Validation for revision of the stage IIIA(T1N2) in the forthcoming ninth edition of the TNM classification for lung cancer

doi:10.21203/rs.3.rs-4727507/v1

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Validation for revision of the stage IIIA(T1N2) in the forthcoming ninth edition of the TNM classification for lung cancer

https://doi.org/10.21203/rs.3.rs-4727507/v1

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Objectives

The 9th edition of the lung cancer tumor-node-metastasis (TNM) staging system downgrades certain non-small cell lung cancer (NSCLC) patients from stage IIIA (T1N2) to IIB. This study aimed to externally validate this stage adjustment.

Methods

Consecutive resected stage IIB and IIIA NSCLC patients were included. Subgrouping was done based on lymph node involvements: IIB N2a1 (single-station N2 without N1 involvement), IIB N2a2 (single-station N2 with N1 involvements) and IIB N0-1. Overall survival (OS) and disease-free survival (DFS) were compared using the Kaplan-Meier method, with propensity score matching (PSM) employed to mitigate potential biases. COX regression models were utilized to assess prognostic differences.

Results

224 stage IIB and 227 stage IIIA cases was included. There were 38, 66 and 120 patients in the IIB N2a1, IIB N2a2 and IIB N0-1 subgroups, respectively. Univariate COX analysis indicated comparable prognoses between the stage IIB N0-1 and IIB N2a1 patients, whereas stage IIB N2a2 patients exhibited poorer outcomes. Upon combining the stage IIB N2a1 and IIB N0-1 subgroups, multivariate COX analysis demonstrated a significantly worse prognosis for stage IIB N2a2 patients compared to those with stage IIB N2a1/0–1 tumors (OS, P = 0.035; DFS, P = 0.021). Further comparisons between stage IIB N2a2 and IIIA patients, following PSM analysis, indicated similar survivals (OS: P = 0.390; DFS: P = 0.210).

Conclusion

The prognosis of stage IIB N2a2 patients was worse than that of remaining stage IIB patients but comparable to that of stage IIIA patients. We proposed that stage IIB N2a2 patients should be maintained as stage IIIA.

non-small cell lung cancer

stage IIB

stage IIIA

prognosis

The 9th edition of the lung cancer TNM staging system

Lung cancer is the most malignant tumor with the highest incidence and mortality in the world^[1]. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of cases^[2]. The lung cancer tumor-node-metastasis (TNM) staging manual, proposed by the International Association for the Study of Lung Cancer, serves as the cornerstone for the standardized treatment of patients with NSCLC^{[3, 4]}.

In 2024, the 9th edition of TNM staging manual for lung cancer^[3] was released, maintaining the existing T staging without alterations. However, notable updates were made to N staging, introducing N2 sub-categories (N2a: single-station N2 metastasis; N2b: multi-station N2 metastasis)^[3]. Additionally, the M staging was further refined, with M1c now subdivided into M1c1 (multiple extra-thoracic metastases in one organ) and M1c2 (multiple extra-thoracic metastases in multiple organs)^{[3, 5]}. From the TNM staging standpoint, T1N1, formerly assigned to stage IIB, has been reclassified to stage IIA. Conversely, T1N2, previously designated as stage IIIA, has been subdivided into T1N2a (stage IIB) and T1N2b (stage IIIA)^[3].

The revisions introduced in the latest staging edition necessitate external validation to confirm their accuracy and generalizability. Within this manuscript, we direct our attention to a specific subgroup of patients transitioning from stage IIIA to IIB (T1N2a). Previous studies suggested that skip N2 metastasis is associated with improved survivals in N2 lung cancer^[6–9]. Therefore, we further separated stage IIB patients into three subgroups: stage IIB N2a1 (single-station N2 without N1 involvement), stage IIB N2a2 (single-station N2 with N1 involvements) and stage IIB N0-1. In this study, we set out to investigate potential prognostic differences among stage IIB NSCLC patients and further externally validate the stage IIB classification in the 9th edition of lung cancer TNM staging manual.

