Mediastinal lymph node dissection in T1 stage lung adenocarcinoma: a retrospective analysis of survival outcomes and prognostic factors from the SEER database

Introduction

Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a dominant health threat, accounting for the majority of cancer-related deaths across the globe (1,2). Among NSCLCs, the proportion of lung adenocarcinoma (AD) has escalated, currently holding the status as the most common subtype (3). This shift in disease spectrum necessitates a parallel transition in therapeutic strategies, which aim towards optimizing survival outcomes.

The advent of low-dose computed tomography screening has increased the detection rates of early-stage lung cancers, presenting unique challenges in their management (3). In the field of lung cancer treatment, there have always been two major controversies regarding surgical strategies for early NSCLC: the scope of application for lobectomy and sublobectomy, and the optimal range for lymph node dissection.

There are some prospective trials which have provided significant results regarding the scope of small peripherally and located early-stage NSCLC. The Japan Clinical Oncology Group 0201 (JCOG0201) study is a prospective, multicenter, observational study initiated in 2002 (3). Its objective was to define the criteria for early-stage non-invasive lung cancer as diagnosed by radiology. In exploratory analyses, the point estimate for the specificity of diagnosing non-invasive AD was 98.7% for tumors ≤2 cm with a consolidation-to-tumor ratio (CTR) ≤0.25. Consequently, the JCOG Lung Cancer Research Group defined this radiological manifestation as non-invasive lung cancer on imaging. Based on this result, JCOG and the Western Japan Oncology Group (WJOG) conducted studies such as 0802 to explore the optimal surgical approach for peripheral small lung cancer. The JCOG0802/WJOG4607L study is a multicenter, open-label, phase 3 randomized controlled trial, demonstrating that segmentectomy for early lung cancer is superior to lobectomy in overall survival (OS) (3). The results indicate that segmentectomy should be the standard surgical procedure for patients with small-sized peripheral NSCLC. Another multicenter, single-arm phase III trial in Japan, JCOG1211, showed that even for lung masses with a main component of ground-glass nodules, a diameter of 2–3 cm, and a CTR of 0.25–0.5, segmentectomy is the standard therapeutic surgery for patients with this type of tumor (4).

As for lymph node dissection, we know that lymph node status is a proven significant prognostic factor in NSCLC (4). Comprehensive mediastinal lymph node dissection (MLND) has been traditionally employed to ensure accurate staging and to decrease the likelihood of locoregional recurrence (5). However, the necessity and extent of MLND, especially for smaller tumors, is a contentious issue (6). While some authors argue for a reduction or even complete elimination of MLND in specific scenarios, this approach could lead to differences in oncological outcomes post-surgical intervention (7). A multicenter, noninferiority, phase 3 trial was conducted by the Cancer and Lymphoma Group B (CALGB) 140503 (7), the Alliance for Clinical Trials in Oncology (Alliance). This study confirms that for rigorously screened lymph node negative peripheral small lung cancer (≤2 cm), complete lymph node dissection (CLND) does not provide disease-free survival (DFS) or relapse-free survival (RFS) benefits compared to limited sampling. Another study focuses on the optimal extent of lymph node dissection required in patients with T1 stage (<3 cm in diameter) radiologically ground-glass opacity-dominant, peripheral, NSCLC tumors (7).

These trials have provided important insights into limited resections. However, these trials more focus on the optimal surgical procedure and the correlation between pulmonary nodule size and mediastinal lymph node metastasis, not the topic of lymph node dissection, leaving a gap in our understanding of the direct impact of MLND on survival (8).

Addressing this knowledge deficit, our study leverages the Surveillance, Epidemiology, and End Results (SEER) database to assess the long-term survival outcomes of lobectomy with or without MLND in patients with early-stage lung AD. Our findings contribute valuable insights to the ongoing discourse on surgical strategy selection in lung AD and may serve to guide clinical decision-making in the future. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1743/rc).

Methods

Study population

Data for this investigation were gleaned from the SEER program managed by the National Cancer Institute (NCI). The SEER*Stat version 8.4.1 software facilitated data extraction from the SEER database. Beijing Chao-Yang Hospital’s review board granted approval for this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

We identified patients diagnosed with lung AD possessing a tumor diameter of less than 3 cm, from 2004 to 2015, whose comprehensive clinical data were catalogued in the SEER database. The SEER codes 8140/3 were used to confirm lung AD diagnosis, and lung C30 and C33 surgery codes verified the patients’ receipt of either lobectomy or lobectomy with MLND. The included patients were pathologically staged as T1, N0–2, M0. Lobectomy was defined as the resection of at least one lobe or bilobectomy, but not an entire lung resection. It also encompassed patients for whom lymph node dissection was not performed, but lymph nodes were procured as part of the lobectomy specimen. MLND was a radical dissection.

Exclusion criteria encompassed the following:

• Lobe or bilobectomy extended with chest wall, pericardium, or diaphragm;
• Presence of more than one primary tumor or concurrent tumors at the time of diagnosis;
• Patients in the lobectomy + MLND group underwent insufficient lymph nodes removed, and patients in the lobectomy group underwent MLND;
• Insufficient detail in patient records;
• Preoperative chemotherapy or radiotherapy.

