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Recently, early-stage lung cancer has been drawing more attention, especially in screening and treatment. Visceral pleural invasion in stage IB cancer is considered as risk factor for poor prognosis. Herein, we aimed to study the distinction between the different locations of visceral pleural invasion.
Methods
In this retrospective cohort study, we summarized 58,242 patient cases that underwent surgery from 2015 to 2018 at Shanghai Chest Hospital. Of those patients, 389 met the inclusion criteria. Patients with PL3 pleural invasion were excluded. The patients were dichotomized into the interlobar pleural and peripheral pleural groups. The outcomes measured were overall survival (OS) and recurrence-free survival (RFS) rates.
Results
According to the initial analysis, the baseline characteristics of the two groups were largely balanced. In multivariate Cox analyses, we found that the location of visceral pleural invasion was not a risk factor for prognosis in the overall population (RFS: P = 0.726, OS: P = 0.599). However, we discovered that relative to patients with peripheral pleura invasion, those with interlobar pleura invasion, PL1 invasion, lesions with greater than 3 cm solid components, and those who underwent segmentectomy had a compromised prognosis. Additionally, tumors larger than 3 cm in size with interlobar pleura invasion showed poor prognosis in patients who underwent postoperative chemotherapy.
Conclusions
In most cases, the location of tumor invasion did not worsen the postoperative prognosis of stage IB non-small cell lung cancer patients with visceral pleural invasion. However, interlobar pleural invasion still had some potential risks compared to that of peripheral pleural invasion.
According to the Global Cancer Statistics in 2020, there were nearly 19.3 million cancer incidences and 10 million cancer deaths in 2020, with lung cancer being the most lethal cancer type [
]. Owing to the increasing emphasis on early screening and timely intervention for lung cancer, the detection rate and prognosis of lung cancer continue to improve. In the United States, the 5-year survival of patients with non-small cell lung cancer (NSCLC) has improved from 16.4% to 25.1% from 1975 to 2015, respectively [
]. The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for NSCLC recommend adjuvant chemotherapy in patients with stage IB disease having risk factors such as poorly differentiated tumors, vascular invasion, wedge resection, visceral pleural invasion, and unknown lymph node status. A recent meta-analysis assessed the role of visceral pleural invasion (VPI) in node-negative NSCLC and found that VPI together with tumor size has a synergistic effect on survival in node-negative NSCLC [
A risk classification system predicting the cancer-specific survival for postoperative stage IB non-small-cell lung cancer patients without lymphovascular and visceral pleural invasion.
The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: a retrospective analysis based on the SEER database.
]. However, some relevant studies concluded that the extent of VPI (PL1-PL2) may not be an independent risk factor in patients with node-negative NSCLC. In this study, we investigated whether the location of VPI, that is the interlobar pleura or peripheral pleura, affects postoperative recurrence and survival. Tumor invasion of the visceral interlobar pleura may be a threat to the adjacent normal lobes.
2. Materials and methods
2.1 Study design
All clinical data were extracted from the clinical medical system of the Shanghai Chest Hospital. This was a retrospective cohort study conducted at a single center. TNM staging was classified according to the 8th version of the American Joint Committee on Cancer (AJCC). In this study, all patients had visceral pleural invasion according to pathological examination. We reviewed the imaging information to categorize these patients into two groups: the peripheral pleural invasion (PPI) group and interlobar pleural invasion (IPI) group (Fig. 1). The PPI was defined as the site of invasion in any visceral pleura except for the lobe fissure (horizontal and oblique fissure). The IPI was defined as a lesion breaking through the pleura at the location of interlobar fissure. Multivariate and subgroup analyses were performed to clarify differences between the two groups. Outcomes were overall survival (OS) and recurrence-free survival (RFS). In addition, three individuals measured the lesion data, one of whom was responsible for verification and proofreading (Fig. S1).