Ethical statement

This study was approved by the Ethics Committee of Peking University People's Hospital. Given the anonymized patient data and retrospective design, written informed consent was not required for this study.

Study Population

The clinical records of 7,931 patients diagnosed with pulmonary malignant tumors and admitted to the Department of Thoracic Surgery at Peking University People's Hospital between 1999 and 2018 (PKUPHTOI dataset) were systematically reviewed. This well-managed dataset has been used before^[10-13]. Inclusion criteria were as follows: (1) Diagnosis of NSCLC; (2) Underwent surgical resection; (3) stages IIB and IIIA (the 9th edition of lung cancer TNM staging manual). Exclusion criteria comprised: (1) Age < 18 years; (2) Presence of N3 disease; (3) Presence of M1 disease; (4) R1/R2 resection; (5) Sublobar resection; (6) Non-systematic lymph node dissection; (7) Primary lung cancer; (8) Receipt of neoadjuvant therapy; (9) History of previous malignancies; (10) Unavailability of clinicopathological data. A total of 2,051 eligible patients were finally included, consisting of 224 individuals with stage IIB and 227 with stage IIIA disease. Figure 1 illustrates the patient selection process. Based on the lymph node metastasis status, the stage IIB patients were further divided into three categories: IIB N2a1, IIB N2a2, and IIB N0-1.

Data Collection

The clinicopathological dataset encompassed various parameters, including age, gender (male/female), smoking history (yes/no), family tumor history (yes/no), preoperative comorbidities (yes/no), body mass index (BMI), American Society of Anesthesiologist (ASA) classification (grades 1/2/3/4), surgical approach (thoracoscopy/thoracotomy), extent of surgical resection (lobectomy, bilobectomy, and pneumonectomy), and postoperative complications. Additionally, histopathological characteristics such as histology (adenocarcinoma, squamous cell carcinoma and other), along with factors like visceral pleural invasion (VPI) (yes/no), lymphovascular invasion (LVI) (yes/no), occurrence of postoperative complications (yes/no), and receipt of postoperative adjuvant therapy (yes/no). Patient outcomes, including mortality and time to recurrence, were also recorded. Complete data analysis was performed in this study.

Surgical procedure

To ensure the absolute accuracy of N staging, we exclusively included patients who underwent radical surgical resections and systemic mediastinal lymph node dissection. The standard protocol of surgery was similar to the one previously described by Xu et.al^[14]. Systemic lymphadenectomy was defined as mediastinal lymph node dissection of at least 3 stations, including station 7 (the subcarinal lymph node), from station 4L, 5, 6, 7, 8 and 9 for the left-side NSCLCs and station 2R, 3A, 4R, 7, 8 and 9 for the right-side NSCLCs. In addition, at least 6 lymph nodes were harvested. As for N1 station lymph nodes, in routine, the station 10, 11 and 12 were dissected intraoperatively. The station 13 and 14 lymph nodes were dissected by resident doctors from the excised specimen, but this procedure was not mandatory.

Follow-up

The routine follow-up strategies for patients in our center have been previously reported^[12]. Specifically，follow-up data were acquired through comprehensive review of medical records, direct patient consultations, and telephonic interviews. Our center adheres to a rigorous postoperative follow-up protocol, involving assessments every three months during the initial two years post-surgery, biannually for the subsequent three to five years, and annually thereafter. Each follow-up session includes thorough physical examinations, monitoring of serum tumor markers, and chest computed tomography scans. Additional diagnostic modalities such as brain magnetic resonance imaging and bone scans are conducted as warranted by clinical indications. The primary endpoints of this study were overall survival (OS) and disease-free survival (DFS). OS was defined as the period from the date of diagnosis to all-cause death or the date of last follow-up. DFS was defined as the period from the date of diagnosis to the date of disease recurrence, death or the last follow-up.

