Impact of imaging features on selecting limited lymph node resection for cT1N0M0 lung cancer
Original Article

Impact of imaging features on selecting limited lymph node resection for cT1N0M0 lung cancer

Hua He1#, Wenteng Hu2#, Changsheng Yi3#, Shuo Sun2, Yu Zhou4, Xiaofei Zeng5, Quan Zhang6, Ruijiang Lin2, Peng Yue2, Minjie Ma2, Chang Chen1,2

1The First School of Clinical Medicine, Lanzhou University, Lanzhou, China; 2Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou, China; 3Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; 4Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, China; 5Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chengdu Medical College, School of Clinical Medicine, Chengdu Medical College, Chengdu, China; 6Department of Thoracic Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, China

Contributions: (I) Conception and design: H He, W Hu, C Yi, M Ma, C Chen; (II) Administrative support: M Ma, C Chen; (III) Provision of study materials or patients: C Yi, Y Zhou, X Zeng, Q Zhang, M Ma; (IV) Collection and assembly of data: H He, W Hu, C Yi, Y Zhou, X Zeng, Q Zhang, S Sun, R Lin, P Yue; (V) Data analysis and interpretation: H He, W Hu, C Yi; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work as co-first authors.

Correspondence to: Minjie Ma, MD. Department of Thoracic Surgery, The First Hospital of Lanzhou University, 1 Donggang West Road, Lanzhou 730030, China. Email: lzutsma@outlook.com; Chang Chen, PhD. The First School of Clinical Medicine, Lanzhou University, 1 Donggang West Road, Lanzhou 730030, China; Department of Thoracic Surgery, The First Hospital of Lanzhou University, Lanzhou, China. Email: 13031411302@163.com.

Background: Controversy still exists in the medical community regarding the performance of limited mediastinal lymphadenectomy (LML) in early-stage lung cancer. The objective of this study was to identify predictors of mediastinal lymph node (mLN) status and analyze its role in guiding surgical strategy.

Methods: A retrospective cohort study was conducted on 2,834 surgical patients with peripheral cT1N0M0 non-small cell lung cancer between 2016 and 2018. Logistic regression was employed to identify predictors of N2 metastasis. Prognosis was compared between groups and independent prognostic factors were identified using Kaplan-Meier and multivariate Cox analysis.

Results: There were 2,126 patients with systematic mLN dissection and 708 with LML. The multivariate analysis showed that N2 metastasis were associated with tumor size and consolidation tumor ratio (CTR). Patients in group A, with CTR >0.5 and tumor size ≤1 cm or CTR ≤0.5, had a significantly lower rate of N2 metastasis compared to those in group B, with CTR >0.5 and tumor size >1 cm (14.2% vs. 0.2%, P<0.001). Additionally, LML demonstrated comparable recurrence-free survival (RFS) and overall survival (OS) in group A, but a worse prognosis in group B compared to systematic lymph node dissection (SND). Furthermore, multivariate Cox regression analysis indicated that SND (vs. LML) was a favorable prognostic predictor for patients in group B [RFS: hazard ratio (HR) =0.71, P=0.005; OS: HR =0.66, P=0.01]. But univariate analysis in group A showed no significant difference in prognosis between SND and LML (RFS: P=0.24; OS: P=0.10).

Conclusions: The combination of CTR and tumor size can predict mLN metastasis and procedure-specific outcome (SND vs. LML). This information may assist surgeons in identifying suitable candidates for LML.

Keywords: Early-stage lung cancer; mediastinal lymph node metastasis (mLN metastasis); systematic lymph node dissection (SND); limited mediastinal lymphadenectomy (LML)


Submitted Apr 14, 2024. Accepted for publication Jul 05, 2024. Published online Aug 13, 2024.

doi: 10.21037/jtd-24-626


Highlight box

Key findings

• The combination of consolidation tumor ratio (CTR) and tumor size can predict mediastinal lymph node metastasis and procedure-specific outcome [systemic lymph node resection vs. limited mediastinal lymphadenectomy (LML)].

What is known and what is new?

• Patients in group A had a significantly lower rate of N2 metastasis compared to those in group B (14.2% vs. 0.2%, P<0.001).

• LML demonstrated comparable recurrence-free survival and overall survival in group A, but a worse prognosis in group B compared to LML.

What is the implication, and what should change now?

• The combination of CTR and tumor size may assist surgeons in identifying suitable candidates for LML.


Introduction

The guidelines recommend systematic lymph node dissection (SND) for all resectable lung cancers to ensure complete resection and accurate staging, regardless of the tumor stage (1,2). However, extensive removal of lymph nodes (LNs) without metastasis not only fails to improve survival (3,4), but also increases the risk of damage to the mediastinal structure and the incidence of postoperative complications (5). Therefore, in clinical practice, many surgeons perform limited mediastinal lymphadenectomy (LML). However, LML may omit potential positive LNs (4), causing patients to miss the opportunity to receive adjuvant treatment and resulting in a poor prognosis (6).

