Impact of extended mediastinal lymph node dissection for stage I ground-glass opacity lesions

Introduction

The prognosis and management of lung cancer is changing. Outcomes for advanced non-small cell lung cancer (NSCLC) have improved with the development of chemotherapy and immunotherapy (1). Significant advances in lung cancer screening programs (2) and surgery have led to breakthroughs in the outcomes of patients with resectable NSCLC. In terms of parenchymal resection, recent studies from Japan and the United States have suggested a clear evidence suggesting the benefit of sublobar resection for peripheral lesions of <2 cm (3,4). Now, surgeons need to evaluate another key component of pulmonary resection, mediastinal lymph node dissection (MLND).

Systematic MLND has been considered an optimal strategy for management of resectable NSCLC because it can provide precise staging and identify occult N2 disease. However, it is also associated with high morbidity, such as recurrent laryngeal nerve damage, chylothorax, and postoperative cardiopulmonary complications. Based on the patterns of tumor spread, the need for systematic MLND has been questioned as lobe-specific MLND exhibited similar oncological outcomes in early-stage NSCLC (5,6). However, the criteria for applying each strategy have not been clearly identified. Since the time when original MLND strategy was first developed, the radiological characteristics of NSCLC have changed. The number of pulmonary lesions with ground-glass opacity (GGO) have increased, and more favorable outcomes of them have been described and validated in many studies (7,8).

Determining the appropriate extent of MLND is primary interest to thoracic surgeons. Multiple guidelines on the minimum requirements for adequate MLND have guided thoracic surgeons. The American College of Surgeons Commission on Cancer suggested one hilar and three or more N2 lymph node dissection as a criterion (9). However, the European Society of Thoracic Surgeons (10) and the International Association for the Study of Lung Cancer (IASLC) mentioned specific stations that should be dissected based on the location of primary lesion (11). However, nodal involvement in GGO-dominant lesions is extremely rare (12). Consequently, the application of MLND based on our previous understanding of NSCLC should be reassessed. Previous studies have revealed that it might be an overtreatment to apply MLND for GGO-dominant lesions with a consolidation tumor ratio (CTR) <0.5 (13) but for pulmonary lesions with a CTR of approximately 0.5, there remains uncertainty about the optimal MLND strategy.

In this study, we retrospectively analyzed the oncologic outcomes of pulmonary lesions with a CTR between 0.3 and 0.7, which have significant proportions of two very different radiologic characteristics (GGO and solid). Then, we assessed the clinical impact of MLND according to the number of N2 stations that were resected. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-703/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Gangnam Severance Hospital (No. 3-2023-0169). The requirement for informed consent was waived due to the retrospective design of the study. Electronic medical records of patients who underwent surgery for NSCLC between January 2013 and December 2019 were reviewed. Of the 812 patients, 476 were diagnosed with stage I adenocarcinoma. The exclusion criteria were as follows: adenocarcinoma in situ (AIS), atypical adenomatous hyperplasia, mucinous invasive adenocarcinoma, neoadjuvant treatment, insufficient surgical margins (R1 or R2 resection), and a CTR <0.3 or >0.7. The criteria for CTR were developed to assess pulmonary lesions with comparable GGO and solid proportion. The study included 138 patients with a CTR of 0.3–0.7.

MLND

The preoperative workup consisted of chest computed tomography (CT) with or without contrast enhancement, positron emission tomography (PET)-CT, brain magnetic resonance imaging (MRI), and endobronchial ultrasound (EBUS) for possible N1 or N2 lesions. Patients with negative EBUS results underwent curative resection.

Systematic MLND was not routinely performed in most patients with GGO lesions, in contrast to those with solid lesions. Intraoperatively, a frozen biopsy of the pulmonary lesion was used to guide the extent of mediastinal lymph node assessment because of the favorable clinical course for minimally invasive adenocarcinoma (MIA). Extensive MLND was avoided for MIA lesions. In cases with enlarged lymph nodes, a frozen biopsy was selectively performed according to the surgeon’s discretion. Four surgeons were included in this study, and they made a final decision regarding the stations to be dissected intraoperatively. We classified the patients into two groups based on the pathological reports of lymph node assessment. As many guidelines require three or more N2 MLND as a minimum criterion for the quality of MLND (9-11), we applied it to classify patients. The extended N2 dissection group included patients with three or more N2 stations dissected, and the limited N2 dissection group included patients with fewer than three N2 stations dissected. Here MLND means full dissection of the lymph node stations according to the IASLC node map (14).

