Inuences of Tumor Size and Pleural Layer Invasion on the Prognosis of Patients with Stage IB Lung Adenocarcinoma

Backgroud: Lung adenocarcinoma (ADC) at stage IB has its own prognostic characteristics. This study aimed to investigate the clinical factors that may affect the prognosis of patients with stage IB ADC. Methods: The data of ADC cases were selected from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2016) and patients in Zhongshan Hospital Aiated to Fudan University (Department of Thoracic Surgery, 2015-2016). Kaplan-Meier method was used to obtain the overall survival (OS). Factors that signicantly related to the prognosis were evaluated by univariate and multivariate analysis (UVA, MVA) using the Cox model. A nomogram was developed and validated to predict the 3-year OSs of those patients. Results: 7605 patients with stage IB ADC were included ultimately and were divided into 2 groups, a training cohort (n = 5,324) and a test cohort (n = 2,281). Besides, there was a validation cohort (n = 272) for the verication of the nomogram model. Those with signicantly older age, male, the white race, lower grades of tumor differentiation, larger tumor size (31-40mm) without pleural layer (PL) invasion as well as receiving sublobectomy suffered from poorer survival (P < 0.001), which were identied as independent factors for stage IB ADC (P < 0.001), and according to which, a nomogram model was created. Conclusion: Age, sex, race, histological grade, surgery to the primary site, and tumor size combined with PL invasion were independent risk factors for stage IB ADC, based on which a nomogram was constructed to predict the prognosis.


Introduction
Lung cancer is the most common malignant tumor with the highest morbidity and mortality worldwide [1]. Adenocarcinoma (ADC) has been the primary subtype of lung cancer, accounting for 55% in recent years, with a strong proliferative capacity and a high degree of malignancy. Some patients have localized tumor in ltration or distant metastasis at the time of diagnosis, and the prognosis is poor [2,3].
The 8 th edition of the TNM staging of the Lung Cancer, launched by the International Union Against Cancer (UICC) on January 1, 2018, had undergone numerous changes and additions compared to the 7 th edition. It is now frequently used to predict the survival of patients with lung adenocarcinoma. In terms of tumor size, the 8 th edition staged a more detailed classi cation of stage Ib tumors (3cm < T2a ≤ 4cm) [4][5][6]. And tumor invasion of the pleural/elastic layer (PL) also belongs to stage IB, which has been reported as a poor prognostic factor in ADC [7,8]. Differences and disputes still existed among patients with stage IB lung adenocarcinoma in survival status and related treatment recommendations [6,[9][10][11][12]. The in uence of clinical factors on survival status was more or less various in studies [13][14][15][16].
SEER recently released the data of patients diagnosed with lung cancer in 2016. Therefore, the purpose of this study was to analyze the factors associated with the prognosis of patients with stage IB lung adenocarcinoma among 2010-2016, especially illustrated whether tumor size and PL play an important role or not, which may help improve the treatment strategy for early-stage lung cancer patients.

Data Sources and patient cohort
The data of patients were collected from the Surveillance, Epidemiology, and End Results (SEER) public use database SEER 18 Regs Custom Data (with additional treatment elds), Nov 2018 Sub (2010-2016).
A total of 8846 patients with complete follow-up data were diagnosed as stage IB (AJCC 8 th ) ADC and performed surgery between 2010 and 2016 in the SEER database. Among them, 7605 patients were nally enrolled in cohort I. The characteristics of these patients are reported in Table 1, which includes age at the time of subsequent cancer diagnosis, race, gender, primary site, pathological classi cation (histology), grade, laterality, rst malignant primary indicator, total no. of malignant and benign tumors, pleural/elastic layer invasion (PL) and tumor size. Finally, 5324 patients with stage IB ADC from the SEER database were randomly assigned to the training cohort, and 2281 were in the test cohort.
A total of 268 ADC at stage IB patients performed surgery for primary ADC lesion in the Department of Thoracic Surgery of Zhongshan Hospital A liated to Fudan University (ZHTS) were included. The selection process is shown in Figure 1.

Statistical Analysis
The distribution of patients' characteristics (gender, race, age, primary site, pathological classi cation, differentiation grade, and chemotherapy, etc.) was summarized using counts and percentages. Statistical analysis was done using R Project (https://www.r-project.org) and SPSS 23.0 software (IBM). Kaplan-Meier method was used for the survival analysis. Multivariate survival analysis was calculated by the Cox proportional hazards regression. The test level was α=0.05, and the difference was statistically signi cant at P<0.05.