The percentage of patients diagnosed with early-stage lung cancer has significantly increased in recent years. This necessitates a reconsideration of the LN evaluation strategy. To avoid unnecessary lymphadenectomy, it is crucial to improve the dependability and accuracy of preoperative prediction of N2 metastasis (7). Computed tomography (CT) and positron emission tomography/CT (PET/CT) has limitations in identifying N2 metastasis due to suboptimal sensitivity (8). Infiltrating mediastinal LN (mLN) staging significantly improves diagnostic accuracy, but it is disadvantageous due to increase cost and the risk of complications. The JCOG0201 trial found that the consolidation tumor ratio (CTR) is a superior predictor of pathological mLN status (9). A previous study suggested that tumor diameter of less than 1 cm is a predictor of negative nodal status (10). There is a lack of research that combines CTR and tumor size to analyze their relationship with N2 metastasis and surgical strategy.

The objective of this study was to evaluate the predictive value of combined CTR and tumor size for predicting N2 metastasis and procedure-specific outcome (SND vs. LML) in clinical T1N0M0 non-small cell lung cancer (NSCLC). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-626/rc).


Methods

Patient selection

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committees of The First Hospital of Lanzhou University (No. LDYYLL2024-35), Henan Cancer Hospital (No. 2024-182-043), Affiliated Hospital of North Sichuan Medical College (No. 2024ER350-13), The First Affiliated Hospital of Chengdu Medical College (No. 2024CYFYIRB-SQ-15), and Henan Provincial People’s Hospital (No. 2024-23). Written informed consent for this retrospective analysis was waived. All participating hospitals were informed and agreed with the study. A total of 3,898 patients with clinically T1N0M0 lesions who underwent surgical resection and pathologically diagnosed with invasive NSCLC at the above five hospitals between 2016 and 2018 were reviewed. Exclusion criteria were as follows: (I) previous lung surgery history, preoperative adjuvant treatment or malignant history; (II) no chest CT scans within 1 month prior to surgery at the surgical facility; (III) multiple lung lesions; (IV) lesions located within two thirds of the lung on CT scans. Finally, a total of 2,126 patients with SND and 708 patients with LML for radiologically peripheral cT1N0 solitary nodule and pathologically invasive NSCLC were reviewed. All patients underwent video-assisted thoracoscopic surgery, which included lobectomy and sublobar resection (segmentectomy and wedge resection). The SND was defined as resection of at least three N1 stations and at least three N2 stations, including subcarinal LNs (11). LML was defined as dissection with an insufficient number of LN stations or omitting LN dissection.

Radiological and histological evaluation

The chest CT scans of all patients were reviewed by two researchers with lung window [width, 1,500 Hounsfield unit (HU); level, −400 HU] and mediastinal window (width, 400 HU; level, 40 HU). Tumor size was defined as the largest diameter in the axial plane. The CTR was calculated as the ratio of the maximum size of the solid component to the maximum tumor size on thin-section CT scan. For pure ground-glass opacity (GGO) nodules: CTR =0; for part-solid nodules: 0< CTR <1; and for pure-solid nodules: CTR =1. All lesions were classified into two groups: 0≤ CTR ≤0.5, 0.5< CTR ≤1. Subsolid nodules include pure GGO nodules and part-solid nodules. The detailed CT scanning parameters are shown in Appendix 1. The final pathologic diagnosis was made by pathologists based on the 2015 World Health Organization classification of lung cancers (12).

Patients follow-up

During the first 2 years, patients underwent follow-up every 3 months, which included abdominal ultrasonography or CT scans and chest CT scans. Subsequently, follow-up was conducted every 6 months for 3 to 5 years and then annually. Chest CTs, brain CT scans or magnetic resonance imaging were also performed. PET/CT scan or biopsy was recommended to confirm suspected recurrences. Recurrence-free survival (RFS) and overall survival (OS) were defined as the interval between the date of surgery and the first recurrence, death, or last follow-up.

Statistical analysis

The independent sample t-test and Pearson’s Chi-square test or Fisher’s exact test were used to compare continuous variables and categorical variables between groups respectively. Logistic regression analysis was conducted to identify the independent risk factors of N2 metastasis. The Kaplan-Meier method and log-rank test were used to estimate and compare RFS and OS among the groups. Finally, Cox proportional hazards regression was used to identify the independent prognostic factors for RFS and OS. The variables with a P value less than 0.10 in the univariate regression model were included in the multivariable regression model.

The statistical analysis was conducted using SPSS software (version 25.0, IBM) and R software (version 3.6.2, www.R-project.org). A significance level of two-sided P value less than 0.05 was used to determine statistical significance.