In this retrospective study, we collected the data of 58,242 patients who underwent surgery from 2015 to 2018 at Shanghai Chest Hospital. Of these, only 389 patients with stage IB NSCLC who had visceral pleural invasion according to postoperative pathological examination were included. Patients with both IPI and PPI were not considered in our study. We excluded patients with any PL3-classified tumors and those with metastatic pleural nodules or potential pleural diffusion. We regarded patients as people with potential risk of pleural diffusion mainly according to the following three aspects. First, CT scan found some small solid nodules on interlobar pleura; Secondly, PET-CT reported the potential pleural metastasis; Third, patients with unknown pleural effusion. In addition, multiple pulmonary nodules and wedge resection surgery cases were removed from our patient list to prevent any potential bias in the analysis and prognosis. Patients with unknown postoperative T, N, and M stages as well as non-specific pathological reports were also excluded from our study.
2.3 Preoperative preparation
All patients in our study underwent comprehensive examination before surgery. A thoracic computerized tomography (CT) scan or enhanced CT scan was used for initial recognition of the tumor and to identify the location of pleural invasion. Positron emission tomography-computed tomography (PET-CT) was performed to identify pleural metastasis and distant progression. Brain magnetic resonance imaging was performed to screen for cerebral embolisms and brain metastases. A pulmonary function test as well as an optional arterial blood gas analysis was used to assess surgical tolerance. Moreover, echocardiography, electrocardiography, and plate movement were conventionally performed.
2.4 Surgical technique
From 2015 to 2018, three main surgical operations performed included: open surgery, video-assisted thoracic surgery (VATS), and robot-assisted thoracic surgery (RATS). Tumors were resected mainly via lobectomy and segmentectomy. Some patients also underwent intraoperative conversion to thoracotomy because of anatomic variation, difficulty in dissociating tissue, and intraoperative uncontrollable bleeding. Frozen section pathological procedure was performed routinely to confirm the status of the margins. The lymph nodes were dissected routinely for examination using the paraffin technique. Groups 2R, 4R, 7, 8, 9, 10R, and 11R underwent right-sided surgery and groups 4L, 5, 6, 7, 8, 9, 10L, and 11L underwent left-sided surgery.
2.5 Statistical analysis
Continuous variables were expressed as the mean ± standard deviation (SD). The difference in continuous variables was calculated using two independent sample t-tests, and the categorical variables were analyzed by Fisher's exact test or Chi-squared test. We adopted the product-limit method (Kaplan–Meier method) and log-rank test to assess OS and RFS. The Cox regression analyses (using the stepwise regression method) were used to identify prognostic factors for stage IB patients with VPI where variables with a P-value <0.2 were selected to be analyzed in the multivariable Cox model. A subgroup analysis was performed to compare the two groups, PPI and IPI, in specific populations. We manually converted multiple categorical variables to dummy variables for regression analysis. A P-value of 0.05 was used as an acceptable statistical significance level. Statistical analysis was performed using SAS (version 9.4) and R software (version 4.0.3).
3. Results
3.1 Baseline characteristics between PPI and IPI
In our retrospective study, the median follow-up time was 52.8 months (ranging from 0.1 to 87.9 months). The baseline variables between the PPI group and IPI in this study were almost balanced. The variables of sex, age, body mass index, hospital stay, laterality, size, consolidation tumor ratio (CTR), surgical technology, extent of pleural invasion, lymph node resection, pathology, and adjuvant therapy were assessed. We discovered that there was one patient with vascular invasion in the PPI group and 13 patients with nerve invasion (five in the IPI group and eight in the PPI group). Eight patients had STAS (spread through air spaces) in the cohort, and in the PPI group, two patients received neoadjuvant therapy (Table 1).
Table 1Baseline Characteristics between PPI group and IPI group.
In the univariate and multivariate Cox analyses for RFS, we found no correlated risk factors to RFS. However, age (P = 0.03), hospital stay (P = 0.01), solid lesion size (P = 0.03), and adjuvant therapy (P = 0.02) were found to be significantly relevant prognostic factors to OS. Postoperative chemotherapy cannot influence RFS but can benefit OS (Table 2). Together with the survival analysis in Fig. 2 (RFS: P = 0.20; OS: P = 0.16), the results in Table 2 also indicate that the different locations (IPI or PPI) were not risk factors for postoperative prognosis in the overall population (RFS: P = 0.22; OS: P = 0.20).
Table 2Univariate and multivariate analyses of prognostic factors of OS and RFS.
