High PD-L1 expression correlates with lymph node metastasis in patients who have undergone radical surgery for primary pulmonary adenocarcinoma

Introduction

Currently, immune checkpoint inhibitors (ICIs) are useful in certain lung cancer patients, and programmed cell death ligand 1 (PD-L1) expression is an important indicator in the choice of treatment. In addition, ICIs have become a mainstay in the treatment of lung cancer surgery, with reports of preoperative or postoperative administration of ICIs resulting in pathological complete response and improved prognosis (1,2). Previous studies have shown that tumor-infiltrating lymphocytes in the tumor microenvironment produce interferon-γ, which upregulates PD-L1 expression (3), and that oncogenic signals resulting from mutations or deletions of tumor suppressor genes enhance PD-L1 expression (4). However, the detailed mechanisms of PD-L1 expression remain unclear.

Over time, clarification of the relationship between PD-L1 expression and various factors in lung cancers has shown that high expression of PD-L1 is associated with a poorer prognosis than low PD-L1 expression (5,6). Zhang et al. (5) also showed that PD-L1 expression was increased in males, smokers, patients with squamous cell carcinoma, a higher histological grade, larger tumor size, positive lymph node metastasis, and higher tumor-node-metastasis (TNM) stage. Miyazawa et al. (7) reported that the PD-L1 positivity rate was higher in men, smokers, pathological stage IIIA or higher cases, venous invasion, and lymphatic invasion, and that PD-L1-positive tumors were more frequent in acinar-predominant invasive adenocarcinoma and solid-predominant invasive adenocarcinoma than other adenocarcinoma subtypes.

On the other hand, there are also reports of the absence of a statistically significant association between PD-L1 expression and age, sex, histology, and smoking status in patients with predominantly stage IV non-small cell lung cancer (NSCLC), and that no statistically significant association was observed between PD-L1 expression and survival (8). Hence, although PD-L1 expression might be related to various factors and prognosis, there is no clear consensus regarding this relation.

Therefore, we performed a retrospective study on PD-L1 expression and its related factors to accumulate knowledge on PD-L1 and its correlation with prognosis. The clinical significance of this study lies in its exclusive analysis of patients with primary lung adenocarcinoma who underwent radical surgery, including those with early stage. We present this article in accordance with the REMARK reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1118/rc).

Methods

Materials and methods

This study included 673 patients with non-small cell non-squamous lung cancer who underwent radical surgery (lobectomy, bilobectomy, or pneumonectomy) between January 2017 and December 2022 at the Department of Thoracic Surgery, Iwate Medical University. Among them, histological types other than adenocarcinoma, cases with unknown PD-L1 tumor proportion score (TPS), simultaneous multiple lung cancers, advanced cancer of pathological stage IV or higher, in situ adenocarcinoma, and cases with insufficient data were excluded, and 453 patients were included. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Iwate Medical University Institutional Review Board (permit number MH2023-052) and individual consent for this retrospective analysis was waived. Patients’ TNM stage was determined based on the international staging criteria published by the International Association for the Study of Lung Cancer (IASLC) in 2017. Specimens of resected lung cancer tissue were fixed in 10% formalin, embedded in paraffin, and cut into 4–5 µm-thick sections. The sections were then immunostained using 22C3 assay (PD-L1 IHC 22C3 pharmDx, DAKO, Santa Clara, CA, USA) to determine the degree of PD-L1 expression by the tumors.

Based on the results of immunostaining, patients were divided into three groups: the high group (PD-L1 TPS ≥50%), the low group (PD-L1 TPS 1–49%), and the negative group (PD-L1 TPS <1%) (Figure 1). We compared various factors among the three groups, and then compared the high group (PD-L1 TPS ≥50%) with the combined low/negative group (PD-L1 TPS <50%). We selected the PD-L1 cutoff value based on its clinical relevance in determining eligibility for ICIs, as well as its reported association with patient prognosis (9,10).

Figure 1 Flowchart of patient inclusion in this study. PD-L1, programmed death-ligand 1; TPS, tumor proportion score.

