Lung cancer is the second most common malignancy in the global cancer spectrum of morbidity and is still the leading cause of cancer mortality (1). The prognosis of lung cancer is poor, and the 2-year overall survival rate of patients with non-small cell lung cancer (NSCLC) and small cell lung cancer is approximately 42% and 15%, respectively (2). The eighth edition of the tumor-lymph node-metastasis (TNM) classification system from the American Joint Committee on Cancer was launched in January 2017, the most accurate and newest classification system (3, 4). However, the role played by some uncommon factors that may be related to T classification in prognosis and the issue of ascending T classification are still not annotated in enough detail in National Comprehensive Cancer Network guidelines and clinical practice (4–6). Precise evaluation of T descriptor plays a crucial role in estimating prognosis and deciding on the most appropriate treatment. Nevertheless, the prognostic difference among parietal pleura invasion, rib invasion, and other established T classifications is still unclear (6).

Previous studies suggested that patients with parietal pleura invasion with tumor size ≤7cm had a close survival rate to patients with T3 descriptor (7, 8). Nevertheless, the results from other studies revealed that the patients with parietal pleura invasion or other chest wall invasion reached worse long-term survival outcomes than other patients in the group for classification T3 or T4 (9, 10). Thus, the prognosis of parietal pleura invasion and rib invasion remains unclear because of the unclear T classification. Besides, it is still inconsistent in view on whether there is a prognostic difference between patients with rib invasion and parietal pleural invasion (8, 11). Therefore, it is important to investigate the prognostic difference and significance of parietal pleura invasion and rib invasion in pathological T (pT) classification with NSCLC. This study aimed to elucidate the significance of the above two factors for survival and their risk grade in pT-classification when combined with different-category tumor sizes.

In the present study, the data of 8681 patients were used to perform principal analysis. The results revealed that parietal pleura invasion and rib invasion were confirmed as independent prognostic risk indicators after adjusting for other confounders. Then, the prognosis of patients with rib invasion had indeed been shown to be worse than that of patients with parietal pleural invasion. Next, a sub-group analysis was conducted in cases with different statuses of chest wall invasion. According to the results of the sub-group analysis, we further re-classify the patients with only parietal pleura invasion into one group for those with tumor size ≤5cm, and another group for those with tumor size over 5cm and put patients with rib invasion in the same group. Based on those classifications, sub-groups of parietal pleura invasion for tumor size ≤5cm and tumor size >5cm got a meaningful stratification effect. The three classifications mentioned above and the classifications pT1, pT2, pT3, and pT4 were conducted to prognostic analysis together. After adjusting for other factors, parietal pleura invasion with tumor size ≤5cm could be considered classification pT3, and parietal pleura invasion with tumor size >5cm might be served as pT4 classification. In addition, rib invasion had the worst survival in that cohort. Parietal pleura invasion plus tumor size ≤5cm is considered pT3; however, patients for parietal pleura invasion plus tumor size >5cm should be treated as pT4. Rib invasion has a poorer prognosis than pT4. Besides, 96 patients with pleural effusion (TxN0M1a classification) were compared with those with rib invasion, which found that the prognosis of pleural effusion was much worse than that of rib invasion. Therefore, we suggested that parietal pleura invasion plus tumor size ≤5cm was treated as pT3; however, parietal pleura invasion plus tumor size with 5.1-7.0cm should ascend to pT4. Those findings may help the treatment plan before surgery. For example, patients diagnosed with NSCLC by biopsy are regarded as early-stage lung cancer only from the tumor size. However, if chest wall invasion is found on imaging, the clinical combined stage may change from early to locally advanced. For patients with locally advanced stages, neoadjuvant therapy may benefit the patients’ complete resection rates (12). Given the prognosis of M1a classification was poorer than rib invasion; hence, rib invasion should continue to be classified as a local disease rather than a metastatic disease. Thus, surgical resection is still an appropriate therapeutic modality for patients with chest wall invasion.