We performed a series of subgroup analyses for further investigation (Fig. 3). In the subgroup analysis of RFS between PPI and IPI, we found that IPI was a hazard to patients with PL1 (P = 0.03) and those with imaging solid size >3 cm (P < 0.01). Regarding OS, patients with IPI were found to not be suitable for segmentectomy (P = 0.03). Further investigation of the IPI group found that patients who underwent lobectomy had better survival results (Fig. S2b). We also conducted another subgroup analysis of RFS for patients with postoperative chemotherapy and found that an imaging solid size of >3 cm was still a risk factor for recurrence (P = 0.04) (Fig. S2d).
Fig. 3Subgroup analysis between PPI and IPI groups.
In the PL1 group, patients with IPI were more likely to experience recurrence and had poorer recurrence-free survival (P = 0.025), while there was no statistical difference between the IPI and PPI groups in PL2 patients (P = 0.58) (Fig. 4a). For OS, there were no significant differences between the IPI and PPI groups in PL1 and PL2 patients (Fig. 4b). In the IPI group, there were no significant differences in RFS or OS between the PL1 and PL2 groups. Similar results were observed in the PPI group (Fig. 4c–d). Regardless of the location of invasion site, the interlobar pleural or peripheral pleura, the extent of pleural invasion (PL1, PL2) does not affect the postoperative prognosis (OS and RFS). However, in patients of PL1 status, patients with interlobar pleural invasion harms the prognosis compared to those of PPI. In PL2 patients, invasion location was not a risk factor.
Fig. 4The correlation between the extent of pleural invasion and the location of tumor invasion.
Prognostic impact of microscopic vessel invasion and visceral pleural invasion and their correlations with epithelial-mesenchymal transition, cancer stemness, and treatment failure in lung adenocarcinoma.
]. Adjuvant therapy has also been recommended for patients with stage IB NSCLC having VPI by some authoritative clinical guidelines. However, in our study, interestingly, the postoperative chemotherapy was found to not influence survival related to recurrence, but only benefit the OS. In addition, the recurrence rates between adjuvant and non-adjuvant patients were not significantly different. The chemotherapy plan in these patients was mainly a two-drug combination regimen, which includes a third-generation chemotherapy drug (paclitaxel, docetaxel, gemcitabine, vinorelbine, or pemetrexed) combined with platinum (carboplatin/cisplatin). Two patients in the study received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy. Nevertheless, due to the small sample size, we did not perform a more detailed comparison of the postoperative treatment plans.
In clinical practice, some tumors, usually called ‘across-lobe tumors’, frequently break through the visceral pleura and invade the adjacent lobes. For these tumors, we usually perform radical lobectomy of the primary lesion and sublobectomy of the adjacent, invaded lobe. In some other peripheral lesions, we discovered that tumor invasion was sometimes not limited to the surface of the visceral pleura (PL2) but extend to the parietal pleura or chest wall (PL3). Moreover, some tumors metastasize to distant organs and pleural nodules via pleural diffusion. According to clinical follow-up results, there seem to be some prognostic differences between the two tumor locations, PPI and IPI. Therefore, we speculated whether the location of pleural invasion was a risk factor for poor prognosis.
As indicated in our study results, the location of VPI was not a risk factor for poor prognosis. By analyzing PL1 and PL2, we found no statistical difference in postoperative survival between PL1 and PL2. Similar results have been reported in other studies. Seok et al. reported that the extent of VPI may not influence survival outcomes in patients with surgically resected N0 NSCLC [
]. In addition, it seems that the extent of pleural invasion and location of VPI were independent variables, with no synergistic effects between them. Regardless of whether the invasion was in the peripheral pleura or interlobar pleura, the extent of pleural invasion (PL1, PL2) did not influence the survival results. However, in the case of PL1, the prognosis of PPI is not as good as that of IPI.
Tumor size is a hot topic in the investigation of VPI. Wang indicated that VPI was an independent factor for survival in N0 NSCLC patients with tumors <4 cm [
]. In a meta-analysis, Prof. He maintained that patients with tumors <3 cm with VPI may have better survival results than those with tumors of 5 cm, regardless of VPI [
The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: a retrospective analysis based on the SEER database.
