Clinical characteristics of post-operative N2 nodal upstaging in non-small cell lung cancer: a retrospective cohort study

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases (1). Accurate mediastinal lymph node staging is the cornerstone of the tumor-node-metastasis (TNM) classification system, which guides therapeutic decisions and provides prognostic information (2). Mediastinal lymph node involvement plays a pivotal role in determining whether surgical resection is a viable treatment option for NSCLC. Various diagnostic modalities, including computed tomography (CT) and positron emission tomography (PET), and invasive techniques such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), are employed for mediastinal staging (3). Among these staging modalities, EBUS-TBNA is recognized in clinical guidelines as the standard of care, providing a minimally invasive and highly sensitive method for sampling intrathoracic lymph nodes (4).

Despite advancements in diagnostic imaging and staging techniques, discrepancies between preoperative clinical and postoperative pathological staging persist in NSCLC. Nodal upstaging, defined as the unexpected pathological detection of metastasis in N2 lymph nodes in patients previously staged as clinical N0 or N1, has been reported in approximately 4.8–24.6% of cases (5-7). This presents significant challenges for preoperative staging, particularly with EBUS-TBNA, which is highly operator-dependent and has a limited ability to detect small and inaccessible lymph nodes.

Previous studies have primarily focused on comparing nodal upstaging rates across different surgical approaches, such as open thoracotomy, video-assisted thoracoscopic surgery (VATS), and robot-assisted thoracic surgery (RATS) (8-12). Hennon et al. analyzed data from the National Cancer Database and found that open thoracotomy had a higher nodal upstaging rate (12.6%) than VATS (11.7%) and RATS (11.2%) (13). However, these studies did not isolate the impact of nodal upstaging on survival outcomes within a single surgical modality, making it challenging to discern whether differences in upstaging rates were attributable to the surgical approach itself or other confounding factors. The impact of nodal upstaging as an independent prognostic factor, separate from the influence of surgical technique, remains unclear. To address this gap, our study aimed to evaluate the clinical and pathological characteristics of nodal upstaging and their impact on long-term survival outcomes, including 5-year overall survival and PFS, in patients who underwent preoperative mediastinal staging with EBUS-TBNA followed by VATS or open thoracotomy. Only patients who met the established criteria for complete mediastinal lymph node dissection (MLND) were included, ensuring standardized evaluation of nodal upstaging across surgical modalities. We hypothesize that patients with postoperative N2 nodal upstaging will not exhibit significantly worse 5-year overall survival but may demonstrate differences in PFS compared to those with unchanged N2 staging. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-531/rc).

Methods

Study design and population

This retrospective study was conducted at a tertiary care academic hospital in South Korea between 2009 and 2019. Patients were identified through a review of hospital electronic medical records and institutional cancer databases. Patients diagnosed with NSCLC and confirmed to have postoperative pathologic N2-positive lymph nodes were included. A formal sample size calculation was not performed due to the retrospective nature of the study. The study included all eligible patients who met the inclusion criteria between 2009 and 2019. A total of 177 patients were enrolled, while those who did not undergo EBUS-TBNA experienced nodal downstaging or had an Eastern Cooperative Oncology Group (ECOG) performance status of 4 (bedridden) were excluded. The follow-up period ended five years after admission or at the time of death, whichever occurred first.

Patients were classified into two groups: the upstaged group, defined as those with unexpected pathological metastasis in the mediastinal lymph nodes (pN2) after being clinically staged as cN0 or cN1 preoperatively; and the unchanged group, whose pre- and postoperative staging remained consistent with N2 as confirmed by EBUS-TBNA. The proportion of upstaging was calculated both within the pN2 cohort and relative to the total study population, excluding those with known preoperative N2 disease. A study flow diagram (Figure 1) outlines patient selection and classification.

Figure 1 Patient inclusion flowchart outlining the selection criteria and classification of study groups. cN, clinical N; EBUS-TBNA, endobronchial ultrasound-transbronchial needle aspiration; N, node; pN, pathological N; SCLC, small cell lung cancer; SNUBH, Seoul National University Bundang Hospital.

