥4 LNs in NSCLC ≤1 cm after sublobar resection. Conclusions The extent of LN dissection is associated with the survival outcomes in patients with NSCLC ≤2 cm after sublobar resection. Dissection of ≥4 LNs should be recommended for NSCLC >1 to 2 cm, whereas surgeons can rely on surgical skills and patient profiles to decide ≥4 LNs or 1 to 3 LNs dissection for NSCLC ≤1 cm during sublobar resection.

increase the drainage and operative time, and may cause damage to neurogenic, vascular, and lymphatic structures in the mediastinum (4).
With the widespread use of high-resolution computed tomography (HRCT), more and more small-sized (≤2 cm) NSCLC are being detected (5). Sublobar resection as an alternative choice for small-sized (≤2 cm) NSCLC can achieve a similar prognosis to that of lobectomy, and its use is increasing (6)(7)(8)(9)(10). However, the optimal number of LNs to be dissected for patients with NSCLC 2 cm or less during sublobar resection has not been standardized (11)(12)(13). Moreover, the 8th tumor, node, and metastases (TNM) classification system subclassified NSCLC tumors 2 cm or less into T1a (≤1 cm) and T1b (>1 to 2 cm) disease owing to the significantly better prognosis for patients with NSCLC ≤1 cm (14). Furthermore, patients with NSCLC ≤1 cm have a lower probability of mediastinal LN metastasis than those with tumors >1 to 2 cm (15,16). However, it is still not clear whether patients with NSCLC ≤1 cm could benefit from less extensive LN dissection.
Hence, this study aimed to investigate the appropriate extent of LN dissection for patients with NSCLC ≤1 cm and >1 to 2 cm after sublobar resection, based on the Surveillance, Epidemiology, and End Results (SEER) database.

Study population
All the patients in our study were selected from the SEER 21 database which covered 21 geographically different registries and made up of 34.6% of the United States population (17). Patients who met the following inclusion criteria were included: (I) pathologically diagnosed as primary NSCLC between January 2010 and November 2015, (II) tumor size ≤2 cm, (III) and wedge resection or segmentectomy performed with or without lymphadenectomy. The exclusion criteria were as follows: (I) insufficient information on the number of resected LNs and clinicopathological characteristics, (II) with another malignant primary tumor during follow-up period and (III) received chemotherapy and/or radiotherapy before the surgery.

Data collection
Demographic variables included age, sex, race and marital status were obtained. Tumor characteristics were consisted of tumor location, histological type, tumor size, and grade. Treatment information including surgical procedures and number of dissected LNs were collected from the SEER database. All the patients were divided into three groups based on the extent of LNs dissection: no-LN dissection, 1 to 3 LNs dissection and ≥4 LNs dissection. Overall survival (OS) was defined as the time from surgery until death from any cause. Lung cancer-specific survival (LCSS) was defined as the time from surgery until death because of lung cancer. The survival time and the cause of death whether due to lung cancer were retrieved from the specific codes provided by SEER database. The last follow-up date was January 2016.

Statistical analysis
All the data were either shown as mean ± standard deviation or number (percent values). We used Pearson χ 2 test to compare categorical variables and one-way analysis of variance (ANOVA) to compare the continuous variables between different groups. Log-rank test and Cox proportional-hazards regression model were applied to evaluate predictive factors of OS and LCSS. In the current study, a two-sided P value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS 26.0 (IBM Corporation, Armonk, NY, USA).

Prognostic impact of lymphadenectomy on outcomes for NSCLC ≤1 cm after sublobar resection
The log-rank test showed that patients with ≥4 LNs dissection and 1 to 3 LNs dissection had significantly better prognosis compared with patients who had no-   (Figure 2A,B).      Table 3).

Prognostic impact of lymphadenectomy on outcomes for NSCLC >1 to 2 cm after sublobar resection
The log-rank test showed that patients with ≥4 LNs dissection had significantly better prognosis compared with those who had 1 to 3 LNs and no-LN dissection in both OS (≥4  Table 4).