Statistical Analysis

Statistical analysis was conducted using IBM SPSS Statistics (version 27.0.1, IBM Corp, Armonk, NY, USA) and R version 4.3.1 (The R Foundation for Statistical Computing, Vienna, Austria; http://www.r-project.org). Categorical variables were presented as frequencies and percentages and compared using Pearson's chi-square test or Fisher's exact test. The Shapiro-Wilk test was utilized to assess whether data follows a normal distribution. Non-normally distributed continuous variables were described using medians and ranges and compared using the Mann-Whitney U test. Survival rates were assessed using the Kaplan-Meier method and the log-rank test. Bonferroni's adjustment was applied in comparisons involving multiple subgroups in the 1:1 analysis. To mitigate bias arising from disparate baseline characteristics, one-to-one propensity score matching (PSM) was performed utilizing the R package "MatchIt" (method=nearest, replace=FALSE). Univariate and multivariate Cox proportional hazards regression analysis (forced enter method) was employed to explore the prognostic factors, with hazard ratios (HR) and 95% confidence intervals (CI) serving as statistical indicators to ascertain independent prognostic factors. The proportional hazards assumption was checked using the Schoenfeld residuals. A two-tailed P value < 0.05 was considered statistically significant.

Clinicopathological characteristics

Based on the aforementioned inclusion and exclusion criteria, a total of 2,051 eligible patients were identified, among which 224 were classified as stage IIB and 227 were classified as stage IIIA (9^th edition of lung cancer TNM staging manual). There were 38 patients in subgroup IIB N2a1, 66 in subgroup IIB N2a2, and 120 in subgroup IIB N0-1. The clinicopathological characteristics of the stage IIB patients are summarized in Table 1. The median age was 63 years (range: 32-86 years), with a predominance of male patients (72.8%). Patients in the IIB N2a2 subgroup exhibited a higher incidence of adenocarcinoma histology (P<0.001), VPI (P=0.02), LVI (P=0.001), and postoperative complications (P=0.007) compared to the other two subgroups. Additionally, a higher proportion of patients in the IIB N2a2 subgroup received postoperative adjuvant therapy (P=0.004).

Patients in stage IIB N2a2 and IIIA group were matched using PSM method, resulting in 66 well-matched pairs. The clinicopathological characteristics between stage IIB N2a2 and IIIA patients were well balanced after PSM (Table 2).

Prognosis analysis

Pairwise comparisons of survival among groups IIB N2a1, IIB N2a2, and IIB N0-1 using Kaplan-Meier and Bonferroni correction showed that group IIB N2a2 patients had the worst OS (5-years OS rate: 73.0% vs. 59.5% vs. 62.7%, P=0.078, Figure 2A; 5-years DFS rate: 65.5% vs. 35.5% vs. 56.6%, P=0.007, Figure 2B), while there was no difference in either OS or DFS between stage IIB N2a1 and IIB N0-1 patients (5-years OS rate: P=0.439; 5-years DFS rate: P=0.398). These results were further supported by univariate results (OS HR: IIB N2a1 vs. IIB N2a2 vs. IIB N0-1=1 vs. 1.840 vs.1.236, P=0.082, Figure 2C; DFS HR: IIB N2a1 vs. IIB N2a2 vs. IIB N0-1=1 vs. 2.142 vs.1.272, P=0.009, Figure 2D).