Following these criteria, a total of 5,398 patients were included in our study (Figure 1).

Figure 1 Patients selection for this study. MLND, mediastinal lymph node dissection; NOS, not otherwise specified; TNM, tumor-node-metastasis.

Data parameters extracted for the study encompassed age, sex, race, histology, surgical procedure, tumor diameter, tumor-node-metastasis (TNM) stage [based on the criteria of the 6^th edition of the American Joint Committee on Cancer (AJCC)], survival time, and radiation and chemotherapy status. Age was classified into three categories for the purpose of analysis: ≤55, 56–75, and ≥76 years.

Statistical analysis

The primary endpoint of this study was defined as OS. The relationships between variables were scrutinized either through Chi-squared testing or via the application of Mann-Whitney and Wilcoxon tests. The Kaplan-Meier method was utilized for the generation of the survival curve. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed through the use of Cox regression analysis. All statistical procedures were performed using the SPSS software, version 22.0 (SPSS Inc., Chicago, IL, USA). Statistical significance was determined by a P value less than 0.05.

Results

In this study, we analyzed data from SEER, encompassing a cohort of 5,398 patients diagnosed with AD having a tumor diameter between 1 and 29 mm (Figure 1). The patients, identified from 2004 to 2015, were categorized into two groups based on their treatment: one group underwent lobectomy with MLND, and the other underwent lobectomy only.

We implemented a stratified analysis based on tumor diameter. At the last follow-up in 2019, 1,693 deaths were reported. The median follow-up duration was 97 months (ranging from 0 to 167 months). Patient baseline characteristics, including demographic and clinical variables, are summarized in Table 1. We observed significant disparities between groups in terms of race, N stage, radiation treatment, and survival status. No significant differences were found regarding sex, age, tumor diameter, and chemotherapy regimen.

To ascertain the influence of surgical choices on patients’ N stage—a crucial prognostic determinant in lung cancer, we stratified patients based on tumor diameter (Table 2). Interestingly, we found no difference between groups.

We subsequently assessed patient survival across the different groups using the Kaplan-Meier survival analysis method, with results reported in Table 3. The survival curves were depicted in Figure 2. The median survival duration for patients with T1a lung AD who underwent lobectomy with MLND was markedly longer (143 months), compared to those who underwent lobectomy alone (79 months, P<0.001). For T1b and T1c lung AD, the survival benefits of lobectomy with MLND over lobectomy alone were 16 months (137 vs. 121 months, P<0.001) and 21 months (108 vs. 87 months, P<0.001), respectively. There were significant differences in survival between the two groups (P<0.001). After removing the positive lymph node patients, the same method was used again for analysis, and the trend was the same (Figure 3).

Figure 2 Kaplan-Meier survival curve in all AD patients with tumor diameter 1–9 mm (A), 10–19 mm (B), and 20–29 mm (C). AD, adenocarcinoma; CI, confidence interval; HR, hazard ratio; MLND, mediastinal lymph node dissection.

Figure 3 After excluding the positive lymph node patients, Kaplan-Meier survival curve in AD patients with tumor diameter 1–9 mm (A), 10–19 mm (B), and 20–29 mm (C). AD, adenocarcinoma; CI, confidence interval; HR, hazard ratio; MLND, mediastinal lymph node dissection.

In a multivariate analysis using a Cox proportional hazards model, we found that lobectomy with MLND emerged as an independent prognostic indicator for patients with T1 lung AD (HR =0.731; 95% CI: 0.639–0.837; P<0.001). This trend remained consistent when we analyzed lung cancer-specific survival (HR =0.690; 95% CI: 0.572–0.833; P<0.001) (Table 4). Other significant prognostic factors for OS included gender, age, N stage, and treatment modalities (radiation and chemotherapy) (Table 4).

Discussion

Since Ginsberg’s study established lobectomy and lymph node dissection as the standard surgical treatment for lung cancer at the Memorial Sloan-Kettering Cancer Center in the 1990s (9), the landscape of lung cancer treatment has significantly evolved (10). Today, CT screening advancements and shifting in lung cancer demographics, which are changing the disease’s spectrum, revealing an increase in ground-glass nodules lesions and a proportional increase in lung AD (10). This shift forces thoracic surgeons to reassess the benefits of lobectomy and MLND—a current debate point, especially for stage IA lung cancer.

Our study adds to this conversation by associating lobectomy and MLND with improved survival in patients with T1 stage lung AD. For smaller or subsolid lung cancers, alternative strategies like sublobar resection should be considered (11). Our research, however, focuses more on solid nodules, but due to limitations in the database, a small number of sub-solid and ground-glass nodules are mixed in, which requires readers to consider, these were different from the JCOG0802 study (11). Another study by Zhang et al. (12), published recently, focuses on MLND for ground glass opacity-dominant lung AD. The results showed that the group without lymph node dissection not only had no metastasis, but also had better postoperative recovery, significantly shortened surgery time and hospital stay, reduced bleeding, and significantly reduced complications.