Statistical analysis

Continuous variables were compared using the Mann-Whitney U test after the normality test, and categorical variables were compared using Fisher’s exact test or the chi-square test. Recurrence-free survival (RFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Propensity-score matching was used to adjust confounding variables such as tumor size, activity on PET, and surgical extent; RFS and OS were again compared according to the extent of MLND. Furthermore, logistic regression analysis in the entire cohort was used to identify risk factors related to postoperative complications (PoCs). Factors with a P value <0.10 in univariate analysis were introduced in multivariable analysis, and backward elimination via the P value approach was used to find significant factors.

Statistical analyses were performed using R version 4.0.4 (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). All tests were two-tailed, and variables with a P value <0.05 were regarded as statistically significant.

Results

Perioperative characteristics

The study cohort was predominantly Asian with 60.1% females (83/138) and 76.8% non-smokers (106/138); the median age was 64.0 years. Sublobar resection was performed in 42.0% participants and mean follow-up duration was 51.8 months. Table 1 describes patients characteristics according to the extent of MLND. Both groups had similar demographic and radiological characteristics, including CTR and radiotracer uptake on PET-CT. The median CTR of both groups was 0.50. However, the extended N2 MLND group had larger median total tumor diameter (20.5 vs. 15.0 mm, P=0.005) and solid component diameter (9.5 vs. 7.0 mm, P=0.002). Furthermore, the proportion of patients with sublobar resection was significantly lower in the extended N2 MLND group (21.0% vs. 50.0%, P=0.008).

Long-term clinical outcome

There was no significant difference in RFS or OS between the two groups (Figure 1). The 5-year RFS in the limited and extended N2 MLND group was 93.2% and 89.5%, respectively (P=0.558), while the OS in the same groups was 97.3% and 91.4%, respectively (P=0.401). After propensity-score matching between two MLND strategies (Table 2), the difference in clinical outcome was also not significant (Figure 2). Cox-proportional hazard regression revealed patients’ history of cardiovascular disease as a significant predictor in RFS [hazard ratio (HR), 4.36; 95% confidence interval (CI): 1.10–17.2; P=0.036; Table 3]. The extent of MLND was not related to long-term clinical outcomes.

Figure 1 Long-term clinical outcome according to the extent of N2 MLND. RFS, recurrence-free survival; OS, overall survival; MLND, mediastinal lymph node dissection.

Figure 2 Long-term clinical outcome according to the extent of N2 MLND after propensity score matching. RFS, recurrence-free survival; OS, overall survival; MLND, mediastinal lymph node dissection.

Early postoperative outcome

Although the patients had comparable long-term outcomes, their clinical courses in the early postoperative period differed according to the extent of MLND. Patients who underwent extended N2 MLND had a significantly higher rate of developing PoC of over grade 2 according to the Clavien-Dindo classification (19.4% vs. 5.2%, P=0.018; Table 1). Specific details of these complication include prolonged air leakage (7/12), pneumonia (1/12), arrhythmia (1/12), chylothorax (1/12), recurrent laryngeal nerve injury (1/12), and others (1/12). Predictive factors for PoC were analyzed using logistic regression. As Table 4 shows, male sex [odds ratio (OR), 8.90; 95% CI: 1.81–43.7; P=0.007] and extended N2 MLND (OR, 4.57; 95% CI: 1.26–16.6; P=0.021) were significant risk factors for complications. Even after propensity score matching, the incidence of PoC was more observed in the extended N2 MLND (3.2% vs. 19.4%, P=0.104; Table 2).

