Influence of pleural invasion on survival in pathologic T3–4N0M0 non-small cell lung cancer: a propensity score matching study based on the Surveillance, Epidemiology, and End Results database

Introduction

Lung cancer represents the most frequently diagnosed and leading cause of cancer-related death worldwide (1). Approximately 80–85% of patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC) (2). Surgical resection, whenever possible, is generally the preferred treatment modality for early-stage NSCLC (3). The 5-year survival rate for patients with NSCLC ranges from 9% to 65%, with this variability being attributable to stage and geographic differences (4).

Pleural invasion (PI) is known to be one of the most important prognostic factors in patients undergoing complete lung cancer resection (5). In 1997, it was incorporated as a negative prognosticator within the fifth edition of tumor, node, metastasis (TNM) classification criteria (6). The International Association for the Study of Lung Cancer (IASLC) recommends classifying PI status as follows: PL0, no evidence of visceral pleural invasion (VPI) surpassing the elastic layer; PL1, invasion surpassing the elastic layer; PL2, invasion to the pleural surface; and PL3, invasion to the parietal pleural, thoracic wall, or both (7). PL1 and PL2 both represent invasion of the VPI, while PL3 represents parietal pleural invasion (PPI). The seventh and eighth editions of the TNM staging system introduced VPI as a size-independent T2 factor, upstaging tumours ≤3 cm to T2a. PPI is a T3 descriptor, as no prognostic differences have been found regarding tumors macroscopically invading the chest wall (8-10).

However, recent IASLC studies have shown that pathologic chest wall or parietal pleura involvement results in poorer survival than other T3 descriptors, with survival rates comparable to those of T4 (11). This topic remains controversial, and it is still unclear whether VPI impacts overall survival (OS), equivalent to PPI in the T3 category. This study thus aimed to determine the prognostic influence of PI and the possibility of modifying the TNM classification of NSCLC. Using the Surveillance, Epidemiology, and End Results (SEER) database, we compared the oncologic outcomes according to PI status in patients who had undergone resection for pT3–4N0M0 NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-860/rc).

Methods

Data collection

We conducted a survival analysis of the patients in SEER database with custom data and additional treatment fields. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and included patients with an NSCLC diagnosis who had undergone radical surgery between 2010 and 2019. The flowchart of patient selection is shown in Figure S1. Exclusion criteria were distant metastasis at diagnosis, lack of available survival information, TNM classification, age, tumor size, stage, chemotherapy or radiotherapy status, node involvement, PI, and histologically confirmed resection. Based on the information in the SEER database, patients with NSCLC were reclassified according to the eighth edition of the TNM classification, and those which did not match the TNM staging were excluded (12). The PI status was obtained from the collaborative stage site-specific factor 2 variables and collaborative stage extension.

Variable definition

In this observational population, we extracted the following information: population baseline data (race, age, sex, cause of death, survival), tumor characteristics (tumor location, histological subtypes, T category, PI) and treatment (resection, radiotherapy, and chemotherapy). In addition, the different histologic types were collected into three categories including squamous cell carcinoma, adenocarcinoma, and other [e.g., neuroendocrine cancers (NEC), neuroendocrine tumor (NET), spindle cell carcinoma]. Surgical resection was divided into wedge resection, segmental resection, lobectomy, and pneumonectomy. According to different T categories and PI status, tumors were divided into six groups (T3PL0, T3PL1/2, T3PL3, T4PL0, T4PL1/2, T4PL3) or four groups (T3 without PI, T3 PI, T4 without PI, T4 PI).

Statistical analysis

Categorical variables were expressed frequencies and percentages, while continuous variables were expressed as the mean and standard deviation or as the median and interquartile range. OS was assessed using the Kaplan-Meier method and compared using the log-rank test; OS was defined as the time interval between surgery and death. The Cox proportional hazard ratios model assessed the variables that significantly influenced OS in multivariable analysis. Variables with two-sided P values ≤0.05 were considered statistically significant. All variables with a P value <0.10 or otherwise considered clinically relevant were included in a multivariable model in stepwise fashion.

Propensity score matching (PSM) was used to balance the potential bias between groups. The baseline characteristics of patients included age, race, sex, histological type, tumor location, surgical type, chemotherapy, and radiotherapy. This study used the nearest-neighbors method to compare the groups (matching ratio =1:1, caliper =0.02) based on the propensity scores. Statistical analysis was performed with the R version 3.6.2 (The R Foundation for Statistical Computing).