Next, Kaplan-Meier curves were used to analyze 3-year relapse-free survival (RFS) and 3-year overall survival (OS) rates in 140 patients in the two groups who were available for postoperative follow-up. The remaining 313 patients were excluded due to referral to other hospitals, incomplete clinical data, or loss to follow-up. Three-year RFS was defined as the period from the date of surgery to the date of diagnosis of relapse, and 3-year OS was defined as the period from the date of surgery to the date of death due to any cause. To identify factors independently associated with high PD-L1 expression, we performed a multivariate logistic regression analysis using lymph node metastasis, maximum standard uptake value (SUV-max), carcinoembryonic antigen (CEA), EGFR mutation, gender, and Brinkman Index as covariates. Furthermore, to evaluate independent prognostic factors for 3-year RFS, a multivariate analysis using the Cox proportional hazards model was conducted. Based on previous literature and clinical relevance, the presence or absence of adjuvant chemotherapy, lymph node metastasis, and PD-L1 expression were selected as covariates for the multivariate analysis of 3-year RFS.

Most patients underwent blood tests, chest X-rays and contrast-enhanced computed tomography (CT) and an additional contrast-enhanced magnetic resonance imaging (MRI) scan of the head every 6 months. We made an overall determination of whether the patient had relapsed based on the results of these tests.

General surgical procedures

Video-assisted thoracic surgery (VATS) lobectomy was performed in all cases with the patient in the lateral decubitus position, under general anesthesia and with the use of a double-lumen endotracheal tube for single-lung ventilation. The affected lung was deflated as soon as the pleural space was opened, with the deflation being maintained throughout most of the operative period. After first creating a 3-cm incision in the sixth intercostal space at the midaxillary line, 5 mm of a flexible thoracoscope (Endoeye Flex, LTF-S190-5; Olympus, Tokyo, Japan) was inserted. General exploratory thoracoscopy was performed, with an additional intercostal incision made at the anterior axillary line at the level of the third intercostal space and the posterior auscultation triangle at the sixth intercostal space. VATS lobectomy was performed via a 3-port method under monitor vision alone. Although the energy devices primarily used included LigaSure^TM Maryland (Medtronic, Minneapolis, MN, USA) and an automatic linear stapler that utilized the Endo GIA Reload with Tri-Staple Technology^TM (Medtronic), other energy devices, and vascular and bronchial staplers were allowed at the surgeon’s discretion. Large vessels and bronchi were divided using a stapler. Relatively small-caliber vessels were divided using an energy device or scissors after the ligation. The specimen was placed in an endoscopic tissue collection bag and retrieved through the sixth intercostal access port after completing the pulmonary resection. If necessary, the access incision was lengthened depending on the size of the specimen. A systematic complete hilar and mediastinal lymph node dissection (ND2a-2) was performed in all cases. Following completion of the procedure, a sealing test was performed prior to closing the wound. The sealing test was confirmed by documentation of reinflation of the lung on the affected side, with a chest tube (Blake^TM, 19 Fr; Ethicon, Somerville, NJ, USA) placed from the fifth intercostal trocar to the apex.

Statistical analysis

JMP Pro version 17.00 statistical software (SAS Institute, Cary, NC, USA) was used for all statistical analyses. Groups were compared using Pearson’s Chi-squared test or Wilcoxon’s rank sum test. Survival rates were estimated using the Kaplan-Meier method, and statistical analysis was performed using the log rank test for equality of survival curves. Multivariate predictors were evaluated using logistic regression analysis, and the odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. On logistic regression analysis, the conventional receiver operating characteristic (ROC) curves were used to determine the cut-off value of each variable with maximal sensitivity and specificity in this study population. For RFS and OS, multivariate analyses were performed using the Cox proportional hazards regression model, and hazard ratios (HRs) with 95% CIs were calculated. Differences between groups were considered significant for values of P<0.05. In this study, continuous data were expressed as the median (range), and categorical data were expressed as counts (proportions).