Results

Predictors of pathologic N2 metastasis

The analysis of predictors of N2 metastasis was conducted in 2,126 patients underwent SND, as SND is considered the gold standard for nodule staging. Table 1 presents the baseline characteristics of patients based on their pathological N2 status. Of the total patients, 8.5% (n=181) had N2 metastasis, out of which 5.4% (n=114) had both N1 and N2 metastasis and 3.1% (n=67) had only N2 metastasis. Patients with N2 positive had a higher number of N2 stations and LNs resected than those with N2 negative (both P<0.001). The median tumor size was 2.3 cm in the N2-positive group and 1.9 cm in the N2-negative group (P<0.001). The N2 positive group had a significantly higher proportion of patients with CTR >0.5 compared to the N2 negative group (98.9% vs. 54.2%, P<0.001).

Table 1

Baseline characteristics according to the pathological N2 status in patients who underwent systematic lymph node dissection

Variables Total (n=2,126) pN2 (−) (n=1,945) pN2 (+) (n=181) P
Age (years) 61 [54–66] 61 [54–66] 60 [53–66] 0.12
   <65 1,453 (68.3) 1,324 (68.1) 129 (71.3) 0.19
   ≥65 673 (31.7) 621 (31.9) 52 (28.7)
Sex 0.24
   Female 1,133 (53.3) 1,044 (53.7) 89 (49.2)
   Male 993 (46.7) 901 (46.3) 92 (50.8)
Smoking history 0.02
   Yes 375 (17.6) 332 (17.1) 43 (23.8)
   No 1,751 (82.4) 1,613 (82.9) 138 (76.2)
Tumor size (cm) 1.9 [1.5–2.4] 1.9 [1.5–2.4] 2.3 [2.0–2.7] <0.001
   0< size ≤1 130 (6.1) 127 (6.5) 3 (1.7) <0.001
   1< size ≤2 1,047 (49.2) 999 (51.4) 48 (26.5)
   2< size ≤3 949 (44.6) 819 (42.1) 130 (71.8)
CTR <0.001
   ≤0.5 892 (42.0) 890 (45.8) 2 (0.2)
   >0.5 1,234 (58.0) 1,055 (54.2) 179 (98.9)
CEA level (ng/mL) <0.001
   >5 319 (15.0) 253 (13.0) 66 (36.5)
   ≤5 1,807 (85.0) 1,692 (87.0) 115 (63.5)
Extent of surgery <0.001
   Segmentectomy 255 (12.0) 252 (13.0) 3 (1.7)
   Lobectomy 1,871 (88.0) 1,693 (87.0) 178 (98.3)
Tumor location 0.90
   Upper lobes 1,266 (59.5) 1,159 (59.6) 107 (59.1)
   Non-upper lobes 860 (40.5) 786 (40.4) 74 (40.9)
Histologic type 0.13
   Adenocarcinoma 1,904 (89.6) 1,749 (89.9) 155 (85.6)
   SCC 130 (6.1) 113 (5.8) 17 (9.4)
   Others 92 (4.3) 83 (4.3) 9 (5.0)
VPI <0.001
   Presence 113 (5.3) 82 (4.2) 31 (17.1)
   Absence 2,013 (94.7) 1,863 (95.8) 150 (82.9)
STAS 0.01
   Presence 65 (3.1) 54 (2.8) 11 (6.1)
   Absence 2,061 (96.9) 1,891 (97.2) 170 (93.9)
No. resected N2 stations 4 [3–4] 4 [3–4] 4 [4–5] <0.001
No. resected nodes 10 [8–13] 10 [8–13] 12 [10–16] <0.001
Adjuvant therapy <0.001
   Yes 487 (22.9) 349 (17.9) 138 (76.2)
   No 1,639 (77.1) 1,596 (82.1) 43 (23.8)

Categorical variables are presented as number (percentage). Continuous variables are presented as median [interquartile range]. CTR, consolidation tumor ratio; CEA, carcinoembryonic antigen; SCC, squamous cell carcinoma; VPI, visceral pleural invasion; STAS, spread through air space.

The multivariate logistic analysis indicated that tumor size [odds ratio (OR) =2.05, 95% confidence interval (CI): 1.48–2.85, P<0.001], CTR (OR =43.64, 95% CI: 13.75–265.46, P<0.001), carcinoembryonic antigen (CEA: OR =2.26, 95% CI: 1.58–3.21, P<0.001), visceral pleural invasion (VPI) (OR =2.19, 95% CI: 1.36–3.44, P<0.001) were independent risk factors for N2 metastasis (Table 2). The N2 metastasis rate was significantly lower in GGO dominant tumors compared to solid dominant tumors (0.2% vs. 14.5%, P<0.001). In solid dominant tumors, the rate of N2 metastasis increased from 1.6% in tumors ≤1 cm to 19.3% in tumors between 2 and 3 cm (Figure 1). Therefore, we classified patients into two groups: group A included those with solid predominant tumors and diameter <1 cm, as well as those with GGO predominant tumors; group B included those with solid predominant tumors and diameter >1 cm. For the entire cohort, the positive rate of N2 in group A was close to 0, which was significantly lower than that in group B (0.2% vs. 14.2%, P<0.001). These finding suggest that patients in group A may be potential candidates for LML.

