We observed that patients with early lung cancer had a significantly higher prevalence of AAA than that of the general population. Old age (especially > 60 years), male sex, smoking history, and CAOD were independent risk factors for AAA development in patients with lung cancer. The significant association between AAA and early lung cancer suggests a potential benefit for optimized screening for AAA in patients with lung cancer eligible for lung resection surgery.
The key pathologic characteristics of AAA include vascular inflammation, oxidative stress, destruction of the aortic extracellular matrix (ECM), and thinning of the aortic wall from loss of vascular smooth muscle cells.[11] The risk factors for AAA in lung cancer we identified would contribute in some way to the pathophysiology of AAA. Male sex is a well-known major predisposing factor (4–6 times more prevalent in men) in AAA development, consistent with our result. Previous studies found that endogenous sex hormone signalling contributed to sex differences in AAA; androgens stimulate key pathological processes in AAA, while oestrogen inhibits these processes.[12] Moreover, CAOD and AAA are closely related; the prevalence of CAOD in AAA is significantly higher than that in the general population and vice versa.[13] It is unclear whether the strong association is simply due to shared risk factors or if there are other causes beyond that.[14] Smoking is a predominant risk factor for not only lung cancer but also AAA. Smoking is known to have a positive relationship with incremental increased growth rate of AAA up to 0.4 mm per year.[15] Moreover, there is a dose-dependent relationship between smoking and AAA; it has been shown that smoking duration and total lifetime smoking exposure both directly correlate with increased risk of AAA.[16]
In our study, AAA prevalence in smokers was 9-fold higher than that in non-smokers, which is much higher than previously reported results (2–5-fold),[17] [18] although the pattern is consistent with previous reports that smoking is an important risk factor for developing AAA.[19] [20] That might be because in our study group, patients with lung cancer were highly likely to be heavy smokers. Moreover, in our study, smoking amount showed a dose-dependent relationship with the prevalence rate of AAA in patients with lung cancer (OR, 1.02; 95% CI, 1.01–1.03; P < 0.001; Table 4), similar to previous study results.[17] Since AAA diameter increases over time, age is also a risk factor, as certain intrinsic damage to the aortic vasculature that contributes to AAA development also accumulates with advancing age in patients with lung cancer.
Although the prevalence of AAA in patients with lung cancer was significantly higher than that in our control group, it was lower than that previously reported (3.8% vs. 11.1%).[21] Even among patients with lung cancer aged > 65 years, the prevalence of AAA was 6%. This could be because AAA prevalence is lower in Asians than in Caucasians.[22] Another possible reason is that the study population of previous studies included higher proportions of patients with advanced lung cancer, squamous cell lung cancer, and small cell lung cancer, which are known to be associated with heavy smoking.[23] Furthermore, almost half of our study population were never smokers. In the univariable logistic regression model, squamous cell lung cancer was related to higher risk of AAA development than adenocarcinoma. This might be related to squamous cell lung cancer being more strongly related than adenocarcinoma to smoking.[24]
Current guidelines recommend interventional treatment (surgical or endovascular repair) only when the AAA diameter exceeds 5.5 cm. For small AAAs (3.0–5.4 cm), regular monitoring with ultrasonography or CT regularly based on its diameter is recommended.[25] Former smokers who quit smoking for > 25 years have similar relative risk of developing AAA as that of never smokers.[26] Furthermore, there is a decline in risk of AAA of approximately 30% for each decade after quitting.[17] Thus, smoking cessation is important with respect to not only lung cancer, but also AAA surveillance and reducing the growth rate of AAA.
Several studies have investigated medications for AAA aimed at reducing aortic inflammation and proteolysis and supporting vascular smooth muscle cell recovery. However, there is no strong scientific evidence that supports pharmacological treatment to reduce AAA growth in humans[27] [28]; the benefit of pharmacologic therapies, such as statins,[29] antihypertensive drugs (beta blockers and angiotensin-converting enzyme inhibitors),[30] [31] metformin,[32] and antibiotics (roxithromycin and doxycycline),[33] [34] in preventing rupture in small AAAs is controversial. However, there is some evidence that high blood pressure increases the risk of developing AAA.[35] Therefore, strict control of blood pressure in patients with lung cancer with AAA might be helpful as a preventive strategy for AAA complications.
Based on the proven cost-effective benefit of population-based AAA screening programs in high-risk groups,[2] the US Preventive Services Task Force (USPSTF) recommends screening with ultrasonography for patients at high risk of AAA (men 65 to 75 years of age with a history of smoking). A previous study found that AAA prevalence is higher in patients with lung cancer.[21] In our study, the prevalence of AAA was also significantly higher in the resectable lung cancer group, indicating that patients with lung cancer are at high risk of AAA. Unlike previous studies, we evaluated the prevalence of AAA in patients with early lung cancer, where the life expectancy is much longer, which will lead to greater benefit from timely AAA management in preventing acute emergencies and subsequent fatalities due to rupture of AAAs. In our real-world database, only 6 out of 39 patients with lung cancer with AAA were diagnosed with AAA and managed by clinicians. The majority of AAAs in patients with lung cancer (84.6%; 33/39) were ignored without risk management to prevent AAA rupture.
There are several limitations of this study. First, there was limited information on family history of vascular disease and lung cancer because our database was retrospectively analyzed. Genetic factors and family history are well-known risk factors for both lung cancer[36] and AAA.[37] Therefore, family history of lung cancer or AAA may be important risk factors for AAA in patients with lung cancer. Second, the prevalence of AAA in the cancer-free group was lower than the general prevalence of AAA in Asian populations.[22] That might be related to characteristics of our study population; the cancer-free control group were younger (mean age 54.4) than 65 years, which is the cut-off age for AAA surveillance.[38] In addition, those who voluntarily undergo regular health check-ups are likely to have a healthier lifestyle, including smoking cessation.