]. However, a study by Dr. Suzuki confirmed that VPI had a negative prognostic effect on pure ground-glass opacity (GGO) but was a risk factor for part-solid tumors [
]. Similarly, a study by Dr. Kim demonstrated that the risk of VPI increased with a larger solid portion in subsolid nodules. In our study, we aimed to clarify the prognostic significance of the CTR in stage IB tumors with VPI. During the data extraction procedure, we discovered that most tumors had a primarily solid component and only a few had CTR<0.5 or even pure-GGO. Besides, in the subgroup analysis, it was indicated that the CTR and even total imaging lesion size were not risk factors for the prognosis of IPI versus PPI. However, the scale of solid components is a key factor. IPI with solid components >3 cm in size had a poorer prognosis than PPI alone. Even after chemotherapy, solid components >3 cm caused a significant difference in RFS between IPI and PPI. This may indicate that larger tumors tend to break through the interlobar fissure and invade the adjacent lobes.
In addition, it is interesting that patients with segmentectomy who have IPI have worse prognosis than those who have PPI. Exploratory survival analysis revealed that lobectomy was recommended for patients with IPI. However, there was no survival advantage in patients with PPI who underwent lobectomy compared to those who underwent segmentectomy. Before that, there were no relevant studies on the feasibility of sublobectomy in patients with VPI. We were uncertain whether the pGGO with VPI in stage IB patients is suitable for segmentectomy or the CTR will be a guide variable to determine the surgical type in stage IB patients with VPI.
Our study has some limitations. Firstly, due to the difficulty of data collection, we did not differentiate between recurrence types, such as distant recurrence, regional recurrence, and pleural recurrence. Secondly, the drug regimens for postoperative chemotherapy differed per individual. This may have had a confounding effect on our results, especially since the doses and intervals also varied. Treatment drugs such as EGFR-TKI, PD1/PD-L1, and other chemotherapy drugs used after recurrence may cause partial bias in overall survival. Finally, this was a retrospective study conducted in a single center. All the deficiencies noted above will be considered thoroughly and addressed in future studies.
5. Conclusion
It was found that, in most cases, the location of tumor invasion did not worsen the postoperative prognosis of patients having stage IB NSCLC with visceral pleural invasion. However, we discovered that patients with interlobar pleura invasion, who have PL1 invasion, lesions with greater than 3 cm solid components, and those who underwent segmentectomy had a compromised prognosis compared to those with peripheral pleura invasion. In patients who underwent postoperative chemotherapy, tumors larger than 3 cm in size with interlobar pleura invasion also showed poor prognosis.
Funding
National Natural Science Foundation of China Project No. 81871497.
Ethical approval
This study was approved by Ethics Committee in Shanghai Chest hospital.
Data availability statement
Data are available on request.
CRediT authorship contribution statement
Jianghao Ren: Conceptualization, Data curation, Formal analysis, Conception and design were performed, Material preparation, data collection were taken, Statistic analysis were operated. Jiangbin Ren: Data curation, Material preparation, data collection were taken. Kan Wang: Data curation, Material preparation, data collection were taken. Yuanyuan Xu: Formal analysis, Statistic analysis were operated. Mingyang Zhu: Statistic analysis were operated. Ting Ren: Formal analysis, Statistic analysis were operated. Zhiyi Guo: Formal analysis, Statistic analysis were operated. Ruonan Li: Formal analysis, Statistic analysis were operated, Formal analysis, Statistic analysis were operated. Jiazheng Huang: Formal analysis, Statistic analysis were operated, All authors contributed to the manuscript writing and final approval of manuscript. Qiang Tan: Conceptualization, Formal analysis, Conception and design were performed, Statistic analysis were operated.
Declaration of competing interest
We declare that we have no conflict of interest.
Acknowledgement
We would like to thank Editage (www.editage.cn) for English language editing.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
A risk classification system predicting the cancer-specific survival for postoperative stage IB non-small-cell lung cancer patients without lymphovascular and visceral pleural invasion.
The modification of T description according to visceral pleural invasion and tumor size from 3.1 cm to 4.0 cm in non-small cell lung cancer: a retrospective analysis based on the SEER database.
Prognostic impact of microscopic vessel invasion and visceral pleural invasion and their correlations with epithelial-mesenchymal transition, cancer stemness, and treatment failure in lung adenocarcinoma.
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