Table 2

Univariate and multivariate logistic regression analysis for mediastinal nodal metastasis in patients who underwent systematic lymph node dissection

Variables Univariate analysis Multivariate analysis
OR (95% CI) P OR (95% CI) P
Age (≥65 vs. <65 years) 0.86 (0.61–1.20) 0.37
Sex (male vs. female) 1.20 (0.88–1.63) 0.24
Tumor size 3.48 (2.59–4.71) <0.001 2.05 (1.48–2.85) <0.001
CTR (>0.5 vs. ≤0.5) 75.50 (24.08–457.06) <0.001 43.64 (13.75–265.46) <0.001
Histologic type
   Adenocarcinoma 1 (ref.)
   SCC 1.70 (0.96–2.83) 0.053
   Others 1.22 (0.56–2.36) 0.57
Location (upper vs. non-upper lobes) 0.98 (0.72–1.34) 0.90
Smoking history (yes vs. no) 1.51 (1.04–2.16) 0.02 0.90 (0.60–1.31) 0.58
Extent of surgery (sublobar resection vs. lobectomy) 0.11 (0.03–0.30) <0.001 0.31 (0.10–1.00) 0.055
CEA (>5 vs. ≤5 ng/mL) 3.84 (2.75–5.33) <0.001 2.26 (1.58–3.21) <0.001
VPI (presence vs. absence) 4.70 (2.97–7.26) <0.001 2.19 (1.36–3.44) <0.001
STAS (presence vs. absence) 2.27 (1.11–4.25) 0.01 1.17 (0.56–2.27) 0.65
No. resected N2 stations 1.60 (1.34–1.92) <0.001 1.09 (0.88–1.34) 0.42

CTR, consolidation tumor ratio; SCC, squamous cell carcinoma; CEA, carcinoembryonic antigen; VPI, visceral pleural invasion; STAS, spread through air space; OR, odds ratio; CI, confidence interval.

Figure 1 Prevalence of lymph node metastasis according to tumor density and tumor size. (A) Proportion of lymph node status stratified by tumor size in all patients; (B) proportion of lymph node status stratified by CTR and tumor size in all patients; (C) proportion of lymph node status stratified by tumor size in patients with subsolid nodules; (D) proportion of lymph node status stratified by tumor size in patients with pure-solid nodules. CTR, consolidation tumor ratio.

Prognostic analysis of patients based on the extent of lymph lode resection

The median follow-up period was 92.7 months. Table 3 shows the baseline characteristics of patients with SND and LML in group A and group B. In group A, there were significant differences in clinicopathological features between the SND and the LML with respect to the age, tumor size, tumor density, extent of surgery, Charlson Comorbidity Index (CCI), number of resected N2 stations and total LNs. There were no significant differences in sex, smoking history, CEA level, tumor location, histologic type, VPI, spread through air space (STAS) or adjuvant therapy between SND and LML in the two groups.

Table 3

Baseline characteristics of patients underwent limited or systematic mediastinal lymphadenectomy

