Risk factors of up-Stage and lymph node metastasis for clinical stage IA3 non-small cell lung cancer

Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for more than 80% of all cases (1). The Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L phase III study demonstrated the benefits of segmentectomy versus lobectomy on the overall survival of patients with small-peripheral NSCLC (2). Since then, lobectomy or segmentectomy has been recommended as the standard surgical procedure for clinical stage (cStage) IA NSCLC patients with tumor diameter ≤20 mm in Japan.

Lobectomy is still recommended as the standard surgical procedure for cStage IA3 NSCLC according to the National Comprehensive Cancer Network guideline (3). However, segmentectomy has been found to be non-inferior to lobectomy in retrospective study (4). A trial to verify the utility of segmentectomy for ground glass-dominant invasive lung cancer with a tumor diameter of 2–3 cm is ongoing (5).

Tumor diameter on computed tomography (CT) and lymphatic invasion (Ly) have been reported to be risk factors for upstaging in early-stage NSCLC patients (6,7). Furthermore, risk factors for lymph node metastasis in cStage IA NSCLC patients were reported to include age, carcinoembryonic antigen (CEA), tumor size, consolidation to tumor ratio (CTR) on CT, and non-upper lobe location (8-11). The utility of the maximum standardized uptake value (SUV_max) on ¹⁸F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) to predict lymph node metastasis for early-stage NSCLC patients has also been reported (12,13). However, it is uncertain whether these factors are valid as adaptation criteria for sublobar resection in early-stage NSCLC patients.

In this study, we retrospectively evaluated risk factors that might predict up-Stage and lymph node metastasis in cStage IA3 NSCLC patients who underwent pulmonary resection. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1348/rc).

Methods

Patients

Among the 1,114 NSCLC patients who underwent pulmonary resection at Kanazawa Medical University between 2016 and 2021, 68 who received wedge resection were excluded. Finally, 410 patients with cStage IA disease including 108 with cStage IA3 were enrolled in this retrospective study (Figure 1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The institutional review committee of Kanazawa Medical University approved the study protocol (approval No. I392) and all patients provided written informed consent.

Figure 1 Patient flow diagram. cStage, clinical stage; NSCLC, non-small cell lung cancer; pStage, pathological stage.

Data including clinical factors such as sex, age, smoking history, CEA, prognostic nutrition index (PNI), neutrophil-to-lymphocyte ratio (NLR), cancer inflammation prognostic index (CIPI), SUV_max, tumor diameter on chest CT, CTR on CT, and lobe involvement were collected. Smoking history was assessed using the Brinkman index, which was calculated by multiplying the number of cigarettes smoked per day by the number of years the patients smoked (14). The PNI was calculated by combining serum albumin levels with the total peripheral lymphocyte count in peripheral blood. Previous studies reported that preoperative PNI is a prognostic factor for NSCLC patients (15,16). Although NLR is defined as the ratio of neutrophil-to-lymphocyte counts and is a parameter of systemic inflammation and stress in critically ill surgical and medical patients (17), it was also reported to be a prognostic factor for NSCLC patients who have undergone pulmonary resection (18,19). CIPI was calculated as CEA (ng/mL) × NLR (20), and has been reported to be a prognostic factor for NSCLC patients treated by pulmonary resection (21,22).

Operative factors and postoperative complications

The operative procedures were stratified into four categories: segmentectomy, lobectomy, bi-lobectomy, and pneumonectomy. Although segmentectomy has recently been adapted for cStage IA1–2 NSCLC patients, lobectomy has been performed as the standard procedure for cStage IA3 NSCLC patients.

Pathological factors

Data on the number of patients with up-Stage, pathological stage, grade of lymph node metastasis, histological type, Ly, vascular invasion, and grade of differentiation were collected.

Recurrence pattern

Recurrence patterns were categorized as local recurrence, lymph node metastasis, intra-thoracic recurrence, and extra-thoracic recurrence.