Discussion
Lymphadenectomy is an important part of the surgical treatment for early-stage NSCLC and can indicate which patients would benefit from subsequent adjuvant therapy.
However, the prognostic impact of LN dissection for patients with NSCLC ≤1 cm and >1 to 2 cm who underwent sublobar resection is still unclear. This study indicated that lymphadenectomy has an important impact on NSCLC ≤2 cm after sublobar resection. For NSCLC >1 to 2 cm, the removal of at least 4 LNs was recommended. More importantly, for patients with NSCLC ≤1 cm, the dissection of 1 to 3 LNs achieved a similar survival compared those with dissection of ≥4 LNs. Our findings have important practical implications for lymphadenectomy for patients with NSCLC ≤2 cm after sublobar resection.
Lymphadenectomy is used for accurate node staging, the detection of occult node metastases, and the guidance of postoperative adjuvant chemotherapy or radiotherapy. It has been demonstrated that incomplete LN retrieval would seriously affect the accurate nodal classification (18,19), but complete mediastinal LN dissection may increase the operative time and morbidity and chest tube drainage (4). Previous study found that there was no association between the extent of lymphadenectomy and the survival benefit for patients with early-stage NSCLC, but they mainly focused on lobectomy (20). By now, the prognostic impact of lymphadenectomy on survival outcomes for patients who undergo sublobar resection is rarely reported. Hence, it is vital to determine the optimal number of LN that should be resected to achieve a balance between the adequate evaluation of the nodal status and minimizing surgical trauma.
Surgical resection is the most effective treatment strategy for early-stage NSCLC according to the 2020 NCCN guideline (2). Previous studies have strongly demonstrated that sublobar resection can achieve equivalent long-term survival compared with lobectomy for early-stage NSCLC (21)(22)(23)(24). Despite the ongoing controversies about the adequacy of sublobar resection for treatment (25,26), its use in early-stage NSCLC is increasing. Clinically, sublobar resection is generally considered acceptable for peripheral small-sized (≤2 cm) NSCLC (9,10). Compared with the standard surgical procedure of lobectomy plus systematic mediastinal lymphadenectomy (27), the significance of lymphadenectomy in sublobar resection is still unclear. The proportion of patients who underwent sublobar resection without lymphadenectomy is significantly higher than lobectomy (28,29). Our study also included a high proportion (44.9%) of patients who did not undergo lymphadenectomy after sublobar resection. Moreover, Patients with NSCLC ≤2 cm who underwent sublobar resection plus dissection of ≥4 LNs or 1 to 3 LNs had better survival outcomes than patients who did not have LN dissection. These results indicated the importance of lymphadenectomy in NSCLC patients who underwent sublobar resection.
Several studies have discussed the association between lymphadenectomy and survival outcomes in patients who underwent sublobar resection for early-stage NSCLC (3,11,13,29). Yendamuri et al. demonstrated that the examination of nine or more LNs was associated with improved survival in patients with stage IA NSCLC (≤2 cm) after sublobar resection due to the avoidance of inaccurate staging and guidance of adjuvant therapy postoperatively (12   reported that NSCLC >1 to 2 cm had a higher rate of nodal metastasis than NSCLC 1 cm or less (13.8% versus 3.5%) (15). These results indicated that small-sized NSCLC patients are a heterogeneous group, some of whom are potentially candidates for less extensive lymphadenectomy. In this study, we found that the dissection of ≥4 LNs does not improve the survival than dissection of 1 to 3 LNs in patients with NSCLC ≤1 cm undergoing sublobar resection. This finding has significant implications for surgical decisions in reducing surgical trauma.
We must acknowledge some limitations in this study. First, because of the nature of this retrospective study, performance bias and selection bias were inevitable. For example, the patients included in the presented study were not designed for lymphadenectomy after sublobar resection. Future randomized trials are necessary to validate our findings. Second, the respective number of dissected N1 and N2 LNs were not recorded in the SEER database, hence it is impossible to determine the appropriate number of LNs dissection specific to different location in sublobar resection. Third, the presence of ground-glass opacity (GGO) component on CT scan is associated with better survival outcomes (34,35) and 8th TNM classification also recommended the invasive component size, rather than the whole tumor size, is considered a better measure for T staging (14). However, the information on consolidation diameter and presence or absence of GGO component are not available in SEER database. Fourth, we evaluated the impact of LNs dissection on prognosis in sublobar resection but not specific to segmentectomy and wedge resection subgroups.

Conclusions
The extent of LNs dissection is associated with the survival in patients with NSCLC ≤2 cm after sublobar resection. Dissection of ≥4 LNs has superior survival compared with 1 to 3 LNs dissection in NSCLC >1 to 2 cm, whereas has equivalent survival for NSCLC ≤1 cm. Hence, dissection of ≥4 LNs should be recommended for NSCLC >1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide ≥4 LNs or 1 to 3 LNs dissection for NSCLC ≤1 cm after sublobar resection.

Acknowledgments
We acknowledge the efforts of the SEER program tumor registries in the creation of the SEER database.  Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Approval was waived by the local ethics committee, as SEER data is publicly available and deidentified.
Open Access Statement: This is an Open Access article