Variables Group A Group B
SND (n=955) LML (n=392) P SND (n=1,171) LML (n=316) P
Age (years) 0.003 0.09
   <65 707 (74.0) 258 (65.8) 746 (63.7) 185 (58.5)
   ≥65 248 (26.0) 134 (34.2) 425 (36.3) 131 (41.5)
Sex 0.62 0.25
   Female 568 (59.5) 239 (61.0) 565 (48.2) 141 (44.6)
   Male 387 (40.5) 153 (39.0) 606 (51.8) 175 (55.4)
Smoking history 0.37 0.83
   Yes 111 (11.6) 39 (9.9) 264 (22.5) 73 (23.1)
   No 844 (88.4) 353 (90.1) 907 (77.5) 243 (76.9)
Tumor size (cm) <0.001 0.16
   0< size ≤1 130 (13.6) 94 (24.0) 0 0
   1< size ≤2 550 (57.6) 231 (58.9) 497 (42.4) 148 (46.8)
   2< size ≤3 275 (28.8) 67 (17.1) 674 (57.6) 168 (53.2)
Tumor density 0.01 0.52
   Pure GGO 622 (65.1) 287 (73.2) 0 0
   Part-solid 275 (28.8) 85 (21.7) 197 (16.8) 58 (18.4)
   Pure-solid 58 (6.1) 20 (5.1) 974 (83.2) 258 (81.6)
CEA level (ng/mL) 0.92 0.10
   >5 62 (6.5) 26 (6.6) 257 (21.9) 83 (26.3)
   ≤5 893 (93.5) 366 (93.4) 914 (78.1) 233 (73.7)
Extent of surgery <0.001 <0.001
   Segmentectomy 198 (20.7) 146 (37.2) 57 (4.9) 48 (15.2)
   lobectomy 757 (79.3) 186 (47.4) 1,114 (95.1) 235 (74.4)
   Wedge resection 0 60 (15.3) 0 33 (10.4)
Tumor location 0.56 0.75
   Upper lobes 603 (63.1) 241 (61.5) 663 (56.6) 182 (57.6)
   Non-upper lobes 352 (36.9) 151 (38.5) 508 (43.4) 134 (42.4)
CCI 0.02 0.55
   0 846 (88.6) 329 (83.9) 980 (83.7) 260 (82.3)
   1–3 109 (11.4) 63 (16.1) 191 (16.3) 56 (17.7)
ECOG score 0.07 0.004
   0 830 (86.9) 328 (83.7) 929 (79.3) 232 (73.4)
   1 72 (7.5) 29 (7.4) 152 (13.0) 41 (13.0)
   2 53 (5.5) 35 (8.9) 90 (7.7) 43 (13.6)
Histologic type 0.16 0.30
   Adenocarcinoma 927 (97.1) 375 (95.7) 977 (83.4) 255 (80.7)
   SCC 8 (0.8) 2 (0.5) 122 (10.4) 34 (10.8)
   Others 20 (2.1) 15 (3.8) 72 (6.1) 27 (8.5)
VPI 0.51 0.10
   Presence 1 (0.1) 1 (0.3) 112 (9.6) 40 (12.7)
   Absence 954 (99.9) 391 (99.7) 1,059 (90.4) 276 (87.3)
STAS 0.19 0.36
   Presence 6 (0.6) 0 59 (5.0) 20 (6.3)
   Absence 949 (99.4) 392 (100.0) 1,112 (95.0) 296 (93.7)
N stage 0.16 0.04
   N0 952 (99.7) 391 (99.7) 907 (77.5) 265 (83.9)
   N1 0 1 (0.3) 86 (7.3) 18 (5.7)
   N2 3 (0.3) 0 178 (15.2) 33 (10.4)
No. resected N2 stations 3 [3–4] 2 [0–2] <0.001 4 [3–5] 2 [2–4] <0.001
No. resected nodes 9 [7–12] 5 [3–7] <0.001 11 [9–14] 7 [5–10] <0.001
Adjuvant therapy 0.64 0.15
   Yes 60 (6.3) 22 (5.6) 427 (36.5) 129 (40.8)
   No 895 (93.7) 370 (94.4) 744 (63.5) 187 (59.2)

Group A: patients with CTR >0.5 and tumor size ≤1 cm or CTR ≤0.5; group B: patients with CTR >0.5 and tumor size >1 cm. Categorical variables are presented as number (percentage). Continuous variables are presented as median [interquartile range]. GGO, ground-glass opacity; CEA, carcinoembryonic antigen; CCI, Charlson Comorbidity Index; ECOG, Eastern Cooperative Oncology Group; SCC, squamous cell carcinoma; VPI, visceral pleural invasion; STAS, spread through air space; SND, systematic lymph node dissection; LML, limited mediastinal lymphadenectomy; CTR, consolidation tumor ratio.

In the patients with group A, there was no significant difference in RFS (P=0.14) and OS (P=0.39) between the SND group and the LML group (Figure 2). However, in patients with group B, the SND group showed better RFS (P=0.03) and OS (P=0.02) than the LML group (Figure 2). Multivariate Cox regression analysis showed that SND was an independent predictor of favorable RFS [SND vs. LML: hazard ratio (HR) =0.71, 95% CI: 0.56–0.91, P=0.005] and OS (SND vs. LML: HR =0.66, 95% CI: 0.47–0.92, P=0.01) in group B. But univariate analysis in group A showed no significant difference in prognosis between SND and LML (RFS: SND vs. LML, HR =0.62, 95% CI: 0.28–1.37, P=0.24; OS: SND vs. LML, HR =0.51, 95% CI: 0.22–1.16, P=0.10) (Table 4). The survival results of subgroup analyses in group A defined by key clinical and demographic characteristics, including age, sex, smoking history, tumor size, CEA level, Eastern Cooperative Oncology Group (ECOG) performance status score, tumor location and histological type were consistent with the overall analysis in a post-hoc exploratory analysis (Figure 3).

Figure 2 Prognosis comparison according to extent of lymphadenectomy in group A and group B. (A) Recurrence-free survival according to extent of lymphadenectomy in group A and group B; (B) overall survival according to extent of lymphadenectomy in group A and group B. The survival was adjusted by age, sex, Charlson Comorbidity Index, smoking history, tumor size, tumor density, Eastern Cooperative Oncology Group performance status score, extent of surgery using multivariate Cox regression model. Group A: patients with CTR >0.5 and tumor size ≤1 cm or CTR ≤0.5; group B: patients with CTR >0.5 and tumor size >1 cm. LML, limited mediastinal lymphadenectomy; SND, system lymph node dissection; HR, hazard ratio; CI, confidence interval; CTR, consolidation tumor ratio.