Statistical analyses

We used Pearson’s Chi-square test of independence to compare the frequencies of variables. Cumulative survival was calculated by the Kaplan-Meier method and survival curves were compared using the log-rank test. The cut-off values for factors associated with recurrence were calculated using receiver operating characteristic (ROC) curve analysis, and prognostic analyses were performed using these cut-off values. Risk factors associated with recurrence were analyzed using Cox proportional hazards regression analysis. Risk factors associated with lymph node metastasis were analyzed using logistic regression analysis. All statistical analyses were two-sided, with statistical significance set at P<0.05. Statistical analyses were performed using JMP software v13.2 (SAS Institute Inc., Cary, NC, USA).

Results

Patient characteristics

The clinicopathological characteristics of the 410 cStage IA NSCLC patients are listed in Table 1. Among them, 302 were cStage IA1–IA2 and 108 were cStage IA3. The Brinkman index, CEA (4.1 vs. 2.8, P<0.01), CIPI (8.95 vs. 6.39, P<0.01), SUV_max (6.22 vs. 1.85, P<0.01), tumor diameter on CT (25 vs. 16, P<0.01), and CTR (1 vs. 0.7, P<0.01) were significantly higher and PNI (50.69 vs. 51.11, P=0.04) was significantly lower in cStage IA3 patients.

Operative factors and postoperative complications

Segmentectomy was performed in 92 patients, lobectomy in 208, bi-lobectomy in 2, and none underwent pneumonectomy for cStage IA1–2, whereas segmentectomy was performed in 3, lobectomy in 102, bi-lobectomy in 1, and pneumonectomy in 2 for cStage IA3. Three patients who underwent segmentectomy were adapted as palliative surgery considering comorbidities. The frequency of segmentectomy was significantly lower for those with cStage IA3 (2.8% vs. 30.5%, P<0.01).

Pathological factors

Pathological stage was categorized as stage 0 in 33 patients, IA1 in 101, IA2 in 110, IA3 in 21, IB in 21, IIA in 1, IIB in 8, and IIIA in 7 for cStage IA1–2 patients, and stage 0 in 1 patient, IA1 in 2, IA2 in 20, IA3 in 44, IB in 16, IIA in 0, IIB in 14, IIIA in 10, and IIIB in 1 for cStage IA3 patients. The rates of patients with up-Stage (53.7% vs. 25.8%, P<0.01) and presence of pathological lymph node metastasis (22.2% vs. 4.3%, P<0.01) were significantly higher for cStage IA3 patients. Histological type was categorized as adenocarcinoma in 265 patients, squamous cell carcinoma in 22, and others in 15 for cStage IA1–2 patients, and adenocarcinoma in 78 patients, squamous cell carcinoma in 22, and others in 8 for cStage IA3 patients. Adenocarcinoma was significantly lower in cStage IA3 patients (72.2% vs. 87.7%, P<0.01). Ly (44.4% vs. 25.5%, P<0.01) and vascular invasion (49.1% vs. 30.5%, P<0.01) were significantly higher in cStage IA3 patients. Differentiation was categorized as G1 in 98 patients, G2 in 168, G3 in 28, and G4 in 8 for cStage IA1–2 patients, and G1 in 21 patients, G2 in 62, G3 in 20, and G4 in 5 for cStage IA3 patients. The rate of G3–4 was significantly higher in cStage IA3 patients (23.1% vs. 11.9%, P<0.01).

Recurrence pattern

Recurrence occurred in 18 (6%) patients for cStage IA1–2 and 29 (26.8%) patients for cStage IA3. In patients who underwent segmentectomy, recurrence occurred in 1 (2%) patient for cStage IA1, 4 (10%) patients for cStage IA2, and none (0%) for cStage IA3. Recurrence was significantly higher in cStage IA3 patients (26.8% vs. 6.0%, P<0.01). Local recurrence (1.8% vs. 0%, P=0.02), lymph node metastasis (13.9% vs. 2.6%, P<0.01), intra-thoracic recurrence (22.2% vs. 5.3%, P<0.01), and extra-thoracic recurrence (9.3% vs. 1.7%, P<0.01) were significantly higher in cStage IA3 patients.

