Characteristics of Ground-Glass Nodules Detected by Low-Dose Computed Tomography as a Regular Health Examination Among Chinese Hospital Employees and Their Parents

Introduction Annual LDCT has been offered as a regular examination among many unit staff in China. Along with the wide application of LDCT, more and more ground-glass nodules were found. We focused on characteristics and relationship of ground-glass nodules detected by LDCT as a regular health examination among Chinese hospital employees and their parents. Methods We recorded LDCT-detected ground-glass nodules (GGNs) in the hospital employees and parents between 2019 and 2020. Clinical information, including age, gender, smoking status was collected and analyzed. Results A total of 5,574 employees and 2,686 employs’ parents ≥60 years in Xiangya hospital performed annual physical examination. In total, LDCT incidentally detected ground-glass nodules 392 (24.78%, 392/1,582) in hospital employees and 254 in parents (10.80%, 254/2,352). The GGN-detection rate was significantly greater in employee group than parent group and more non-smokers in former (P <0.001). The detection rate was significantly greater in female than male both in employees group and parents group, and the proportion of female was bigger in employees group (P <0.001). There were more pure-GGNs both in employees group and parents group. There were less participants with solitary GGN in employee group than parent group (P = 0.033). Besides, there were more large GGNs (≥10 mm) (P <0.001), LU-RADS 4 GGNs (P <0.001) and LU-RADS 4B GGNs (P = 0.003), LU-RADS 4C-5 GGNs (P = 0.001) in parent group than employee group. There were 36 employee–parent pairs (27.07%) both had GGNs among 133 pairs who both performed LDCT. GGNs in employees were smaller and lower-grade than their parents (P < 0.001, P = 0.001). Conclusions Among the employees and parents who had ground glass nodules, 1/4 of them both detected GGNs. Although the detection rate of GGNs in the parent group was lower than that in the employee group, the grade of nodules was significantly higher. All these suggest that the occurrence and development of ground glass nodules may be related to genetic factors.


INTRODUCTION
In recent years, annual LDCT has been applied for early lung cancer screening worldwide, especially in China. LDCT has been offered as a regular examination among many unit staff among which many are not eligible high-risk participants according to NLST. Along with the wide application of LDCT, more and more ground-glass nodules were found. The International Early Lung Cancer Action Program reported that nonsolid and part-solid nodules were found in 9.2% of 57,496 baseline screenings (1,2). Zhang et al. (3) retrospectively analyzed LDCT screening among 15,686 Chinese hospital employees and found that 95.5% of patients with screening-detected lung cancer presented as GGO nodules on CT scans. As family history is the main risk factor for lung cancer, the present study focused on characteristics and relationship of ground-glass nodules detected by low-dose computed tomography as a regular health examination among Chinese hospital employees and their parents.

Participants and CT Scans
LDCT was performed as a part of regular health examination in staff above 40-year-old of the Xiangya Hospital and staff's parents above 60-year-old between 2019 and 2020. The employees below 40-years-old were offered with X-ray but some of them changed for LDCT at their own expense. In general, all the participants were volunteered to take the test. Revolution CT (GE Medical Systems) was used in the examination with 1.3 mm slice thickness, 1mm slice spacing, 100 kV tube voltage, 40-100 mA tube current.

Clinical Data
LDCT-detected ground-glass nodules (GGNS) in hospital employees and parents were recorded. Clinical information, including age, gender, smoking status was collected and analyzed.

Nodule Measurements
Fleischner Society defined "a nodule appears as a rounded or irregular opacity, well or poorly defined, measuring up to 3 cm in diameter" and ground-glass nodule (GGN) manifests as hazy increased attenuation in the lung that does not obliterate the bronchial and vascular margins (4). GGNs include pure groundglass and part-solid nodule. Pure ground-glass nodule has no solid components. A part-solid nodule consists of both groundglass and solid soft-tissue attenuation components. ALL information of nodules were recorded mainly from CT reports by a radiologist, if there were any ambiguous issues about the nodules, the radiologist would check the CT images. Nodules were measured in long-and short-axi length or diameter. Nodules were classified by The Lung Reporting and Data System (LU-RADS) categories (5).

Statistical Analysis
We used the Pearson c 2 test to compare the GGNs detection rate, and paired-t test to compare the characteristics of GGNs in employee-parent pairs. Statistical analysis was performed in SPSS 23.0.

Characteristics of Hospital Employees' Parents and CT-Detected GGN
In total, there were 2,686 employees' parents ≥60 years participated the regular examination, the average age of parents was 67.85 ± 6.18, among them 1,338 were female and 1,348 were male. The overall participation rate of LDCT was 87.57% (2,352/2,686), female and male participation rate was 86.62% (1,159/1,338), 88.50% (1,193/1,348), respectively.

Comparation and Correlation Analysis of GGNs in Hospital Employees and Their Parents
In total, the GGN-detection rate was significantly greater in employee group than parent group (24.78% vs 10.80%, P <0.001). The detection rate was significantly greater in female than male both in employees group and parents group, and the proportion of female was bigger than that in parents' group (P < 0.001). There were more non-smokers in employees than in parents' group (P <0.001). There were more pure-GGNs both in employees group and parents group. There were less participants with solitary GGN in employee group than parent group (68.62% vs 76.38%, P = 0.033). Besides, there were more large GGNs (≥10 mm) (25.19% vs 8.93%, P <0.001), LU-RADS 4 GGNs  (19.29% vs 8.16%, P <0.001) and LU-RADS 4B GGNs (7.87% vs 2.81%, P = 0.003), LU-RADS 4C-5 GGNs (9.84% vs 3.57%, P = 0.001) in parents' group than employees group ( Table 2).
There were 36 pairs (27.07%) had GGNs, among 133 pairs of employees and their mother/father both performed LDCT. There were more female than male employees in those pairs (75%). GGNs in employees were smaller than their parents (6.11 ± 0.62 vs 11.42 ± 1.38, F = 35, P <0.001), and the LU-RADS categories were lower in employees than their parents (2.64 ± 0.11 vs 3.22 ± 0.14, F = 35, P = 0.001). The rate of multiple GGNs was 36.11% in employees and 33.33% in parents among the pairs. However, there was no significant difference in the density of nodules in employees and their parents, neither in gender ( Table 3, Figures 1, 2).