Table 4

Univariate and multivariate Cox regression analysis of recurrence-free survival and overall survival in patients of clinical stage IA non-small cell lung cancer

Variables Recurrence-free survival Overall survival
Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis
HR (95% CI) P HR (95% CI) P HR (95% CI) P HR (95% CI) P
Group A
   Age (≥65 vs. <65 years) 1.35 (0.60–3.04) 0.46 4.06 (1.76–9.37) 0.001 3.25 (1.28–8.26) 0.01
   Tumor size (cm)
    1–<2 vs. 0–<1 0.12 (0.05–0.31) <0.001 0.70 (0.08–5.97) 0.74 0.70 (0.25–1.98) 0.50
    2–<3 vs. 0–<2 0.27 (0.10–0.70) 0.007 0.94 (0.10–8.52) 0.95 0.62 (0.18–2.16) 0.45
   Sex (male vs. female) 2.11 (0.97–4.61) 0.06 1.46 (0.64–3.34) 0.36 1.71 (0.75–3.87) 0.20
   Tumor density
    Part-solid vs. pure GGO 5.66 (1.74–18.39) 0.004 4.66 (1.36–15.96) 0.01 1.37 (0.54–3.42) 0.50
    Pure-solid vs. pure GGO 39.30 (12.80–120.69) <0.001 28.81 (3.45–240.23) 0.002 2.76 (0.79–9.69) 0.11
   CTR (>0.5 vs. ≤0.5) 15.32 (7.09–33.09) <0.001 2.28 (0.68–7.68) 0.18
   ECOG score
    1 vs. 0 2.16 (0.74–6.31) 0.16 3.71 (1.35–10.20) 0.01 2.25 (0.77–6.58) 0.13
    2 vs. 0 1.31 (0.31–5.59) 0.71 2.75 (0.79–9.49) 0.11 1.26 (0.33–4.76) 0.73
   CCI (1–3 vs. 0) 1.24 (0.43–3.60) 0.69 0.64 (0.15–2.73) 0.54
   Location (upper vs. non-upper lobes) 2.03 (0.81–5.05) 0.12 1.74 (0.68–4.40) 0.24
   Smoking history (yes vs. no) 1.87 (0.70–4.96) 0.20 2.13 (0.79–5.74) 0.13
   Extent of surgery (sublobar vs. lobectomy) 1.36 (0.62–3.00) 0.44 1.71 (0.75–3.90) 0.20
   CEA (>5 vs. ≤5 ng/mL) 3.20 (1.21–8.49) 0.02 2.14 (0.76–6.01) 0.51 2.79 (0.95–8.20) 0.06 2.40 (0.81–7.09) 0.11
   STAS (presence vs. absence) 10.57 (1.43–78.32) 0.02 1.03 (0.12–8.50) 0.98
   Extent of lymphadenectomy (SND vs. LML) 0.62 (0.28–1.37) 0.24 0.51 (0.22–1.16) 0.10
   Pathologic N stage
    N1 vs. N0 46.68 (6.26–348.10) <0.001 9.32 (0.89–98.07) 0.06
    N2 vs. N0
   Adjuvant therapy (yes vs. no) 4.21 (1.59–11.15) 0.004 3.76 (1.20–11.78) 0.02 1.44 (0.34–6.14) 0.62
Group B
   Age (≥65 vs. <65 years) 1.03 (0.84–1.27) 0.75 1.53 (1.15–2.04) 0.004 1.45 (1.07–1.96) 0.01
   Tumor size (2–<3 vs. 1–<2 cm) 1.66 (1.34–2.06) <0.001 1.22 (0.98–1.52) 0.07 2.09 (1.52–2.89) <0.001 1.78 (1.27–2.51) <0.001
   Sex (male vs. female) 1.28 (1.04–1.57) 0.01 1.12 (0.89–1.43) 0.33 1.47 (1.10–1.98) 0.01 1.17 (0.83–1.65) 0.38
   Tumor density (pure-solid vs. part-solid) 3.37 (2.25–5.06) <0.001 2.55 (1.69–3.85) <0.001 3.10 (1.76–5.44) <0.001 2.26 (1.27–4.03) 0.005
   ECOG score
    1 vs. 0 1.25 (0.94–1.68) 0.12 1.10 (0.71–1.70) 0.66
    2 vs. 0 1.10 (0.77–1.56) 0.60 1.61 (1.05–2.46) 0.03
   CCI (1–3 vs. 0) 0.97 (0.73–1.27) 0.80 1.38 (0.97–1.97) 0.07 1.26 (0.87–1.82) 0.21
   Histologic type
    SCC vs. adenocarcinoma 0.69 (0.47–1.01) 0.058 1.43 (0.94–2.19) 0.09
    Others vs. adenocarcinoma 0.81 (0.52–1.27) 0.35 1.44 (0.86–2.41) 0.17
   Location (upper vs. non-upper lobes) 1.25 (1.02–1.55) 0.03 1.29 (1.04–1.60) 0.01 1.10 (0.82–1.48) 0.52
   Smoking history (yes vs. no) 1.34 (1.07–1.69) 0.01 1.10 (0.84–1.44) 0.48 1.62 (1.19–2.21) 0.002 1.29 (0.89–1.86) 0.18
   Extent of surgery (sublobar vs. lobectomy) 1.11 (0.79–1.56) 0.54 1.56 (1.01–2.39) 0.04 2.04 (1.26–3.31) 0.004
   CEA (>5 vs. ≤5 ng/mL) 1.61 (1.29–2.01) <0.001 1.24 (0.99–1.56) 0.057 1.69 (1.24–2.31) <0.001 1.23 (0.89–1.69) 0.20
   VPI (presence vs. absence) 2.00 (1.52–2.63) <0.001 1.39 (1.05–1.84) 0.02 1.42 (0.93–2.19) 0.10
   STAS (presence vs. absence) 1.56 (1.07–2.28) 0.02 1.10 (0.75–1.62) 0.61 1.69 (1.01–2.83) 0.04 1.33 (0.79–2.23) 0.28
   Extent of lymphadenectomy (SND vs. LML) 0.76 (0.60–0.96) 0.01 0.71 (0.56–0.91) 0.005 0.61 (0.45–0.84) 0.002 0.66 (0.47–0.92) 0.01
   Pathologic N stage
    N1 vs. N0 2.07 (1.46–2.95) <0.001 1.40 (0.97–2.02) 0.07 2.18 (1.34–3.55) 0.002 2.37 (1.41–4.01) 0.001
    N2 vs. N0 3.99 (3.17–5.01) <0.001 2.36 (1.81–3.06) <0.001 3.92 (2.85–5.41) <0.001 4.19 (2.85–6.16) <0.001
   Adjuvant therapy (yes vs. no) 3.01 (2.45–3.70) <0.001 1.91 (1.50–2.43) <0.001 1.54 (1.15–2.05) 0.004 0.83 (0.59–1.18) 0.30