Results

Characteristics of patients

A total of 9,185 surgically treated patients with NSCLC met the inclusion criteria. The median follow-up time after surgery was 33 months (interquartile range: 14–63 months). From the total number of patients, 1,770 (19.27%) had VPI and 1,007 (10.96%) had PPI (Table 1). The proportions of patient’s gender, age, race, histologic type, T category, tumor location, chemotherapy, and radiotherapy between patients without and with PI were significantly different (P<0.001). The differences in the proportion of surgical types between patients with tumors without and with PI were not significantly different (P=0.68). Compared with that of squamous cell carcinoma, the proportion of pleural involvement in adenocarcinoma was lower (29.01 vs. 36.18), with a higher proportion of VPI (20.26 vs. 19.71) and a lower proportion of PPI (8.75 vs. 16.46). With worse PI, the proportions of patients undergoing radiotherapy and chemotherapy significantly increased.

OS in groups with different T categories and PI statuses

Tumors were stratified into six groups according to different T categories and PI statuses. In patients with T4 tumors, the 5-year OS rates of T4 PL0, PL1/2, and PL3 were 52.8%, 38.4%, and 31.7%, respectively. Figure 1A indicates that patients’ OS significantly decreased with worsening PI (P<0.001). As shown in Table S1, both univariable and multivariable survival analyses for patients with T4 tumors indicated that the presence of pleural involvement was significantly associated with worse prognosis [PL1/2 vs. PL0: hazard ratio (HR) =1.42, 95% confidence interval (CI): 1.25–1.62, P<0.001; PL3 vs. PL0: HR =1.91, 95% CI: 1.58–2.30, P<0.001]. Furthermore, age, gender, chemotherapy, and radiotherapy were identified as significant predictors of OS.

In patients with T3 tumors, the 5-year OS rates of T3PL0, PL1/2, and PL3 subgroups were 60.9%, 52.2%, and 46.5%, respectively. Figure 1B indicates that patients’ OS significantly decreased with worsening PI (P<0.001). As shown in Table S2, both univariable and multivariable survival analyses for patients with T3 tumors indicated that the presence of pleural involvement was significantly associated with worse prognosis (PL1/2 vs. PL0: HR =1.26, 95% CI: 1.13–1.41, P<0.001; PL3 vs. PL0: HR =1.34, 95% CI: 1.19–1.51, P<0.001). Besides age, gender, chemotherapy, and radiotherapy, histologic and surgical types were also identified as significant predictors of OS.

Figure 1 Kaplan-Meier survival curves of OS between groups (based on T categories and PL status). (A) Survival curve for patients with T4. (B) Survival curve for patients with T3. OS, overall survival; PL, pleural layer.

OS after PSM in patients with stage T3 and T4 disease

The PSM model included eight variables: age, gender, race, histologic type, tumor location, surgical type, chemotherapy, and radiotherapy. After PSM, the discrepancy of all variables was balanced (see Tables S3-S6).

OS after PSM for the T4PL0, T4PL1/2, and T4PL3 subgroups

After PSM, 626 matched pairs were divided into the T4PL0 and T4PL1/2 subgroups, and 196 matched pairs were divided into the T4PL1/2 and T4PL3 subgroups. A significant difference in OS was found between the T4PL0 and T4PL1/2 groups (P<0.001; Figure 2A). However, there was no significant difference in OS between the T4PL1/2 and T4PL3 subgroups (P=0.25; Figure 2B).

Figure 2 The Kaplan-Meier survival curves of OS between groups based on T categories and PI status after PSM. (A) Survival curve of OS for patients with T4 (PL0, PL1/2). (B) Survival curve of OS for patients with T4 (PL1/2, PL3). (C) Survival curve of OS for patients with T3 (PL0, PL1/2). (D) Survival curve of OS for patients with T3 (PL1/2, PL3). OS, overall survival; PSM, propensity score matching; PL, pleural layer; PI, pleural invasion.

OS after PSM for the T3PL0, T3PL1/2, and T3PL3 subgroups

After PSM, 1,138 matched pairs were classified into the T3PL0 and T3PL1/2 subgroups, and 663 matched pairs were classified into the T3PL1/2 and T3PL3 subgroups. Analysis of OS revealed a statistically significant difference between the T3PL0 and T3PL1/2 groups (P=0.001; Figure 2C). However, the OS comparison between the T3PL1/2 and T3PL3 groups did not show a statistically significant difference (P=0.12; Figure 2D).