Variables and outcomes

We collected the following data at the time of admission and postoperative period: Patient-related variables included sex, patient age, ECOG performance status, smoking status, tuberculosis (Tbc) and pulmonary function test (PFT) results. Tumor-related variables comprised histological subtype, clinical and pathologic stage, the number of pathological N2 lymph nodes, N2 involvement pattern, and the anatomical location of the primary tumor. Treatment-related variables included the use of neoadjuvant, adjuvant chemotherapy (Ctx) and radiation therapy (Rtx).

The primary outcomes were 5-year overall survival and PFS. These outcomes were compared between the two groups to evaluate the impact of nodal upstaging on long-term survival. The clinical, radiological, and pathological characteristics of the two groups were retrospectively reviewed.

Preoperative staging

Preoperative staging was performed using a combination of CT, PET-CT, and EBUS-TBNA. Lymph nodes with a short-axis diameter greater than 1 cm on CT and/or a maximum standardized uptake value (SUV) greater than 2.5 on PET-CT were considered suspicious for metastasis (3). CT images were obtained by using a 16-row multidetector CT scanner (Mx8000 IDT; Philips Healthcare, Andover, MA, USA), 64-row multidetector CT scanner [Brilliance 64 and IQon Spectral CT by Philips Healthcare; SOMATOM Definition Edge by Siemens Healthineers (Erlangen, Germany)], or 256-row multidetector CT scanner (iCT 256; Philips Healthcare). Images were reconstructed using a slice thickness of 1 mm with an increment of 1 mm. All PET-CT examinations were performed using the same scanner (Biograph mCT, Siemens Healthcare, Erlangen, Germany) equipped with a lutetium oxyorthosilicate (LSO) scintillator. Patients fasted for at least 6 hours before imaging, and blood glucose levels were confirmed to be <140 mg/dL prior to ¹⁸F-fluorodeoxyglucose (FDG) administration. The injected ¹⁸F-FDG dose was 5.18 MBq/kg of body weight. PET images were acquired in three-dimensional (3D) mode and reconstructed using the ordered subset expectation maximization (OSEM) algorithm. Real-time EBUS-TBNA was performed with the patient under moderate sedation using intravenous midazolam and fentanyl. Systematic inspection and sampling of the mediastinal, hilar, and interlobar lymph nodes were conducted according to the International Association for the Study of Lung Cancer (IASLC) lymph node map, covering nodal stations such as 2R, 4R, 10R, 11L, 10L, 4L, and 2L (14). Nodal sampling was prioritized for nodes with a short-axis diameter ≥5 mm on sonography, following a sequential approach from N3 to N2, and then to N1. Core tissue sampling was performed in at least two passes whenever feasible (15). Rapid on-site evaluation was not conducted during the procedure.

Surgical approach

All patients underwent MLND during resection surgery, which was performed using either VATS or open thoracotomy. While VATS was the predominant approach, a subset of our patients underwent open thoracotomy following VATS. To ensure consistent and thorough lymph node dissection, only patients meeting the established criteria for complete MLND were included in this study. This approach necessitated the dissection of lymph nodes from at least three mediastinal stations, with a minimum of six lymph nodes removed, as recommended by the European Society of Thoracic Surgeons (ESTS) guidelines. The final pathology report established the pathological N stage, and nodal zones and stations were defined according to the IASLC lymph node map (16). Pathological diagnoses were based on the 2011 International Association for the Study of the Liver classification system.

Ethical considerations

This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (SNUBH IRB No. B-1912-580-101). Due to the retrospective study design, the requirement for informed consent was waived. This study was conducted in accordance with the principles of the Declaration of Helsinki and its subsequent amendments.

Statistical analysis

Baseline characteristics are presented as mean [standard deviation (SD)] or median (interquartile range) for continuous variables and as numbers (percentages) for categorical variables. Comparisons between the upstaged and unchanged groups were performed using χ² test for categorical variables, Wilcoxon rank-sum test for nonparametric continuous variables, and t-test for parametric continuous variables.