The prognostic difference between the parietal pleura invasion and rib invasion remains unclear. Previous studies majorly paid attention to the role of resection for chest wall on the prognosis of NSCLC patients who had the disease with chest wall invasion (13, 14). In addition, for patients with chest wall invasion who received surgical resection, the extent of nodal involvement (15, 16), the completeness of resection (15, 16), blood transfusion (17), and forced vital capacity (17) were confirmed to be associated with prognosis. Nevertheless, it was controversial whether the depth of invasion affects the prognosis for patients with chest wall invasion. In the studies by Robert J. Downey et al. and Hidehito Matsuoka et al., patients with only parietal pleura invasion did not have a more significant survival improvement, compared with patients with rib invasion (15, 18). The studies from Francesco Facciolo et al. and Alain Chapelier et al. analyzed the data of patients with chest wall invasion, respectively, and got the contrary results that the depth of chest wall involvement impacted the prognosis of those patients (16, 19). The present study results also revealed that rib invasion had a worse survival over the parietal pleura invasion. The survival analyses of studies by Robert J. Downey et al. and Hidehito Matsuoka et al. were not adjusted for other confounders. Therefore, other factors might affect their results, such as age, gender, and differentiation grade. In the clinical practice and TNM staging system, tumor size and differentiation are still essential indicators to confirm the combined stage and to estimate the prognosis (3, 5, 20). Nevertheless, previous studies had neglected to consider the two abovementioned factors when exploring the effect of depth of chest wall invasion on patients’ prognosis (8, 16, 18). In the present study, differentiation grade and tumor size, which were considered factors affecting prognosis, were recognized and adjusted by us. We conclude that after adjusting for these confounding factors, the prognosis of rib invasion is much worse than that of pleural invasion. These findings might provide information for investigating the difference between parietal pleura invasion and rib invasion to The International Association for the Study of Lung Cancer (6).

The role played by parietal pleural invasion and rib invasion in the T classification still needs to be revealed. Although the ^eighth edition staging system classified chest wall invasion as descriptor pT3 (4), the effect of depth of chest wall invasion on prognosis had been found (8, 19). As shown in the study by Zhao Mengmeng et al., patients with rib invasion had a worse prognostic trend than other patients, and were finally served as pT4 classification (8). Our study also found that rib invasion might be an independent poor prognostic factor and even had much worse survival than pT4 classification. We also found that the patients with rib invasion prognosis were much better than those with pleural metastasis. Thus, rib invasion could be served as a pT4 descriptor. This also proves that operation is still an important treatment for those patients. In addition, a recent study found that patients with visceral pleura invasion and tumor size of 3.1-4cm should consider re-classification from T2a to T2b (21). The results from the study by Qi M et al. let us note whether patients with parietal pleura invasion will also have a pT-classification ascending performance after combining with the influence of tumor size. Based on this, we performed the sub-group analysis in the cases with parietal pleura invasion. As a result, we revealed that patients with parietal pleura invasion and tumor size with 5.1-7.0cm could be appropriately upstaged from pT3 (stage IIB) to pT4 (modified stage IIIA). Those findings may provide information for accessing prognosis, treatment decisions, and the development of the next new staging system.

This study has several limitations. First, although the data we used were from a large population-based cohort, some important information was not detailed, such as the completeness of resection, the number of resected ribs, and the area where the tumor invaded the chest wall, as we could not obtain it in the SEER database. Second, we did not further categorize the cases of rib invasion because of the small scale of patients. Third, we excluded patients without surgery to ensure that all patients only had localized-invasion disease and did not have pleural metastases. However, this selection criterion caused our study to lose a proportion of patients with chest wall invasion who did not undergo surgery. Of note, it is challenging to identify parietal pleural invasion on imaging. Thus, for patients who do not undergo surgical removal of the tumor, it is not possible to ascertain whether there is pleural involvement or not. Therefore, those shortcomings caused our results to apply only to patients after operation. Finally, given this study belonged to a retrospective study, it was impossible to avoid selection bias. Therefore, more studies are necessary to validate our findings further.

Rib invasion has a poorer prognosis than pT4. Patients with parietal pleura invasion and tumor size of 5.1-7.0cm could be appropriately up-classified from pT3 to pT4.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics committee of Shanghai Pulmonary Hospital and Sun Yat-sen University Cancer Center. The ethics committee waived the requirement of written informed consent for participation.

D.X, Z-XL, L-LW, C-WL, and G-WM contributed to the study design, data collection, data analyses, data interpretation, and manuscript drafting. L-LW, L-HQ, S-QX, W-KL, and C-WL contributed to data analyses and manuscript review. W-KL, L-LW, L-HQ, C-WL, G-WM, and DX contributed to data interpretation and manuscript review. All authors contributed to the final approval of the manuscript.

This study was supported by Shanghai ShenKang Hospital Development Centre (SHDC22020218), Science and Technology Commission of Shanghai Municipality (21Y11913400), Shanghai Pulmonary Hospital Foundation (fkxr1904), and Outstanding Young Medical Talent of Rising Star in Medical Garden of Shanghai Municipal Health Commission “Dong Xie”. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The funding bodies played a role in the interpretation of data, in writing, and in reviewing the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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