OS in patients with T3 but not PI, T3 with PI, T4 but not PI, and T4 with PI

No significant differences were found between the T4PL1/2 and T4PL3 subgroups or between the T3PL1/2 and T3PL3 subgroups. Consequently, these groups were merged to form two aggregated cohorts: T4 PI and T3 PI.

Subsequent stratification yielded four distinct cohorts: T3 without PI, T3 with PI, T4 without PI, and T4 with PI; the 5-year OS rates observed for these groups were 60.9%, 49.6%, 52.8%, and 36.6% (P<0.001), respectively. Notably, T3 with PI exhibited a lower OS than did T4 without PI (Figure 3).

Figure 3 The OS Kaplan-Meier curves for T3–4N0M0. Kaplan-Meier curves of different PI statuses and T category groups (median OS for T3 without PI vs. T3PI vs. T4 without PI vs. T4PI: 88 vs. 59 vs. 66 vs. 36 months, respectively; P<0.001). OS, overall survival; PI, pleural invasion.

OS after PSM in the T3 PI and T4 without PI subgroups

PSM was conducted to elucidate the differences between the T3 PI and T4 without PI subgroups. After PSM, 1,646 matched pairs were divided into the T3 PI and T4 without PI subgroups (Table S7). Before PSM, a significant difference in OS was observed between the T3 PI and T4 without PI and subgroups (P=0.01; Figure 4A). However, after PSM, no significant differences in OS were revealed between the two matched groups (P=0.30; Figure 4B).

Figure 4 Kaplan-Meier survival curves of OS between T3 PI and T4 without PI before and after PSM. (A) The survival curve for the OS for patients before PSM (5-year OS for T3 PI vs. T4 without PI: 49.6% vs. 52.8%; P=0.01. (B) Survival curve of OS for patients after PSM (5-year OS for T3 PI vs. T4 without PI: 50.0% vs. 51.8%; P=0.30). OS, overall survival; PSM, propensity score matching; PI, pleural invasion.

Discussion

During the past several decades, several studies have demonstrated that patients with VPI have worse outcomes, with a higher rate of mediastinal lymph node metastases, malignant pleural effusion, and postoperative recurrence (13-16). Despite concerns regarding the effects of VPI severity on T category, the eighth edition of TNM classification states that only tumors ≤3 cm (T1) with VPI should be upgraded to T2a, whereas VIP is not a descriptor for tumors >3 cm (10). However, Yoshida et al. noted the substantial impact of VPI and suggested that tumors smaller than 7 cm be reclassified to a higher T stage in the forthcoming TNM staging system revision (17). Yang et al. reported that the OS of patients with VPI and N0 tumors is associated with a poorer OS than that of patients with N1 or N2 tumors (18). Several studies suggest that patients with VPI and tumors larger than 3 cm should potentially be upgraded (7,19-22). PPI is a T3 descriptor that is similar to chest wall infiltration (CWI), as no prognostic differences have been found for tumors macroscopically invading the chest wall (23). Furthermore, the classification of T3 tumors with PL3 or CWI did not escalate with the increased extent of PI (10). A recent study suggests an upward revision of its category (24).

In this series, we analyzed the impact of PI on the survival of patients with NSCLC using a large dataset from the SEER database. Considering the differences between the T3N0M0 and T4N0M0 tumors (in stages IIB and IIIA, respectively), we proposed a method to incorporate PI into the T status in the revised TNM classification. We performed multivariable analysis to exclude the effects of other factors and found that the independent prognostic factors of T4N0M0 were pleural involvement status, age, gender, chemotherapy, and radiotherapy; meanwhile, the independent prognostic factors of T3N0M0 were pleural involvement status, age, gender, chemotherapy and radiotherapy, histologic type, and surgical type.

Based on the multivariable analysis results, we applied propensity score PSM to address variable imbalances between the subgroups, thus more accurately characterizing the survival differences of PI across these groups. The analysis indicated that all levels of PI (VPI, PPI) correlated with poorer prognoses. However, no survival difference was observed between the VPI and PPI groups in T3–4N0M0 (Figure 2B,2D).