Survival outcomes were analyzed using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. To evaluate the independent association of nodal upstaging with 5-year overall survival and PFS, we performed Cox proportional hazards regression models, adjusting for all relevant clinical and pathological variables. Subgroup analyses were performed to evaluate whether the association between nodal upstaging and survival outcomes differed according to the presence of lymph nodes that were inaccessible by EBUS-TBNA. Patients who were lost to follow-up were censored at the time of last known contact in all survival analyses. Given the retrospective nature of the study and the minimal amount of missing data, no imputations were performed for missing values. All statistical analyses were conducted using R statistical software version 4.2.3 (R Project for Statistical Computing), and a two-sided P value of <0.05 was considered statistically significant.

Results

Patient characteristics

A total of 1,255 patients diagnosed with lung cancer between 2009 and 2019 who underwent lung resection with EBUS-TBNA were initially identified. After excluding 10 cases of small cell lung cancer (SCLC), 1,245 patients were considered for the study. Among these, 853 patients were classified as postoperative N0 stage, 191 as N1 stage, and 177 as N2 stage (Figure 1). Among 177 patients with postoperative N2-positive nodes, 53.1% (n=94) experienced nodal upstaging, whereas 46.9% (n=83) retained their initial nodal staging. When considered relative to the total eligible population without known preoperative N2 disease (n=1,162), this represents 8.1% of patients. The baseline clinical characteristics are summarized in Table 1, with no significant differences between the upstaged and unchanged groups, except for age. Patients in the unchanged group were younger than those in the upstaged group (61.5 vs. 65.7 years; P=0.005).

Histological cell type and surgical extent were also comparable between the groups. Most patients were diagnosed with adenocarcinoma (69.9% vs. 70.2%; P=0.40) and lobectomy was the predominant type of lung resection performed (89.2% vs. 95.7%; P=0.18). Both groups showed similar clinical staging and primary tumor distribution across the lung lobes.

Patients in the upstaged group had fewer pathologic N2 nodes identified in the postoperative final pathology report compared to those in the unchanged group (1.87±1.71 vs. 3.29±2.99, P<0.001).

Features of upstaged mediastinal lymph nodes

Evaluation of the EBUS-TBNA findings, focusing on the characteristics of pathologic N2 lymph nodes, revealed no significant differences in anthracosis pigmentation, calcification, or central hilar structures between the upstaged and unchanged groups (Table S1). Table 2 summarizes the specific features of the N2 nodes responsible for upstaging.

Subcarinal (38.3%) and aortic lymph nodes (21.3%) were the most common sites of nodal upstaging. Among the lymph nodes accessible by EBUS, 40% of upstaged nodes measured <5 mm in size, highlighting the challenge of detecting smaller nodes during preoperative mediastinal staging.

Survival and PFS

Survival outcomes were evaluated over a 5-year follow-up period, ending at either the time of death or 5 years post-admission, whichever came first. Throughout the follow-up period, survival outcomes were monitored and compared between the upstaged and unchanged groups. Unadjusted Cox regression analysis showed no significant difference in 5-year overall survival between the upstaged and unchanged groups (HR 0.93, 95% CI: 0.60–1.45, P=0.76; Table 3). Similarly, Kaplan-Meier stratified analysis revealed no significant difference in 5-year overall survival between the two groups (Figure 2A). However, after excluding cases with lymph nodes inaccessible by EBUS-TBNA, a higher overall survival rate was observed in the upstaged group than in the unchanged group (Figure 2B). Despite this trend, the subgroup analysis based on the presence of inaccessible lymph nodes showed no significant differences [hazard ratio (HR) 0.60, 95% confidence interval (CI): 0.36–1.01]. Progression-free survival (PFS) was significantly higher in the upstaged group (Figure 3). To account for potential confounding factors, a multivariate Cox regression analysis was conducted. The model adjusted for age, sex, smoking status, tumor histology, type of operation, and pathologic staging—variables selected based on prior evidence of their prognostic relevance in lung cancer outcomes. Multivariate Cox regression analysis further identified upstaging as an independent factor associated with improved PFS (HR 0.555, 95% CI, 0.336–0.915; P=0.02; Table 3).