Univariate and multivariate analysis

The risk factors for postoperative recurrence in cStage IA NSCLC patients were analyzed (Table 2). The cut-off values of factors associated with postoperative recurrence were calculated using ROC curve analysis. The following cut-off values were determined: age, 66 years; PNI, 52.15; NLR, 2.06; CIPI, 10.28; SUV_max, 3.17; and CTR, 0.8. However, the cut-off value of smoking status and CEA was determined without ROC curve analysis (Brinkman index, 600; and CEA, 5). Univariate analysis showed that age (P<0.01), CEA (P<0.01), NLR (P=0.01), CIPI (P<0.01), SUV_max (P<0.01), CTR (P<0.01), Ly (P<0.01), vascular invasion (P<0.01), and cStage (P<0.01) were significant risk factors for postoperative recurrence. Furthermore, multivariate analysis showed that age [hazard ratio (HR): 2.31, 95% confidence interval (CI): 1.29–4.12, P<0.01], CIPI (HR: 1.84, 95% CI: 1.00–3.42, P=0.04), SUV_max (HR: 5.70, 95% CI: 2.19–18.21, P<0.01), Ly (HR: 2.71, 95% CI: 1.28–6.05, P<0.01), and cStage (HR: 2.46, 95% CI: 1.32–4.75, P<0.01) were risk factors for postoperative recurrence.

Survival analysis

Relapse-free survival (RFS) data for cStage IA NSCLC patients are shown in Figure 2. RFS rates were significantly worse for cStage IA3 patients compared with those for patients at other cStages (5-year RFS: IA1 vs. IA2 =96.4% vs. 90.5%, IA1 vs. IA3 =96.4% vs. 66.1%, P<0.01, IA2 vs. IA3 =90.5% vs. 66.1%, P<0.01).

Figure 2 RFS for NSCLC patients with cStage IA. RFS rates were significantly worse in cStage IA3 (5-year RFS: IA1 vs. IA2 =96.4% vs. 90.5%, IA1 vs. IA3 =96.4% vs. 66.1%, P<0.01; IA2 vs. IA3 =90.5% vs. 66.1%, P<0.01). cStage, clinical stage; NSCLC, non-small cell lung cancer; RFS, relapse free survival.

Risk factors of recurrence, upstage, and lymph node metastasis for cStage IA3 patients

Next, we evaluated risk factors for postoperative recurrence in cStage IA3 NSCLC patients (Table 3). The following cut-off values were determined: age, 65 years; PNI, 52.50; NLR, 2.11; CIPI, 16.98; SUV_max, 5.53; and CTR, 0.8. Univariate analysis showed that NLR (P=0.01), CIPI (P<0.01), SUV_max (P<0.01), Ly (P<0.01), and vascular invasion (P=0.01) were significant risk factors for postoperative recurrence. Multivariate analysis showed that CIPI (HR: 3.21, 95% CI: 1.47–6.92, P<0.01) and SUV_max (HR: 2.64, 95% CI: 1.09–7.41, P=0.03) were risk factors for postoperative recurrence.

Then, relationships between clinicopathological characteristics and risk factors of up-Stage in cStage IA3 NSCLC patients were analyzed (Table 4). The following cut-off values associated with up-Stage were determined: age, 72 years; PNI, 51.95; NLR, 3.87; CIPI, 7.24; SUV_max, 3.07; and CTR, 0.8. However, the cut-off value of smoking status and CEA were determined without ROC curve analysis (Brinkman index, 600; and CEA, 5 ng/mL). Univariate analysis showed that CTR (P<0.01) and Ly (P<0.01) were significantly different among patients stratified by up-Stage. Multivariate analysis showed that CTR [odds ratio (OR): 5.88, 95% CI: 1.77–19.50, P<0.01] and Ly (OR: 2.80, 95% CI: 1.19–6.56, P=0.01) were risk factors for up-Stage.