Based on the aforementioned findings, we further combined IIB N2a1 and IIB N0-1 into one group (IIB N2a1/0-1), again compared with IIB N2a2, showing a significant difference in both DFS and OS between these two groups (5-year OS rate: 65.2% vs 59.5%, P=0.03, Figure 3A; 5-year DFS rate: 58.8% vs 35.5%, P=0.002, Figure 3B). The results of univariate Cox analysis show that stage IIB classification (IIB N2a1/0-1 vs. IIB N2a2) was a potential prognostic factor for both OS and DFS (OS HR: IIB N2a1/0-1 vs. IIB N2a2 =1 vs. 1.560, P=0.032, Table S1; DFS HR: IIB N2a1/0-1 vs. IIB N2a2 =1 vs. 1.780, P=0.003; Table S2). The multivariate Cox analysis further confirmed that stage IIB classification was an independent prognostic factors for both OS and DFS (OS: HR: IIB N2a1/0-1 vs. IIB N2a2 =1 vs. 1.556, P=0.035, Figure 3C, Table S1; DFS:HR: IIB N2a1/0-1 vs. IIB N2a2 =1 vs. 1.626, P=0.021; Figure 3D, Table S2).

Prognostic comparisons between Stage IIB N2a2 and IIIA patients

The survival outcomes of stage IIB N2a2 and stage IIIA patients were compared. Before PSM, there was no significant disparity in survivals between these two groups (5-year OS rate: 59.5% vs. 54.2%, P=0.727, Figure 4A; 5-year DFS: 35.5% vs. 43.0%, P=0.482, Figure 4B). After PSM, the survival rates between the two groups remained statistically similar (5-year OS rate: 59.5% vs. 56.4%, P=0.390, Figure 4C; 5-year DFS: 35.5% vs. 46.2%, P=0.210 Figure 4D). Univariate Cox analysis further indicated no significant differences in OS and DFS between the two groups (OS HR: IIB N2a2 vs. IIIA =1 vs. 0.812, P=0.391, Figure 5A, Table S3; DFS HR: IIB N2a2 vs. IIIA =1 vs. 0.757, P=0.212, Figure 5B, Table S4).

Our research team possesses a wealth of experience in the refinement of lung cancer TNM staging, having actively contributed to the advancement of previous iterations^{[13, 15-21]}. We have previously observed variations in prognosis among NSCLC patients within the same TNM stage^[16-19]. In this study, we aimed to assess prognostic differences among NSCLC patients in different stage IIB subgroups based on the 9^th edition TNM staging criteria. Our findings revealed that the prognosis of stage IIB N2a2 (single-station N2 with N1 involvements) patients were significantly inferior to that of other stage IIB patients but comparable to that of stage IIIA patients. Consequently, we proposed that part of stage IIB (N2a2) patients should be maintained as stage IIIA. However, further validation is warranted to corroborate our conclusion.

As of now, there has been no research exploring and validating the rationality of downstaging certain patients, such as T1N2a patients, in the 9^th edition TNM staging criteria. Our study specifically focuses on this patient subset and utilizes our center's well-maintained data to validate this new staging adjustment. Following rigorous statistical analyses including multivariate Cox analysis and PSM, our study innovatively proposed that patients with T1N2a1 diseases should indeed be downstaged to stage IIB, consistent with the 9^th edition TNM staging criteria. However, patients with T1N2a2 diseases should remain classified as stage IIIA. Our research holds significant clinical implications, as accurate TNM staging constitutes the fundamental cornerstone for guiding subsequent patient management strategies. Our findings raise the possibility that certain NSCLC patients classified as stage IIB according to the 9^th edition TNM staging criteria may be underestimated. The imprecise staging might ultimately have detrimental effects on their treatment and surveillance. For instance, in clinical practice, when physicians encounter patients with N2a2 involvements, according to the 9^th edition of the TNM classification for Lung Cancer, they classify these patients as stage IIB. Relative to the previous classification as stage IIIA, clinicians might incline toward recommending less aggressive treatment modalities and less intensive surveillance strategies to these patients. However, such approaches may unfavorably impact the prognosis of these individuals.