Figure 2 Comparison of 5-year overall survival between upstaged and unchanged patients, with and without exclusion of cases with inaccessible lymph nodes. (A) Kaplan-Meier survival curves comparing 5-year overall survival between upstaged and unchanged patients. (B) Kaplan-Meier survival estimates for 5-year overall survival after excluding cases with inaccessible lymph nodes on endobronchial ultrasound-transbronchial needle aspiration.

Figure 3 Kaplan-Meier curve depicting progression-free survival in relation to disease relapse.

Discussion

This study aimed to determine whether postoperative N2 nodal upstaging in NSCLC patients impacts long-term survival outcomes. Our study evaluated the clinical and pathological characteristics of nodal upstaging and their impact on long-term outcomes in patients with surgically proven N2 NSCLC who underwent EBUS-TBNA staging and resection via VATS or open thoracotomy. Among 177 patients, the N2 nodal upstaging rate was 53.1%, with the subcarinal and aortic nodes being the most common stations contributing to upstaging, often involving lymph nodes <5 mm in size. Five-year overall survival did not differ significantly between the upstaged and unchanged groups; however, the PFS was significantly higher in the upstaged group. Multivariate analysis identified nodal upstaging as an independent factor associated with improved PFS, suggesting that nodal upstaging does not necessarily lead to worse long-term outcomes. Moreover, excluding upstaging caused by inaccessible nodes further improved survival outcomes.

In our cohort, the postoperative N2 nodal upstaging rate was 53.1% (n=94), while the rate relative to the total study population excluding known N2 disease was 8.1%. This pN2-based proportion is higher than the 4.8–24.6% reported in previous studies (5-7), likely because our calculation was restricted to patients with pN2 disease and included nodal stations inaccessible to EBUS-TBNA, such as stations 3, 5, and 6. The systematic use of MLND during VATS, following the ESTS guidelines, enabled thorough pathological evaluation of the resected specimens and likely enhanced the detection of occult metastases. This finding is consistent with those of Moon et al., who reported a similar upstaging rate of 52.3% in patients with NSCLC, highlighting the prevalence of occult nodal metastases despite preoperative staging (17).

Several studies (5,7,18-21) have identified risk factors for nodal upstaging in patients with NSCLC, which can be broadly categorized into patient-related factors, such as history of diabetes mellitus, rheumatoid arthritis, and other comorbidities, and tumor characteristics, including tumor localization, T stage, SUVmax, and histology. Bordas-Martínez et al. demonstrated that incorporating patient age, lymph node short-axis diameter, SUVmax, and anatomical location into a probability-mapping model significantly improved pre-sampling stratification (22). Our findings suggest that nodal upstaging primarily occurred in small mediastinal nodes and at specific nodal stations. Subcarinal lymph nodes (station 7) accounted for the highest proportion of upstaged nodes (38.3%). The anatomical complexity of the subcarinal region and the potential for small or micrometastases can lead to false-negative results during EBUS-TBNA staging. Prior studies have indicated that despite negative preoperative invasive mediastinal staging, subcarinal pN2 disease can still be present, underscoring the importance of routine lymph node dissection or sampling of station 7 during surgery to minimize understaging (23).

Furthermore, aortic lymph nodes (stations 5 and 6), including the subaortic (aortopulmonary window) and para-aortic (ascending aortic or phrenic) nodes, accounted for 21.3% of upstaged cases in our study. These nodal stations are often inaccessible via EBUS-TBNA because of their anatomical position, which may contribute to false-negative preoperative staging results. Although classified as an N2 disease, aortic lymph node involvement has been associated with a better prognosis than involvement of other N2 nodal stations (24). Research suggests that patients with isolated metastases to these nodes may have survival outcomes similar to those of patients with N1 disease. This has led to discussions on reclassifying the prognostic significance of metastasis in these regions to better reflect their clinical behavior. Rami-Porta et al. address the evolving TNM staging system, including updated N group classifications and their implications-highly relevant to nodal staging and prognostic stratification (25). The relatively favorable outcomes observed in aortic lymph node involvement may be attributed to their unique lymphatic drainage pathways and potentially lower tumor burden than those of other mediastinal stations.