Results

Based on PD-L1 expression of the entire population of 453 cases, 57 cases (12.6%) were identified as the high group, 133 cases (29.4%) as the low group, and the remaining 263 cases (58.0%) as the negative group. As a result, the combined low/negative group consisted of 396 cases (87.4%).

Analysis of the three groups indicated statistically significant differences in the following characteristics: gender (P=0.01), Brinkman Index (P=0.01), CEA (P=0.005), SUV-max (P<0.001), visceral pleural invasion (pl) (P<0.001), venous invasion (P<0.001), and lymph node metastasis (P<0.001) (Table 1). Comparison between the high group and the low/negative group revealed statistically significant differences in gender (P=0.02), Brinkman Index (P=0.005), CEA (P=0.007), SUV-max (P<0.001), visceral pleural invasion (pl) (P<0.001), venous invasion (P<0.001), lymph node metastasis (P<0.001), and EGFR mutation (P=0.03) between the two groups (Table 2). In addition, the use of postoperative adjuvant chemotherapy according to pathological stage is summarized (Tables 1,2). All patients with stage I disease who received adjuvant therapy were with tegafur-uracil (UFT). In contrast, platinum-based chemotherapy was administered predominantly to patients with stage II or higher disease. However, UFT was also used in a small number of cases: two patients with stage IIA, two with stage IIB, and one with stage IIIA. The others included patients who underwent chemoradiotherapy or participated in clinical trials. In stage IIB, one patient received osimertinib, a tyrosine kinase inhibitor (TKI), and another received platinum-based chemotherapy and ICIs. In addition, details regarding the node (N) status related to Tables 1,2 are provided in Figures S1.

Three-year RFS and 3-year OS were analyzed in the 140 patients who could be followed. The median observation period for 3-year RFS was 21.0 months in the high group, and 36.0 months in both the low and negative groups. Similarly, the median observation period for 3-year OS was 21.0 months in the high group, and 36.0 months in the low and negative groups. In the three-group comparison for 3-year RFS, the number of recurrence events and censored cases were as follows: 4 events and 3 censored cases in the high group, 8 events and 17 censored cases in the low group, and 8 events and 43 censored cases in the negative group. Three-year RFS rates were 42.9% in the high group, 68.0% in the low group, and 84.3% in the negative group. A statistically significant difference was observed among the three groups (log-rank test, P=0.007) (Figure 2). For 3-year OS, the number of deaths and censored cases were 1 and 16 in the high group, 2 and 36 in the low group, and 3 and 82 in the negative group, respectively. Three-year OS rates were 90.0% in the high group, 92.7% in the low group, and 94.9% in the negative group. No significant difference in 3-year OS was observed among the three groups (log-rank test, P=0.64) (Figure 3). Next, we conducted a survival analysis comparing the high group and the low/negative group. Three-year RFS rate in the low/negative expression group was 79.0%, with 16 recurrence events and 60 censored cases. A significant difference was observed between the two groups (log-rank test, P=0.006) (Figure 4). Similarly, 3-year OS rate in the low/negative group was 94.2%, with 5 deaths and 118 censored cases. No statistically significant difference in 3-year OS was found between the two groups (log-rank test, P=0.41) (Figure 5). For reference, the analysis of 3-year RFS according to stage is also presented in the Figures S2-S4.

Figure 2 Comparison of 3-year recurrence-free survival rates between the three PD-L1 groups: high, low, and negative groups. PD-L1, programmed death-ligand 1.

Figure 3 Comparison of 3-year overall survival between the three PD-L1 groups: high, low, and negative groups. PD-L1, programmed death-ligand 1.

Figure 4 Comparison of 3-year recurrence-free survival between the high and low/negative PD-L1 groups. PD-L1, programmed death-ligand 1.

Figure 5 Comparison of 3-year overall survival between the high and low/negative PD-L1 groups. PD-L1, programmed death-ligand 1.