Furthermore, relationships between the clinicopathological characteristics and risk factors of lymph node metastasis in cStage IA3 NSCLC patients were analyzed (Table 5). The following cut-off values associated with lymph node metastasis were determined: age, 68 years; PNI, 41.87; NLR, 2.11; CIPI, 7.24; SUV_max, 3.34; and CTR, 0.8. The cut-off value of smoking status and CEA was determined without ROC curve analysis (Brinkman index, 600; and CEA, 5). Univariate analysis showed that PNI (P=0.01), SUV_max (P=0.01), Ly (P<0.01), and vascular invasion (P<0.01) were significantly different among patients stratified by lymph node metastasis. Multivariate analysis showed that PNI (OR: 25.51, 95% CI: 1.63–398.90, P=0.02) and Ly (OR: 13.22, 95% CI: 2.18–80.08, P<0.01) were risk factors for lymph node metastasis.

Discussion

In this study, we analyzed risk factors for recurrence, upstage, and lymph node metastasis in NSCLC patients with cStage IA3 disease. Our findings demonstrated that tumor CIPI and SUV_max were significant risk factors for recurrence in cStage IA3 NSCLC patients. CIPI was reported to be a significant factor for recurrence in cStage IA3 NSCLC patients in the present study, as in our previous analysis (22). SUV_max was reported to predict recurrence in patients with surgically resected NSCLC (23-25), suggesting it might also predict recurrence in cStage IA3 NSCLC patients.

CTR and Ly were revealed as risk factors for up-Stage in cStage IA3 NSCLC patients in this study. In previous studies, the tumor diameter, value of CT, and Ly were reported as risk factors for up-Stage in early-stage NSCLC patients for whom sublobar resection was insufficient (6,7). Preoperative imaging findings including CTR or CT value might be important indicators for the selection of surgical procedures for early-stage NSCLC patients because Ly is difficult to evaluate preoperatively.

Although age, CEA, tumor size, CTR, and non-upper lobe location have been reported as risk factors for lymph node metastasis in cStage IA NSCLC patients (8-11), PNI and Ly were risk factors for lymph node metastasis in cStage IA3 NSCLC patients in this study. Although Ly was reported as a risk factor for lymph node metastasis in a previous study (7), Ly would not be considered valid for deciding on an indication of sublobar resection for early-stage NSCLC patients because Ly is difficult to evaluate preoperatively. PNI has been reported as a prognostic factor for NSCLC patients who underwent pulmonary resection or who are undergoing trimodality therapy for locally advanced disease (15,16,26). Furthermore, PNI was reported to predict lymph node metastasis in NSCLC patients (27). Although the issue of how to determine the cutoff value of PNI for lymph node metastasis remains unclear, the results in this study suggest that PNI might be used in deciding on an indication of sublobar resection for early-stage NSCLC patients.

Although segmentectomy is recommended as the standard surgical procedure for cStage IA NSCLC patients with tumor diameter ≤20 mm on the basis of the JCOG0802/WJOG4706L trial (2), the validity of sublobar resection for early-stage NSCLC patients with tumor diameter 20–30 mm remains uncertain. Although cancer control by segmentectomy was not inferior compared with that by lobectomy for cStage IA3 NSCLC patients with a radiologically pure-solid nodule (4), lobectomy appears to have a better survival rate compared with segmentectomy for cStage IA3 NSCLC patients (28). Although a trial to verify the utility of segmentectomy for ground glass-dominant invasive lung cancer with tumor diameter of 2–3 cm is ongoing (5), large sample size randomized control trials are needed to reveal the validity of segmentectomy for cStage IA3 NSCLC patients.

This study had several limitations. First, this study was retrospective and potentially included unobserved confounding and/or selection bias. Second, the study was performed at a single institution, and the study population was relatively small.

Conclusions

In summary, our findings describe risk factors for recurrence, upstage, and lymph node metastasis in cStage IA3 NSCLC patients. The CIPI and SUV_max were significant risk factors for recurrence, CTR and Ly were risk factors for up-Stage, and PNI and Ly were risk factors for lymph node metastasis in cStage IA3 NSCLC patients. Although large sample size randomized control trials are needed to reveal the validity of segmentectomy for cStage IA3 NSCLC patients, at present, an indication for segmentectomy should be carefully considered for cStage IA3 NSCLC patients with these risk factors.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1348/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1348/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1348/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-2025-1348/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 institutional review committee of Kanazawa Medical University approved the study protocol (approval No. I392), and all patients gave written informed consent.

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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