Group A: patients with CTR >0.5 and tumor size ≤1 cm or CTR ≤0.5; group B: patients with CTR >0.5 and tumor size >1 cm. HR, hazard ratio; CI, confidence interval; GGO, ground-glass opacity; CTR, consolidation tumor ratio; ECOG, Eastern Cooperative Oncology Group; CCI, Charlson Comorbidity Index; CEA, carcinoembryonic antigen; STAS, spread through air space; SND, systematic lymph node dissection; LML, limited mediastinal lymphadenectomy; SCC, squamous cell carcinoma; VPI, visceral pleural invasion.

Figure 3 Subgroup analysis of RFS and OS in patients with group A. Group A: patients with CTR >0.5 and tumor size ≤1 cm or CTR ≤0.5. CEA, carcinoembryonic antigen; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; RFS, recurrence-free survival; CI, confidence interval; SND, system lymph node dissection; LML, limited mediastinal lymphadenectomy; OS, overall survival; CTR, consolidation tumor ratio.

In the entire cohort, the N2 detection rate of SND was significantly higher than that of LML (8.5% vs. 4.7%, P=0.001). We defined the N2 missed diagnosis rate of LML as the decrease in the N2 detection rate from LML to SND and the N2 missed diagnosis rate of LML was 3.8%. In patients with group B, the N2 detection rate of SND was still higher than that of LML (15.2% vs. 10.4%, P=0.04) and the N2 missed diagnosis rate of LML was 4.8%. However, in patients with group A, there was no significant difference in the N2 detection rate between SND and LML (0.3% vs. 0%, P=0.16) and the N2 missed diagnosis rate of LML was only 0.3%.

Prognostic analysis of patients based on the extent of surgery

The baseline characteristics of patients who underwent sublobar resection and lobectomy in the group A and group B are shown in Table S1. The clinicopathological characteristics were significantly different between sublobar resection and lobectomy in two groups with respect to age, tumor size, tumor density, location, ECOG performance status score and the number of resected N2 stations and LNs. In the patients with group A, there was no significant difference in RFS (P=0.56) and OS (P=0.44) between lobectomy and sublobar resection. In patients with group B, there was no significant difference in RFS (P=0.16) between lobectomy and sublobar resection. However, the lobectomy showed better OS (P=0.02) than sublobar resection (Figure S1). Multivariate Cox regression analysis showed that the extent of surgery was not an independent predictor of RFS but sublobar resection was an unfavorable predictor of OS (sublobar resection vs. lobectomy: HR =2.04, 95% CI: 1.26–3.31, P=0.004) in group B (Table 4). Extent of surgery was not an independent predictor of RFS or OS in group A (RFS: P=0.44; OS: P=0.20) (Table 4). The survival results of the subgroup analyses in group A were consistent with the overall analysis (Figure S2).


Discussion

In this study, we demonstrated the value of CTR combined with tumor size in predicting mLN metastasis. In patients with group A, LML showed a similar prognosis compared to SND and showed a low N2 missed diagnosis rate. Therefore, avoiding complete LN dissection under the guidance of CTR and tumor size may be a new strategy to reduce surgical trauma in early-stage lung cancer.