To clarify the factors independently associated with high PD-L1 expression, we performed a multivariate logistic regression analysis. The results demonstrated that both high SUV-max (OR: 6.08; 95% CI: 2.89–12.8; P<0.001) and the presence of lymph node metastasis (OR: 2.14; 95% CI: 1.10–4.16; P=0.02) were significantly correlated with high PD-L1 expression (Table 3). At this time, ROC curves were used to determine the cutoff values that yielded the highest combined sensitivity and specificity. The optimal cutoff values determined by ROC curves analysis were 3.55 for SUV-max [sensitivity: 0.82, specificity: 0.64, area under the curve (AUC): 0.79], 3.9 for CEA (sensitivity: 0.47, specificity: 0.71, AUC: 0.61), and 500 for the Brinkman Index (sensitivity: 0.54, specificity: 0.69, AUC: 0.61).

In addition, to evaluate independent prognostic factors for RFS, a multivariate analysis using the Cox proportional hazards model was performed. Based on findings from this study and previous literature, the covariates selected for multivariate analysis included PD-L1 TPS, presence of lymph node metastasis, administration of adjuvant chemotherapy, and SUV-max. The results demonstrated that lymph node metastasis (HR: 8.61, 95% CI: 2.48–29.86, P<0.001) and higher SUV-max (HR: 4.46, 95% CI: 1.33–14.93, P=0.01) were significantly associated with shorter RFS. In contrast, neither PD-L1 TPS (HR: 1.80, 95% CI: 0.40–8.04, P=0.44) nor the administration of adjuvant chemotherapy (HR: 2.18, 95% CI: 0.47–10.21, P=0.32) were identified as statistically significant predictors of RFS (Table 4).

Discussion

Evaluation of PD-L1 expression is important for selecting ICIs in the treatment of NSCLC, as well as for predicting prognosis (1,2,11-14). Although several reports have evaluated PD-L1 expression and its correlation with prognosis (5-7,15), detailed mechanisms of the correlation remain unclear. The main objective of the present study was to elucidate the clinical significance of PD-L1 expression in primary lung adenocarcinoma cases. This study demonstrated that 3-year RFS rates in patients with pulmonary adenocarcinoma expressing higher levels of PD-L1 were significantly worse than the corresponding rates among patients expressing lower PD-L1 levels. In multivariate analysis, lymph node metastasis and SUV-max were independent factors related to high PD-L1 expression by the tumor in primary pulmonary adenocarcinoma patients. Furthermore, multivariate analysis using the Cox proportional hazards model revealed that lymph node metastasis and SUV-max were independent prognostic factors for RFS, regardless of PD-L1 expression levels. This result might suggest that high PD-L1 expression in patients who have undergone radical surgery correlates with lymph node metastasis and SUV-max in primary pulmonary adenocarcinoma patients, and might indicate the risk for recurrence in the postoperative period.

In this study, since PD-L1 levels were measured in resected specimens, i.e., the primary tumors, in all cases, there was no need to consider the possibility of PD-L1 mismatch between primary tumors and metastases (16). In addition, all patients in this study underwent ND2a-2 lobectomy, which allowed for more detailed pathological evaluation of the lymph nodes.

Our study showed a correlation between PD-L1 expression and gender, Brinkman Index, CEA, SUV-max, visceral pleural invasion, venous invasion, lymph node metastasis, and EGFR mutation, which is generally similar to the results of a previous study (5). In addition, some studies have reported that EGFR-negative patients have higher PD-L1 expression (5,15,17). Previous reports have shown that ICIs are less effective in EGFR-positive patients (18), and that TKI is less effective in high-PD-L1-expressing tumors (19), suggesting that the tumor microenvironment in EGFR-positive patients may influence PD-L1 expression (20,21).

It has been reported that high SUV-max is associated with PD-L1 expression in NSCLC (22). Our study similarly demonstrated that SUV-max is also an independent factor associated with high PD-L1 expression. In addition, the optimal cut-off value in our study was 3.55, but there is a wide range of reported results (9,22).