Therefore, we divided the participants into four groups based on the presence or absence of PI. After PSM and survival analysis, we found that patients with PI had worse survival across all stages. Notably, the 5-year OS for patients with T3 PI tumors was 50.0% compared to 51.8% for T4 without PI, and no significant difference in survival was found (before PSM: P=0.01; after PSM: P=0.30), which suggested that T3 tumors with PI should be upstaged to T4.

Additionally, VPI was observed in 18.1% of T3N0M0 tumors, significantly less frequently than in T4N0M0 tumors (21.8%), which is consistent with previously reported rates which range from 11.5% to 26.8% (14,25-27). Other studies have indicated that VPI increases with tumor size (19,26,28), significantly so in tumor sizes larger than 3 cm (29). Multiple factors affect survival outcomes: as the influence of one factor (tumor size) increases, another factor (PI) may correspondingly decrease. This may explain why statistical analysis revealed no significant survival differences between the VPI and PPI groups.

The extent of VPI can be described as PL1 and PL2, but it remains unclear whether the distinction between PL1 and PL2 is relevant to survival. Kawase et al. and Adachi et al. found no evidence of a significant survival difference between PL1 and PL2 regardless of the status of lymph node involvement (22,30). However, other studies have reported a significant difference in OS between patients with PL1 and PL2 (23,31,32). We did not perform stratification of OS with PL1 and PL2 combined with tumor size, which was a limitation of our study. Therefore, a prognostic model that includes the detailed depth of VPI should be constructed in subsequent research.

Moreover, the chest wall comprises the parietal pleura, soft tissue, intercostal muscles, and ribs (33). The SEER database does not clearly differentiate between PL3 and CWI. Considering the presence of PPI in patients with CWI, Matsuoka et al. found no significant difference in survival rates across the different extents of CWI (parietal pleura: 32.5%; subpleural tissue: 30.0%; ribs: 38.5%) (8). Additionally, in recent research by Ugalde et al., no significant differences in OS associated with PL3 and CWI as T3 descriptors (log-rank P=0.26) was found (24). In the IASLC’s recommendations for the ninth edition TNM classification, clinical T3-PPI/CWI aligns well with the other cT3 descriptors; however, pathologic T3-PPI/CWI corresponds to pT4. Due to the inconsistent findings, they did not recommend reclassifying T3-PPI/CWI (11). In our study, the PL3 and CWI subgroups were consolidated, with the results being consistent with the related IASLC studies. Additionally, we found no difference in long-term survival between pathologic T3PL1/2 and T3PL3, T3 PI comparable to T4 (Figures 2D,4B).

This study had certain limitations which should be noted. First, as a retrospective study spanning over a decade, selection bias could not be ruled out. Second, SEER does not include detailed information on the patients’ condition, smoking history, postoperative complications, gene mutation detection, programmed cell death ligand 1 (PD-L1) detection, adjuvant therapeutic agents and dose, which are necessary for prognosis. Additionally, SEER does not specify residual tumor classification (R0, R1, or R2), which is crucial in understanding the oncological outcomes of different surgical approaches, particularly in comparing wedge resection, segmentectomy, and lobectomy. Finally, due to insufficient data on cancer recurrence and disease-free survival, we were unable to assess the relationship between progression-free survival and PI. Fortunately, the clinical information is standard. Reasonable and scientific PSM analysis methods were applied in our study to reduce the covariate imbalance and selection bias, and the conclusions drawn from the findings are sound.

Conclusions

PI was found to be a risk factor for poor prognosis in patients with pT3–4N0M0 NSCLC. Our results recommend future studies exploring the prognostic value of various T3–4 subcategories to allow PI to be separated from other T descriptors and confounders.

Acknowledgments

The preliminary results of this study were presented in part at the 31st European Conference on General Thoracic Surgery of the European Society of Thoracic Surgeons, Milan, Italy on June 4–6, 2023 (Oral presentation, O-079).

The authors would like to thank Ramón Rami-Porta, a thoracic surgeon from Hospital Universitari Mútua Terrassa, Terrasa, Spain, for reviewing the manuscript and providing relevant comments on different issues of the TNM classification of lung cancer.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-860/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-860/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-860/coif). W.Z. receives financial support from China Scholarship Council during his studies in Germany. H.B. is from Charité Research Organisation GmbH (CRO), Berlin, Germany. The other 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).

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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