Correlation analysis of clinical, pathological, imaging and genetic features of ground-glass nodule featured lung adenocarcinomas between high-risk and non-high-risk individuals

Lung cancer is the most common cancer and the most common cause of death from cancer worldwide [1, 2]. As early as 2011, a national lung cancer screening in the US suggested that, compared with radiography, screening with the use of low-dose computed tomography (LDCT) reduced mortality from lung cancer by 20% [3]. This is one of the greatest discoveries in lung cancer screening and clinical diagnosis trial so far. Since then, regular LDCT screening has been recommended to individuals at high risk for lung cancer for earlier screening, diagnosis and treatment, and guidelines for lung cancer screening have been formulated and improved gradually [4, 5]. In the Chinese Expert Consensus on Screening and Management of Lung Cancer [6], individuals at high risk for lung cancer are defined as the ages of 40 and older who have a 20 pack- (or 400 cigarette-)year smoking history and currently smoke or have quit within the past 15 years; have a history of environmental or occupational exposure (such as asbestos, beryllium, uranium, radon, etc.); are complicated with chronic obstructive pulmonary disease or diffuse pulmonary fibrosis, or have a history of pulmonary tuberculosis; or have a history of malignant tumor or a family history of lung cancer, especially those of first-degree relatives. Thanks to the breakthroughs in medical technology and the improvement of standard of living, the popularized chest CT facilitates the detection of early stage lung cancer manifesting as ground-glass nodules (GGNs) [7]. However, no consensus on the screening and diagnosis of GGN-featured lung cancers has been reached at home and abroad. Hence, by analyzing the correlation of the clinical, pathological, imaging and genetic features of GGN-featured lung adenocarcinoma between different risk populations, this study aims to provide a reference for the screening and diagnosis of early stage lung cancers.

The progress and popularization of imaging technology effectively promote the detection and treatment of pulmonary GGNs [11, 12]. Pulmonary GGNs can be observed in inflammation, hemorrhage, and even early stage tumors, some of them are temporary; however, if they persist for more than 3 months, they cannot be excluded as early stage lung adenocarcinoma [13]. Compared with solid nodules, GGN-featured lung adenocarcinoma has an indolent course following the natural progression of AAH–AIS–MIA–IAC. Its volume doubling time (VDT) ranges from 759 to 1832 days. Lengthy VDT is associated with better prognosis and lower invasion [14]. In the 2021 WHO Classification of Lung Tumors, AIS has been added to the group of glandular precursor lesions along with AAH [9]. In this study, the frequency of AAH + AIS totaled 12.70%, and that in the non-high-risk group was higher than that in the high-risk group (14.33% vs 8.43%, P < 0.001). Heidinger et al. recommended a 36-month follow-up for both single and multiple pulmonary GGNs [15]. However, in this study, the number of patients with a follow-up of less than 3 months accounted for nearly 50% of the total and in both high-risk and non-high-risk groups. Only 18.78% were followed up for more than 12 months. Few patients were followed up for more than 36 months. The time from detection to diagnosis in the non-high-risk group was even shorter than that in the high-risk group. It can be seen that patients at non-high-risk level may experience more stress caused by their living environment and anxiety, uncertainty about the progress of nodules, as well as the impact of surgery on lung function. Although GGNs can be diagnosed and treated at an early stage, the advantages and disadvantages of indolent tumor surgery still need further verification. Hence, efforts should be made to figure out more scientific management, follow-up and treatment strategies, so as to improve the survival and quality of life of patients while avoiding excessive diagnosis and treatment and relieving their psychological burden [16, 17].

In Europe and the US, individuals at high risk for lung cancer are defined as those aged 50 and older who have a 30 pack-year smoking history [18]. Given the domestic conditions, individuals at high risk for lung cancer in China was defined in 2019 [6] as those aged 40 and older who have a 20 pack- or 400 cigarette-year smoking history and currently smoke or have quit within the past 15 years; have a history of environmental or occupational exposure (such as asbestos, beryllium, uranium, radon, etc.); are complicated with chronic obstructive pulmonary disease or diffuse pulmonary fibrosis, or have a history of pulmonary tuberculosis; or have a history of malignant tumor or a family history of lung cancer. Plenty of domestic and foreign researches showed that LDCT screening for people at high risk could effectively detect early stage lung cancers and reduce their mortality [19, 20]. Since 2005, a number of earlier screening and treatment programs have been carried out in China, effectively encouraging public participation in lung cancer screening and earlier diagnosis [21, 22]. In this study, 1,800 patients with GGN-featured lung adenocarcinoma detected in our hospital from 2009 to 2021, divided into high-risk group and non-high-risk group, were analyzed statistically. The high-risk group was dominated by male smokers, while the non-high-risk group by female non-smokers. As a whole, more women than men were included in this study (69.72% vs 30.28%), consistent with previous reports on the predominance of female non-smokers in lung adenocarcinoma [23, 24]. In this study, 60.83% of the total patients were detected during their physical examination, and the proportion in the high-risk group was slightly lower than that in the non-high-risk group [302 (59.33%) vs 793 (61.43%)], without no significant difference. However, it also suggests: (1) due to the rising incidence of lung cancer among non-high-risk individuals, screening for non-high-risk individuals should not be ignored [25, 26] and the current screening criteria for people at high risk for lung cancer in China may not be applicable to the screening of early stage lung cancer manifesting as GGNs. (2) Additional attentions should be paid to the popularization of physical examination and screening, especially among people at high risk for lung cancer. In addition, no significant difference was founded in clinical staging between groups (P = 0.488). For pathological classification, the frequency of IAC in the high-risk group was higher than that in the non-high-risk group (55.81% vs 43.00%), while the frequency of precursor lesions (AAH + AIS) in the high-risk group was lower than that in the non-high-risk group (8.43% vs 14.33%), indicating significant differences (both P < 0.001). It can be seen that, the high-risk factors for lung cancer are also for the progression of tumors.