In previous studies, several clinical series have reported the favorable prognosis of skip metastasis (N2a1)^[6-9]. Therefore, it is necessary to further investigate the prognosis of patients with skip metastasis and sequential metastasis (N2a2) among those diagnosed with stage IIB (N2a). Our results were consistent with prior studies, demonstrating that patients with N2a1 exhibit markedly superior prognoses compared to those with N2a2. The prognostic outcomes of N2a1 patients resembled those of remaining stage IIB patients, which underscored the legitimacy of downstaging such individuals from stage IIIA to stage IIB. For the observed phenomenon of better prognosis in N2a1 patients compared to poorer prognosis in N2a2 patients, our interpretations were as follows: (1) patients with N2a2 status typically harbored a greater tumor burden, a factor previously associated with poorer prognosis in existing literature^{[6, 9, 22]}; (2) due to incomplete lymph node dissection or limitations in pathological diagnostic techniques, N2a2 patients may indeed present with multi-station N2 lymph node involvements. However, given our stringent inclusion criteria, which exclusively included patients undergoing systematic lymph node dissection, coupled with the esteemed reputation of our pathology department as one of the premier medical pathology centers in mainland China, the likelihood of this scenario is considered minimal; (3) the occurrence of skip metastasis (N2a1) is attributed to several factors. One of the main reasons is the anatomical connectivity within the lymphatic system^{[23, 24]}. Abundant lymphatic vessels and networks beneath the pleura provide a direct pathway for tumor cells to bypass the intrapulmonary and hilar lymph nodes, draining directly into the ipsilateral mediastinal lymph nodes. In theory, without these direct pathways, tumors may only metastasize to the hilar lymph nodes, failing to extend to the mediastinal lymph nodes. Therefore, N2a1 and N1 patients might have similar prognosis.

Our study had several limitations that warrant consideration. Firstly, it was a single-center retrospective study, inherently susceptible to bias. Secondly, the sample size within the stage IIB subgroups was relatively small, potentially limiting the statistical power of our results. Future investigations with larger sample sizes are warranted to address this limitation. Lastly, it remains uncertain whether the conclusions drawn from our exploration of pathological staging in this article are equally applicable to clinical staging. Our database lacks detailed records of clinical lymph node metastasis. Therefore, more detailed data are needed to validate our findings.

In conclusion, our study indicated that the prognosis of stage IIB (N2a2) patients was inferior to that of other stage IIB patients but comparable to that of stage IIIA patients. Thus, we proposed retaining stage IIB (N2a2) classification within the original stage IIIA designation. However, our conclusions warranted further validations.

TNM, tumor-node-metastasis

NSCLC, non-small cell lung cancer

OS, overall survival

DFS, disease-free survival

PSM, propensity score matching

N2a1, single-station N2 without N1 involvement;

N2a2, single-station N2 with N1 involvement;

BMI, body mass index;

ASA, American society of anesthesiologist physical status classification system;

VPI, visceral pleural invasion;

LVI, lymphovascular invasion;

HR, hazard ratio;

CI, confidence interval;

Conflict of interest statement:

The authors declare no conflict of interest.

Funding:

This work was supported by Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences (2021RU002); CAMS Innovation Fund for Medical Sciences (CIFMS, 2022-I2M-C&T-B-120) and the National Natural Science Foundation of China (No.92059203)

Author contribution statement:

(I) Conception and design: Ke-Zhong Chen and Jing-Sheng Cai

(II) Administrative support: Ke-Zhong Chen and Yun Li

(III) Provision of study materials or patients: Tong Wu and Jing-Sheng Cai

(IV) Collection and assembly of data: Tong Wu and Jing-Sheng Cai

(V) Data analysis and interpretation: Tong Wu and Jing-Sheng Cai

(VI) Manuscript writing: Tong Wu and Jing-Sheng Cai

(VII) Final approval of manuscript: All authors

Data availability statements

The data underlying this article will be shared on reasonable request to the corresponding author.