Patient Characteristics
Among stage IB patients, the predominant age group was 71-80 years in the SEER database, while ≤60 years was the majority in the validation cohort. For the differentiated grade, the vast majority was moderately differentiated in all databases. Most of the patients enrolled in our study were performed surgery with Lobectomy + LN dissection. Details were described in table 1.

Contribution and validations of the nomogram
A nomogram relating to 6 independent risk factors (age, race, sex, tumor histological, grade, surgery, and group), which were concluded from MVA (Fig. 3). 3-year overall survival (OS) could be calculated by the Points at the top of the model (Fig. 3A). The internal evaluation was performed (Fig. 3B) as well as the external evaluation (Fig. 3C) with the same database. The C-indexes for 3-year OS were 0.644±0.015 (training cohort, SEER database) and 0.625 ± 0.024 (test cohort, SEER database).
Furthermore, we veri ed our nomogram model by individuals with entirely different characteristics of the data (Fig. 4), the C-index of which was 0.690 ± 0.079 (database in our department).
In general, IB ADC patients who had a younger age, female sex, non-black-or-white race, lower differentiated level or performed pneumonectomy had longer predicting survival time. For the groups, those in group 1, which meant the tumor size was less than 30mm had the best clinical outcomes, followed by 31-40mm tumor size with no PL invasion, and those with 31-40mm tumor size with PL invasion behaved worst in survival time.

Discussion
In our study, we found that in patients with stage IB ADC, the differences in tumor size or PL invasion didn't cause differences in living conditions, while the survival times appeared different once both of them were considered together. However, Rami-Porta's study also suggested that 3-cm cutoff point still separates T1 from T2 tumors, but tumor size arises as a more important prognostic factor, because, from ≤1 cm to 5 cm, each centimeter separates tumors with a signi cantly different prognosis [17].
The pleural invasion was well-positioned as a T2 descriptor and led to a worse prognosis even after adjusting for the current tumor size cut points [17][18][19][20][21]. Our result was similar to the research result that IB patients with both pleural invasion and tumor size between 3.1-4.0cm had a closer survival status to the stage IIA patients [14]. Other researchers showed that the presence of PL, not the depth of invasion, was associated with postoperative survival [19,22,23], but con icted to the conclusion that survival differences existed among different PL stages [24,25]. More studies can be focused on this phenomenon to illustrate the probable mechanism.
Recently, the therapy strategy for IB lung cancer patients had been widely discussed. The recent National Comprehensive Cancer Network (NCCN) guidelines stated that adjuvant chemotherapy could be used for patients with stage IB NSCLC having high-risk factors including poorly differentiated tumors, vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and unknown lymph node status (Nx), which independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy [26]. NSCLC Meta-analysis Collaborative Group's meta-analysis [27], mainly on stage IB-IIIA patients, achieved the conclusion that preoperative chemotherapy signi cantly improves overall survival in resectable NSCLC and some other studies reached the similar conclusion that ACT may improve the OS of completely resected patients with a solid predominant tumor pattern in stage IB ADC [28,29]. In contrast, there were also studies that showed that adjuvant chemotherapy was associated with worse OS than observation or no signi cant survival advantage for patients with stage IB NSCLC, but with signi cant OS bene t in stage IIA setting based on the 8th edition staging [6,30].
According to our research, visceral pleural involvement was not an independent prognostic factor in patients with stage IB lung cancer based on the 8 th editions of AJCC TNM staging system. To decide whether patients should be treated with adjuvant chemotherapy, both tumor size and PL can be considered.
The limitation of this study is that, rstly, because the SEER database used in this study has no chemotherapy-related records for lung cancer patients diagnosed in 2016, it is unable to conduct further statistical analysis on lung cancer treatment. In addition, this study is only a retrospective study, and further experiments are needed to verify or clarify the relevant conclusions.

Conclusion
The combination of tumor size and PL invasion is a signi cant clinical character of different prognosis in patients with stage IB lung adenocarcinoma (AJCC 8 th TNM classi cation), which may help the selection of patients who might bene t from chemotherapy and more advanced treatment.

Declarations
Ethics approval and consent to participate 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. All procedures performed in this study were in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the ethics committees of Zhongshan Hospital A liated to Fudan University (Shanghai, China)

Competing interests
The authors declare that they have not competing interests.