In terms of gene expression, the incidence of EGFR mutation in Asian population is more than a half, significantly higher than that in Europe and the US, and occurs predominantly in exons 19 and 21 [2, 27]. In this study, the incidence reached 61.73%, 87% of which occurred in exons 19 and 21, consistent with the above-mentioned research results. It was reported that EGFR mutation tended to occur in female non-smokers [28, 29]. In this study, no significant difference was found in EGFR mutation in terms of gender, smoking history and risk grouping, which may be due to the difference between early stage lung adenocarcinoma and middle- and advanced-stage lung adenocarcinomas. A previous comparative analysis between advanced- and early stage lung adenocarcinomas also confirmed that EGFR mutation was not correlated with gender, but the proportion of smokers in patients with early stage lung adenocarcinoma was higher than that in the advanced [30]. Ren et al. also stated that EGFR mutation was not correlated with gender [31]. Besides, we found that there was no statistical difference in the detection rate of EGFR + patients between the high-risk group and the non-high-risk group (P = 0.824). The TP53 gene is the most frequently mutated gene across all cancer types [32]. Mutant TP53 endows cancer cells with more malignant, playing an important role in therapy resistance and poor prognosis [33, 34]. Previous researches showed that the incidence of TP53 mutations varied greatly in non-small cell lung cancer and was correlated with the pathological subtypes, reaching 81% in lung squamous cell carcinoma, 46% in lung adenocarcinoma [35], and 90% in small cell lung cancer [36]. In this study, even in patients with early stage lung adenocarcinoma, the incidence of TP53 mutations was as high as 13.95%. In addition, cigarette smoking produces a heavy burden of TP53 mutations [37]. In this study, the proportions of smokers and TP53 mutations in the high-risk group were significantly higher than those in the non-high-risk group (both P < 0.001). The KRAS gene is a member of the rat sarcoma viral oncogene family (RAS), and the incidence of KRAS mutation in Asia is 5–15% [38]. In this study, the incidence of KARS mutation was 6.76%. There is, however, no consensus on the impact of cigarette smoking on the frequency in KARS mutations [39, 40]. Choi et al. found that KRAS mutation was common in male smoker and associated with invasive mucinous adenocarcinoma on histologic analysis [41]. In this study, the incidence of KARS mutation in the high-risk group dominated by male smokers was higher than that in the non-high-risk group (P < 0.001), indicating the impact of cigarette smoking on the frequency of KARS mutations.

Targeted therapy renewed the treatment mode for lung cancers. However, for concurrent TP53 mutations in EGFR mutated lung cancers, the prognosis may be affected by the poor effect of targeted therapy [33, 42, 43]. According to previous researches, concurrent TP53 mutations were very common in EGFR mutated lung adenocarcinoma with an incidence of 54.6–64.6% [44], which is inconsistent with the incidence of 18.84% in this study. This may be because most of the cases in this study are early stage lung cancers manifesting as GGNs. In this study, the proportion of males in the EGFR + /TP53 + group was higher than those in the EGFR + /TP53- and EGFR-/TP53- groups. The proportion of patients with clinical stage IA lung adenocarcinoma in the EGFR + /TP53 + group was significantly lower than those in the EGFR + /TP53- and EGFR-/TP53- groups. The frequency of IAC in the EGFR + /TP53 + group was higher than those in the other groups. It suggests that EGFR + /TP53 + is prone to promote the growth, invasion and metastasis of tumor cells [45, 46], thus affecting the survival and prognosis of patients with tyrosine kinase inhibitor (TKI) treatment. For patients with GGN-featured lung cancer, a follow-up after surgery rather than targeted treatment is recommended. However, some patients suffered a recurrence of multiple nodules after surgery. Therefore, the necessity of targeted treatment after surrey for GGN-featured lung cancers complicated with gene mutations is worth of further study.

Screening for non-high-risk individuals should not be ignored due to the rising incidence of early stage lung cancers manifesting as GGNs among non-high-risk individuals. Besides, the existing screening criteria for people at high risk for lung cancer in China may not be applicable to the screening of early stage lung cancers manifesting as GGNs. The popularization of physical examination among people at high risk for lung cancer in China is still insufficient, and the follow-up time for patients with GGNs should be extended. Efforts should be made to figure out more scientific management, follow-up and treatment strategies. Although similar to that in lung adenocarcinoma, gene mutations in GGN-featured lung cancers still have their own characteristics. The necessity of targeted treatment after surrey for GGN-featured lung cancers complicated with gene mutations is worth of further study.