DISCUSSION
Due to the application of LDCT screening for early stage lung cancer, the number of lung cancer appeared as GGO or GGN is increasing. GGO/GGN is a non-specific radiologic finding, can caused by inflammation or neoplastic proliferation and so on. In Asia, GGO nodules were detected in 7.5% of 2,255 asymptomatic Korean adults (6), and 28.69% of 1,279 LDCT positive participants in a screening program in Taiwan China (7). In our study, the proportion of GGN detected using screening CT was 24.78% in employees group and 10.80% in parents' group. The different detection rates among studies are probably due to different calculation methods, population ages and performing methods. In the study in Korean, participants were above 45 years old and CT machines with 5-mm thickness with 4-mm intervals were used. However, in the study in Taiwan participants were 19-86 years old and nodule >4 mm in diameter was identified as positive, all CT scans were performed on thin-slice (0.625 mm) machines.
As the age of participants increasing, Zhang et al. showed the lung cancer detection rate were increasing gradually in the "age ≤40 years", "40 < age ≤ 55 years" and "age >55 years" group, respectively (2). However, we found no significantly increasing of GGNdetection rate as age increasing, the most significant rate was in group "41 to 60 years", but there were more large, high-grade nodules representing high risk of malignancy in the older-group. Our findings showed age was a key factor for risk of malignance consistent with Zhang's study. Besides, Li et al. found the average age at diagnosis had significantly decreased from 66.40 to 59.06 in the past two decades using a cumulative meta-analysis (8).
Many authoritative guidelines proposed heavy smoking history as the key factor for risk assessment of lung cancer, that meant most female would not be eligible for lung cancer screening. However, more and more studies showed the proportion of female non-smokers with lung cancer was increasing in recent years, especially in East Asia. She et al. found 587 (65%) of 898 cases with solitary pure GGNs pathologically confirmed as lung adenocarcinoma were female in Shanghai, China (9). Hattori et al. from Japan evaluated 616 surgically resected clinical N0M0 non-small cell lung cancers and found the rate of female was 62% (10). A study in Korea showed 162 (56%) female of 288 patients (non-smoker 68.1%) with lung adenocarcinoma proven by surgery and which appeared as GGNs (11). In our study, the detection rate was significantly greater in female than male either in employee group (nonsmokers, 89.02%) or parent group (non-smokers, 76.72%), and in each age group as well. Our study was completely consistent with these researches, as for reasons of these findings are still ambiguous. It may be related to genetic susceptibility (such as EGFR high mutation rate) (12), estrogen and receptors (13), air pollution indoor (such as second-hand smoking or cooking) (14,15), and history of lung diseases, however further investigation is need to be conducted. As for non-smokers, especially female in Asian, it's worthy to determine high-risk factors for lung cancer about them based on those possible causes above. Maybe there should be a new adjusted screening criterion for this population, so as to achieve early effective diagnosis and treatment of lung cancer.
In our study, there were 27% employee-parent pair had GGNs at the same time. This result reminded us GGNs may be related to genetic factors, family environment and living habits as well. In recent decades, many researches showed consistently that family history is important etiology for cancers especially lung cancer. Ooi et al. (16) found that the risk of lung cancer in patients with a family history of lung cancer was 2.4 times compared with those without family history. Guo et al. (17) showed the risk of lung cancer in the first-degree relatives of lung cancer patients was about seven times higher than that of healthy people. However, there are a few studies on genetics, family history and living habits about GGNs currently. Because most GGNs remain on follow and few participants have received resection, we have no more genetic information between them to date.
As for lung cancer, genetics had been proved to be a key etiology, but it remains uncertain about family history and living habits. Therefore, the potential relevance of employee-parent pairs is worthy for us to follow on.
Furthermore, former studies discovered first-degree female relatives was a stronger predictor than first-degree male relatives for lung cancer, and a first degree family member with cancer diagnosis before age 50 were associated with increased lung cancer risk, especially among never smokers (18)(19)(20)(21). In our research, there were more female (75%) than male employees detected GGNs when their parents had GGNs too, and all of them were non-smokers. It may indicate that female nonsmokers are more likely to obtain genetic susceptibility of GGNs from parents. In addition, we found GGNs in employees were less and lower-grade than nodules in their parents among the 36 employee-parent pairs. We speculated nodules in employees would be at earlier stage and grow into nodules like their parents' when they get old. We also found GGNs of parents in employee-parent pair group were larger and higher-grade than GGNs of parent-only. Whether it suggested that larger and more suspicious nodules were more likely to be passed on to offspring need further research.

CONCLUSION
Our study retrospectively analyzed LDCT-detected GGNs among employees and parents. Among the employees and parents who had ground glass nodules, 1/4 of them both detected GGNs. Although the detection rate of GGNs in the parent group was lower than that in the employee group, the grade of nodules was significantly higher. All these suggest that the occurrence and development of ground glass nodules may be related to genetic factors.