Regarding prognosis, some previous studies have reported that higher PD-L1 expression in lung cancer patients tends to be associated with worse prognosis (5-7), while others have reported that PD-L1 expression is not associated with prognosis (8,23,24). Recent study has indicated that patients with PD-L1-negative early lung cancer may exhibit a more favorable prognosis, even when treated with ICIs upon recurrence (25). Thus, although PD-L1 might be an important prognostic factor, there is no clear consensus as to its role as a prognostic marker. In our survival analysis, there was no statistically significant difference in 3-year OS in groups classified according to PD-L1 expression, although there was a significant difference in 3-year RFS. The reasons for the lack of statistically significant difference in OS include the fact that the follow-up period in this study was only three years, which was shorter than the usually assessed period of five years, the extremely small number of cases with high PD-L1 expression, and the large number of advanced cases in the high PD-L1 expression group in this study. Additionally, the long-term survival due to ICIs might have influenced the results. Therefore, the relationship between PD-L1 expression and prognosis needs to be carefully considered, and further case accumulation and accurate evaluation are required to validate our results.

In recent years, there has been remarkable progress in the perioperative treatment for lung cancer. There have been reports of good prognosis with postoperative chemotherapy using ICIs (11), and of not only good prognosis, but also pathological complete response with preoperative or perioperative chemotherapy (1,2). These findings highlight the growing importance of elucidating the clinical implications of PD-L1 expression levels. Further accumulation of real-world data, as demonstrated in the present study, will contribute to a deeper understanding of the biological and clinical significance of PD-L1 expression. As shown in Tables 1,2, the limited use of postoperative TKIs and ICIs in our study is likely attributable to the timing of their insurance approval, which occurred only toward the end of the case collection period.

Since the reports of the JCOG0802/WJOG4607L (26) and JCOG1211 studies (27), reduced lung resection has become an option in applicable cases, contributing to improving the quality of life of patients with early-stage lung cancer. On the other hand, it has been reported that higher rates of locoregional recurrence after segmentectomy still constitute a major clinical problem and have been reported in 10.5–20.7% of cases (26,28,29), and depending on the location of the tumor, upper segment tumors tend to be more prone to lymph node metastasis than basal segment tumors (30).

Needless to say, although preserving respiratory function is extremely important, based on the results of our study we suggest that the extent of resection and lymph node dissection should be carefully selected in patients with high PD-L1 expression or high tumor SUV-max before surgery.

This study has several limitations. First, this study is a retrospective analysis conducted at a single institution, and external validation using an independent cohort has not been performed. Furthermore, the relatively small number of OS events may have limited the statistical power of the analysis. This study may be subject to selection bias due to the exclusion of cases with missing PD-L1 expression data or multiple primary tumors, potentially resulting in an overrepresentation of patients with relatively favorable prognoses. Additionally, we were unable to adequately adjust for all confounding factors that may affect prognosis. In the survival analyses, cases with missing key variables such as RFS and OS were excluded, leading to a missing data rate of approximately 30.9%. Data on postoperative adjuvant chemotherapy was also incomplete, which could have influenced the prognostic outcomes. When evaluating PD-L1 expression, heterogeneity within tumors, differences in antibody clones, and variability in assessment methods across institutions complicate standardization. In this study, PD-L1 expression was assessed postoperatively; given potential discrepancies between preoperative and postoperative samples and the challenges of intraoperative evaluation, interpretation should be made with caution. In the future, prospective multicenter studies and long-term follow-up are needed to corroborate our results.

Conclusions

High PD-L1 expression correlates with lymph node metastasis and SUV-max in patients who underwent radical surgery for primary pulmonary adenocarcinoma. Lymph node metastasis and SUV-max were identified as a potential independent risk factor for postoperative recurrence and might be a risk factor for recurrence in the postoperative period.

Acknowledgments

The authors would like to thank the staff members of the Department of Thoracic Surgery at Iwate Medical University for their valuable support.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1118/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1118/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1118/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-2025-1118/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. The study was approved by the Iwate Medical University Institutional Review Board (permit number MH2023-052) and individual consent for this retrospective analysis was waived.

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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