Discussion

With increasing evidence for parenchymal-preserving surgery in lung cancer, progress in MLND has been made recently (8,13,15). This study reported clinical outcomes according to the extent of N2 MLND and questioned its applicability in all patients with early-stage lung cancer.

Because thoracic surgeons encounter many patients with GGO components, the extent of optimal has been debated. Compared to the era when systematic MLND was first introduced, early-stage lung cancer with a smaller size and different radiologic findings have increased (16). As tailored therapy for patients is applied, surgeons may need to decide which mediastinal lymph nodes should be dissected or sampled based on patient characteristics. Accurate staging with meticulous MLND is important. However, if tumor characteristics provide sufficient information regarding less aggressive features and nodal involvements, the universal application of extensive MLND may be detrimental to some patients (6).

A multicenter prospective trial on selective MLND recently revealed several criteria that can be applied depending on the tumor characteristics (13). The authors even did not perform MLND to lesions with a CTR of <0.5 owing to their favorable clinical outcome. Pulmonary lesions with GGO have shown significantly different clinical outcomes from solid lesions. For pure GGO lesions, which are more commonly observed in lung cancer screening programs, the 5- or 10-year recurrence rates seem closer to zero, and some clinicians argue that they should be classified as a different category of NSCLC. Masses with a CTR ≤0.25 were recognized as radiologically non-invasive lesions and their clinical outcomes were reported from the JCOG 0804 trial (17).

Preservation of the normal mediastinal lymph node structure has several clinical benefits. Most N2 nodes are located near important structures, such as the vagus and recurrent laryngeal nerves, bronchial arteries, and other great vessels, and damaging these structures can result in a poor postoperative course. In our study, specific complications such as arrhythmia, chylothorax, and recurrent laryngeal nerve injury were also related to the damage of these structures. Furthermore, recent studies on immunotherapy in other cancers have demonstrated the benefit of preserving normal lymph node structure. Normal lymph nodes in the tumor-draining area exhibit antitumor activity and suppress tumor growth (18,19); thus, alteration of these structures could result in suppressed immuno-oncologic activity. Although GGO-dominant lesions might not increase the immunologic burden compared with upregulation of immune checkpoints initiated by invasive nodules (20), preservation of lymph node structure may be important in preventing local recurrence or a second primary lung cancer.

Many surgical societies have demanded the standardization of MLND (10,21-23). Recently, following a surgical database study, the concept of uncertain resection R(un) has brought attention to the quality of MLND in lung cancer surgery (21). We agree that reporting on the completeness of lung cancer resection should be prioritized to improve the quality of current procedures. However, if they are applied without considering patient-specific circumstances, surgeons may miss the goal of achieving optimal patient outcomes. Even though extensive resection is not challenging or difficult in terms of surgical technique, it is always important to apply the “do no harm” principle for patients.

This study has several limitations. First, the retrospective design with a limited number of patients could have led to a significant bias in interpreting the data. Second, the criteria for CTR of 0.3–0.7 allowed inclusion of patients with a broad range of tumor characteristics and these should be validated in other clinical settings. Third, the extent of parenchymal resection could bias the clinical outcomes. In the extended N2 MLND group, the proportion of patients who underwent lobectomy was significantly higher than in the limited N2 dissection group. More patients data would be necessary to compare the impacts of sublobar resection or lobectomy. Lastly, intraoperative frozen biopsy results or surgeons’ decisions may have led to differences in the surgical extent even though CTR and PET activities were similar between the two groups. These biases should be addressed in future prospective studies.

Conclusions

In conclusion, our study indicates that extended N2 MLND for pulmonary lesions with CTR between 0.3 and 0.7 could have a negative impact on early postoperative outcomes, without significant long-term oncologic benefit. Therefore, the applicability of the general MLND strategy should be reconsidered in patients with GGO-containing lesions. Further prospective studies and thorough discussions among surgical societies are necessary to provide a solid background for applying appropriate MLND approaches according to tumor characteristics.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-703/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-703/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-703/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-703/coif). The authors have no conflicts of interest to declare.

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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of Gangnam Severance Hospital (No. 3-2023-0169). The requirement for informed consent was waived due to the retrospective design of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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