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Table 1

The baseline characteristics of the included stage IIB NSCLC patients
Characteristic	IIB N2a1 (n = 38)	IIB N2a2 (n = 66)	IIB N0-1 (n = 120)	P
Sex				0.124
Male	26 (68.4%)	43 (65.2%)	94 (78.3%)
Female	12 (31.6%)	23 (34.8%)	26 (21.7%)
Age, years				0.103^a
Median (range)	60.5 (37–86)	61 (37–81)	64.5 (32–80)
Smoking				0.083
No	21(55.3%)	33(50.0%)	45(37.5%)
Yes	17(44.7%)	33(50.0%)	75(62.5%)
Family tumor history				0.110
Without	38 (100%)	60 (90.9%)	107 (89.2%)
With	0 (0.0%)	6 (9.1%)	13 (10.8%)
Preoperative comorbidity				0.239
Without	14 (36.8%)	23 (34.8%)	56 (46.7%)
With	24 (63.2%)	43 (65.2%)	64 (53.3%)
BMI				0.328^b
< 18.5	1 (2.6%)	2 (3.0%)	5 (4.2%)
18.5–24	13 (34.2%)	29 (43.9%)	62 (51.7%)
>=24	24 (63.2%)	35 (53.0%)	53 (44.2%)
ASA grade				0.573^b
1	5 (13.2%)	13 (19.7%)	26 (21.7%)
2	30 (78.9%)	52 (78.8%)	87 (72.5%)
3	3 (7.9%)	1 (1.5%)	6 (5.0%)
4	0 (0.0%)	0 (0.0%)	1 (0.8%)
Surgical type				<0.001
Thoracoscope	32 (84.2%)	58 (87.9%)	73 (60.8%)
Thoracotomy	6 (15.8%)	8 (12.1%)	47 (39.2%)
Surgical extent				0.146^b
Lobectomy	34 (89.5%)	60 (90.9%)	95 (79.2%)
Bi-lobectomy	3 (7.9%)	5 (7.6%)	13 (10.8%)
Pneumonectomy	1 (2.6%)	1 (1.5%)	12 (10.0%)
Histology				<0.001
Adenocarcinoma	28 (73.7%)	54 (81.8%)	44 (36.7%)
Squamous	9 (23.7%)	8 (12.1%)	64 (53.3%)
Other	1 (2.6%)	4 (6.1%)	12 (10.0%)
VPI				0.020
Without	30 (78.9%)	34 (51.5%)	77 (64.2%)
With	8 (21.1%)	32 (48.5%)	43 (35.8%)
LVI				0.001
Without	27 (71.1%)	36 (54.5%)	96 (80.0%)
With	11 (28.9%)	30 (45.5%)	24 (20.0%)
Postoperative complications				0.007^b
Without	35 (92.1%)	60 (90.9%)	119 (99.2%)
With	3 (7.9%)	6 (9.1%)	1 (0.8%)
Adjuvant therapy				0.004
Not performed	17 (44.7%)	19 (28.8%)	65 (54.2%)
Performed	21 (55.3%)	47 (71.2%)	55 (45.8%)
a Kruskal-Wallis H test
b Fisher's exact test
N2a1, single-station N2 without N1 involvement; N2a2, single-station N2 with N1 involvement; BMI, body mass index; ASA, American society of anesthesiologist physical status classification system; VPI, visceral pleural invasion; LVI, lymphovascular invasion