While the relationship between tumor diameter, mediastinal lymph node metastasis, and postoperative complications has been studied (13,14), reports are inconsistent about whether MLND increases complications like recurrent laryngeal nerve injuries, lymphatic fistulas, increased blood loss, and extended hospital stays (15,16). Our study, though, zeroes in on patients’ long-term survival with or without MLND, an area we feel is insufficiently covered in current literature.

The advent of targeted therapy and immunotherapy has also dramatically transformed lung cancer treatment (17). These therapies can significantly prolong lung AD patients’ survival without surgical intervention, highlighting the necessity of longer-term follow-up to accurately evaluate MLND’s benefit. Many studies have gauged lymph node dissection’s impact on survival by comparing 3- or 5-year survival outcomes (18,19).

A retrospective study by Shen-Tu et al. (20), a meta-analysis by Pan et al. (21), and our current study support the survival benefits of MLND. Shen-Tu et al. (20) retrospectively studied 317 NSCLC patients and found that MLND was associated with longer survival time and lower mortality compared with the MLND group. The follow-up time was at least 10 years. However, their study included more patients with tumors with diameters of over 3 cm and no further stratification of pathological types, which will lead to confusion in the choice of surgical procedure. Pan et al. (21) studied 8,631 stage IA NSCLC patients who underwent lobectomy or lobectomy with MLND and concluded that there was a time trend in prognosis differences between the lobectomy group and lobectomy with MLND group for T1b and T1c stage NSCLC patients. And it can be inferred from their study that a longer follow-up period is beneficial to the accuracy of data results. However, their study did not consider the effect of postoperative N stage, perioperative chemotherapy or radiotherapy, shorter follow-up, and included data of squamous cell carcinoma. Our study, which contained AD only, includes a median follow-up of 97 months, providing a more realistic estimation of long-term outcomes.

There are significant differences in the N stage between the lobectomy alone group and the lobectomy with MLND group, and in theory, MLND will identify more N1–2 patients. In theory, MLND will identify more N1–2 patients who will get more effective treatment, while failure to perform MLND will lead to some N1–2 patients to be undetected, thus delaying treatment. Still, almost 84% of patients had negative lymph nodes, and operation choice did not affect the N stage of patients (Table 2). Then, we compared the survival difference with the Kaplan-Meier survival curve after removed the positive lymph node patients and found that the progress of MLND was better than lobectomy only for patients without postoperative lymph node metastasis (Figure 3).

Using the Cox regression model, we found that lobectomy + MLND was an independent prognostic factor for T1 lung AD patients (vs. lobectomy; HR =0.731; 95% CI: 0.639–0.837; P<0.001) (Table 3). When we analyze lung cancer-specific survival, the trend is consistent (vs. lobectomy; HR =0.690, 95% CI: 0.572–0.833, P<0.001). Other significant prognostic factors included gender, age, N stage, radiation, and chemotherapy.

However, there are limitations in this study. The first is the unknown treatment of mediastinal lymph node-positive patients after surgery or during their recovery state. Especially in recent years, with the rapid development of treatment ways of lung AD, which affect the survival of patients. Furthermore, there may be a small amount of data about mixed-density nodules and ground glass nodules in the filtered data due to database restrictions, which may have some impacts on the results. Third, the pathological subtypes and risk factors of lung AD were not further classified, and we couldn’t get preoperative staging data. Fourth, some data were relatively small. Just as illustrated by Figure 2A and Figure 3A, compared with lobectomy only, lobectomy + MLND brought survival benefits to patients with T1 stage lung AD, no matter what their diameter. However, due to the small number of cases in the group of lobectomy alone with a tumor diameter of 1–9 mm, there was a larger deviation in the survival curve, which, although not affecting survival trends, affected our judgment of their prognosis. Fifth, it is unknown regarding why the decision was made not to perform MLND in some of these cases. It is, however, possible that this decision might have been based on poor performance status or other comorbidities, where the surgeon felt that limiting anesthesia time, etc., would be preferable. Poor performance and comorbidities might, however, impact OS. Finally, no data were available about the disease progression features in both groups. Through literature, we learned that factors related to recurrence and metastasis include old age, high carcinoembryonic antigen (CEA), smoking history, intracavitary dissemination, pleural invasion, intravascular invasion, the number of lymph node metastases, and positron emission tomography-computed tomography (PET-CT)’s maximum standardized uptake value (SUVmax) (22-24).

Despite these limitations, we observed a significant survival advantage in lobectomy combined with MLND compared to lobectomy alone for T1 stage lung AD patients, regardless of the AD size.

Conclusions

In conclusion, for patients with stage T1 lung AD, our study suggests that the OS of lobectomy combined with MLND is superior to that of patients who undergo lobectomy alone. Given these findings, we recommend MLND for stage T1 lung AD patients. However, a prospective randomized controlled study with modern staging and invasive staging could provide more comprehensive guidance for treatment in the future.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1743/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1743/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1743/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 and its subsequent amendments.

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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