In our study, a significant proportion of upstaged patients (42.6%) had positive lymph nodes of <5 mm, highlighting the role of small lymph nodes in nodal upstaging. Although these small nodes could not be directly categorized as micrometastases, they plausibly contributed to the upstaging observed in these cases. Micrometastases are clusters of malignant cells measuring between 0.2 and 2 mm in their greatest diameter. These small metastatic deposits may be missed during EBUS-TBNA due to technical limitations, especially in nodes with minimal tumor involvement. Malignant cells primarily spread via the lymphatic system, and the formation of micrometastases often represents an early stage of tumor dissemination preceding the development of bulky lymph node metastases (26).

The prognostic significance of lymph node micrometastases in NSCLC is generally unfavorable compared to that in cases without micrometastases, as micrometastases indicate early tumor dissemination (27). However, when promptly treated with adjuvant chemotherapy, as in our study, patients with micrometastases may exhibit better outcomes than those with macrometastases at the same stage. In our study, all patients with upstaging received adjuvant chemotherapy similar to the treatment regimens of patients without upstaging (Tables S2,S3). This consistent administration of adjuvant therapy may have mitigated the negative impact of micrometastases, contributing to the improved PFS observed in the upstaged group. Additionally, the relatively lower tumor burden in upstaged patients could have resulted in a less aggressive disease course, further enhancing survival outcomes. These results align with the findings of Deng et al., who reported that while lymph node micrometastases are associated with disease recurrence and poor survival in some cases, their impact may vary depending on tumor biology and adequacy of treatment strategies (28).

Our findings highlight the important clinical implications of using EBUS-TBNA in nodal staging for patients with NSCLC. Although micrometastases and inaccessible lymph nodes may sometimes be missed during preoperative evaluation, these limitations do not necessarily compromise long-term outcomes, as demonstrated by the favorable PFS in the upstaged patients in our study. These results suggest that even if micrometastases or small inaccessible nodes are not identified preoperatively, thorough pathological assessment and appropriate postoperative management can mitigate their impact on survival. However, particular attention should be paid to subcarinal lymph nodes, which accounted for the highest proportion of upstaged cases in our study. Careful inspection and sampling of this region during EBUS-TBNA are essential to reduce the likelihood of upstaging.

Our study had several limitations. First, this was a retrospective review conducted at a single institution, which introduced inherent biases associated with retrospective analyses and registry-level data. Second, the outcome of nodal upstaging in our study was confined to postoperative N2 nodes, and the sample size, although significant, remained limited, which could restrict the generalizability of our findings, particularly when considering other N stages or lymph node stations beyond those studied here. Further research is needed to evaluate nodal upstaging across different NSCLC stages. Finally, while multivariate regression analysis was performed to adjust for key variables, such as sex and age, unmeasured confounders, including comorbidities or treatment-specific factors, may still have influenced overall survival.

Despite these limitations, the study’s strengths include a well-characterized patient cohort, adherence to standardized MLND criteria, and robust statistical adjustment for confounders. Additionally, the inclusion of detailed nodal station analysis provides valuable insights into the prognostic heterogeneity of N2 disease.

Conclusions

Among patients with N2 NSCLC, N2 nodal upstaging, often due to small or inaccessible lymph nodes, did not significantly worsen 5-year overall survival and PFS. When upstaging caused by inaccessible nodes was excluded, the survival outcomes appeared to be even more favorable. These findings reinforce the value of EBUS-TBNA as an effective tool for preoperative mediastinal staging of patients with NSCLC. These findings also suggest that nodal upstaging should not be solely used as a negative prognostic indicator when determining treatment plans for NSCLC patients.

Acknowledgments

We would like to thank all the thoracic surgeons and surgical staff at Seoul National University Bundang Hospital for their expertise and dedication in performing the surgeries included in this study. We also thank Professor Junghoon Kim, Department of Radiology, and Professor Ho-Young Lee, Department of Nuclear Medicine, for their valuable assistance and expertise in image interpretation.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-531/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-531/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-531/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-531/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 need for informed consent was waived due to the retrospective study design. This study was approved by the Institutional Review Board of Seoul National University Bundang Hospital (SNUBH IRB No. B-1912-580-101). This study complied with the principles of 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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