To minimize surgical damage to patients, it is important to preserve normal LNs and lung parenchyma (13). Maintaining a balance between accurate nodule staging and reducing damage to the mediastinal structure is a major challenge for surgeons. The key is to tailor a risk-based LN assessment strategy based on the biological characteristics of the tumor. However, achievement in minimizing damage from mLN dissection without compromising prognosis is still at an exploratory stage. Previous studies have suggested that patients with small tumor size (≤2 cm) may be the candidates for LML based on less LN metastasis (14-16), while others have suggested that the LN metastasis of small tumors should not be ignored (17,18). Tumors with GGO presence are less biologically aggressive than those with GGO absence (19-22). Previous studies have shown that the frequency of LN metastasis increases significantly with the increase of solid components in mixed ground-glass nodules (23,24). Therefore, we combined the tumor size and CTR to analyze the prevalence of N2 metastasis and found that the N2 metastasis rate of group A undergoing SND was significantly lower than that of group B undergoing SND (0.3% vs. 15.2%, P<0.001).

We further investigated the effect of N2 prediction by CTR combined with tumor size on procedure-specific outcomes (SND vs. LML; sublobar resection vs. lobectomy). Univariate Cox regression analysis showed that RFS and OS were similar in group A patients between SND and LML (RFS: P=0.24; OS: P=0.10). But multivariate Cox regression analysis in group B showed significant difference in prognosis between SND and LML (RFS: P=0.005; OS: P=0.01). In addition, the N2 missed diagnosis rate of LML increased from 0.3% in group A to 4.8% in group B. The worse prognosis of LML in patients with group B may be due to underestimation of nodal stage and missed appropriate adjuvant therapy. Therefore, the above results showed that: (I) LML may be a feasible strategy in patients with group A given its similar prognosis and staging accuracy to SND; (II) to ensure better prognosis and staging accuracy, SND remains the standard procedure for patients with group B. Similarly, the previous studies indicated that CTR ≤0.5 (25), tumor size less than 1 cm (26) are important predictors of negative nodal status in early-stage NSCLC. A recent prospective study suggested that patients with CTR ≤0.5 do not require mLN dissection in cT1N0 NSCLC (27). The LML in this study included but was not limited to omission of mLN dissection, so further studies are needed to verify this conclusion in terms of prognosis.

Significant progress has been made in preserving as much lung parenchyma as possible. The LCSG821 trial laid the foundation for lobectomy, which subsequently became the standard surgical procedure based on the fact that sublobar resection had a higher mortality and local recurrence rate than lobectomy for T1N0 lung cancer (28). Increased detection rates for early lung cancer have led to renewed interest in sublobar resection for early lung cancer. JCOG1211 is the first prospective study to demonstrate that segmentectomy should be considered as the standard of care for GGO-predominant clinical stage IA NSCLC (29). In this study, multivariate Cox regression analysis showed that sublobar resection achieved similar RFS (P=0.44) and OS (P=0.20) compared to lobectomy in group A. In JCOG0802/WJOG4607L, the tumor diameter was larger for solid or solid-predominant tumors. As a result, it was shown that lung parenchyma-preserving surgery had non-inferior survival compared with lobectomy (30). Therefore, sublobar resection may be a feasible strategy in patients with group A.

There were several limitations to this study. First, there may be potential differences in surgical management, such as differences in the extent of lung and mLN resection between different hospitals and surgeons. Although we were unable to assess the factors that influenced treatment decisions, we performed multivariate analyses to reduce selection bias as much as possible. Second, the assessment of CTR may be subjective, which may affect the promotion and use of this feature in clinical practice.


Conclusions

In conclusion, CTR combined with tumor size demonstrated predictive value for N2 status and procedure-specific outcome (SND vs. LML). It may assist surgeons in identifying appropriate candidates for LML using imaging information.


Acknowledgments

Funding: This work was supported by the Natural Science Foundation of Gansu Province (Nos. 21JR1RA092 and 21JR1RA118), the Natural Science Foundation of China (Nos. 82272943 and 82102126), and The First Hospital of Lanzhou University youth fund (No. ldyyyn2022-50).


Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-626/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-626/dss

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-626/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 Ethics Committees of The First Hospital of Lanzhou University (No. LDYYLL2024-35), Henan Cancer Hospital (No. 2024-182-043), Affiliated Hospital of North Sichuan Medical College (No. 2024ER350-13), The First Affiliated Hospital of Chengdu Medical College (No. 2024CYFYIRB-SQ-15), and Henan Provincial People’s Hospital (No. 2024-23). Written informed consent for this retrospective analysis was waived. All participating hospitals were informed and agreed with 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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Cite this article as: He H, Hu W, Yi C, Sun S, Zhou Y, Zeng X, Zhang Q, Lin R, Yue P, Ma M, Chen C. Impact of imaging features on selecting limited lymph node resection for cT1N0M0 lung cancer. J Thorac Dis 2024;16(8):5138-5151. doi: 10.21037/jtd-24-626

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