Table 2

The baseline characteristics of the stage IIB (N2a2) and stage IIIA NSCLC patients before and after PSM
Characteristic	Before PSM			After PSM
Characteristic	IIB N2a2 (n = 66)	IIIA (n = 227)	P	IIB N2a2 (n = 66)	IIIA (n = 66)	P
Sex			0.408			0.854
Male	43 (65.2%)	160 (70.5%)		43 (65.2%)	44 (66.7%)
Female	23 (34.8%)	67 (29.5%)		23 (34.8%)	22 (33.3%)
Age, years			0.401^a			0.577^a
Median (range)	61 (37–81)	61 (34–81)		61 (37–81)	62 (34–81)
Smoking			0.240			0.862
No	33 (50.0%)	95 (41.9%)		33 (50.0%)	32 (48.5%)
Yes	33 (50.0%)	132 (58.1%)		33 (50.0%)	34 (51.5%)
Family tumor history			0.581			0.753
Without	60 (90.9%)	213 (93.8%)		60 (90.9%)	61 (92.4%)
With	6 (9.1%)	14 (6.2%)		6 (9.1%)	5 (7.6%)
Preoperative comorbidity			0.204			0.157
Without	23 (34.8%)	99 (43.6%)		23 (34.8%)	31 (47.0%)
With	43 (65.2%)	128 (56.4%)		43 (65.2%)	35 (53.0%)
BMI			0.406			0.501^b
< 18.5	2 (3.0%)	11 (4.8%)		2 (3.0%)	4 (6.1%)
18.5–24	29 (43.9%)	116 (51.1%)		29 (43.9%)	33 (50.0%)
>=24	35 (53.0%)	100 (44.1%)		35 (53.0%)	29 (43.9%)
ASA grade			0.605			0.306^b
1	13 (19.7%)	47 (20.7%)		13 (19.7%)	13 (19.7%)
2	52 (78.8%)	171 (75.3%)		52 (78.8%)	48 (72.7%)
3	1 (1.5%)	9 (4.0%)		1 (1.5%)	5 (7.6%)
4	0 (0.0%)	0 (0.0%)		0 (0.0%)	0 (0.0%)
Surgical type			0.005			1.000
Thoracoscope	58 (87.9%)	161 (70.9%)		58 (87.9%)	58 (87.9%)
Thoracotomy	8 (12.1%)	66 (29.1%)		8 (12.1%)	8 (12.1%)
Surgical extent			0.069			0.266^b
Lobectomy	60 (90.9%)	192 (84.6%)		60 (90.9%)	60 (90.9%)
Bi-lobectomy	5 (7.6%)	12 (5.3%)		5 (7.6%)	2 (3.0%)
Pneumonectomy	1 (1.5%)	23 (10.1%)		1 (1.5%)	4 (6.1%)
Histology			0.003			0.118^b
Adenocarcinoma	54 (81.8%)	138 (60.8%)		54 (81.8%)	49 (74.2%)
Squamous	8 (12.1%)	77 (33.9%)		8 (12.1%)	16 (24.2%)
Other	4 (6.1%)	12 (5.3%)		4 (6.1%)	1 (1.5%)
VPI			0.250			0.159
Without	34 (51.5%)	135 (59.5%)		34 (51.5%)	42 (63.6%)
With	32 (48.5%)	92 (40.5%)		32 (48.5%)	24 (36.4%)
LVI			0.694			0.164
Without	36 (54.5%)	130 (57.3%)		36 (54.5%)	28 (42.4%)
With	30 (45.5%)	97 (42.7%)		30 (45.5%)	38 (57.6%)
Postoperative complications			0.968			0.572
No	60 (90.9%)	206 (90.7%)		60 (90.9%)	58 (87.9%)
Yes	6 (9.1%)	21 (9.3%)		6 (9.1%)	8 (12.1%)
Adjuvant therapy			0.006			0.554
No	19 (28.8%)	109 (48.0%)		19 (28.8%)	16 (24.2%)
Yes	47 (71.2%)	118 (52.0%)		47 (71.2%)	50 (75.8%)
a Mann-Whitney U test
b Fisher's exact test
N2a2, single-station N2 with N1 involvement; BMI, body mass index; ASA, American society of anesthesiologist physical status classification system; VPI, visceral pleural invasion; LVI, lymphovascular invasion

No competing interests reported.

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Validation for revision of the stage IIIA(T1N2) in the forthcoming ninth edition of the TNM classification for lung cancer

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