Abstract
Background/Aim: Lung diseases are common in patients with abdominal aortic aneurysms (AAA). This study evaluates the prevalence of lung cancer (LC) in high-risk patients screened for AAA. Patients and Methods: Six hundred and one male patients (≥65 years of age, cardiovascular high-risk profile) were enrolled and followed prospectively over a median of 16.5 months. Results: In 29 patients (4.8%) LC and in another 50 patients (8.3%) AAA were found. The prevalence of LC among patients with AAA was even higher (9 of 50, 18.0%). Twenty-one patients had an initial diagnosis of LC, with an incidence of 12.0% (6 of 50) in patients with AAA. During follow-up, 14 of 70 patients with AAA and/ or LC (20.0%) deceased. The highest mortality was found in patients with LC only (8 of 20, 40.0%), followed by patients with both AAA and LC (3 of 9, 33.3%), while patients with AAA only had the lowest mortality rate (3 of 41, 7.3%). Conclusion: In patients with a high cardiovascular risk profile, a high prevalence of both AAA and LC were found, whereby the prognosis is largely determined by the LC. Therefore, LC is of particular importance in the setting of screening and surveillance of AAA.
In an ageing population multimorbidity is frequent. Various diseases show an age-related prevalence and due to shared risk factors, some morbidities often coincide. Malignant diseases and aneurysms of the abdominal aorta (AAA) are observed in 4%-40% of patients (1-5). These observations may have diagnostic and therapeutic implications.
AAA is a disease which occurs predominantly in the elderly and shows a strong association with nicotine consumption (6). Smoking is also the dominant risk factor for lung cancer (LC), which is the leading cause of cancer-related death in the western world (7, 8). Although LC mortality in high-risk smokers can be reduced by low-dose computed tomography (CT) screening, there are no nationwide screening programs for LC due to unclear benefit-to-harm ratio (9, 10). On the contrary, population-based screening programs have been implemented for AAA, for instance in Germany since 2018.
In the present study we 1) evaluated the prevalence of LC in patients undergoing screening for AAA who were hospitalized for known or suspected cardiopulmonary disease and 2) further examined the cardiovascular and cancer-related mortality during follow-up.
Patients and Methods
Study design. This study evaluated the prevalence of LC in patients with a high cardiovascular risk profile, screened for AAA.
Setting. Enrollment started on January 1, 2018 until January 2019, in the First Department of Medicine, University Medical Centre Mannheim. A part of this study collective has been reported previously in the context of AAA screening (11).
The study was conducted according to the principles of the Declaration of Helsinki and was approved by the local ethical committee, Medical Ethic Commission II, Faculty of Medicine Mannheim, University of Heidelberg, Germany. Data protection was in accordance with the EU Data Protection Directive. Informed consent was obtained from all patients and data were analyzed anonymously.
Participants. Male patients, ≥65 years of age admitted to the emergency department of a single tertiary-care institution were enrolled. All patients presented with cardiopulmonary symptoms (chest pain, dyspnea) and were diagnosed at least with two cardiovascular risk factors. Ultrasound screening for AAA was performed during hospital stay. Patients unable to give informed consent were excluded.
Variables
High cardiovascular risk profile. A high cardiovascular risk profile was defined as the presence of at least two of the following cardiovascular risk factors: hypertension, history of smoking, chronic obstructive pulmonary disease (COPD), diabetes or hyperlipidaemia.
AAA screening. Screening for AAA was performed in accordance to the German national screening program, which was introduced in 2018, by ultrasound evaluation of the abdominal aorta and measurement with the leading edge to leading edge method. Ultrasound was performed by two experienced sonographeurs.
Data collection. Data were collected anonymously. Comorbidities and cardiovascular risk factors were recorded. Chronic kidney disease (CKD) was defined as glomerular filtration rate (GFR) < 60 ml/min/1.73 m2.
Thoracic imaging. Due to symptoms at presentation, thoracic imaging (either chest radiography or CT of the thorax) was performed as routine admission procedure in the emergency room. Further evaluations were performed according to the current guidelines of the American College of Chest Physicians (12) upon detection of suspicious lesions.
Chest radiographs (Multix FD; Siemens Healthineers, Erlangen, Germany) were obtained in the 125 to 150 kVp range with a distance of 150 cm from film to focus. In most cases only posterior-anterior view was performed. If available, lateral view was also analyzed. CT (Somatom Definition, Siemens Healthineers) was conducted with the following parameters: 120 kVp, 250 mA, 3-mm collimation, one rotation of the X-ray tube per second and table speed of 2 mm/s.
All patients with diagnosed AAA received a chest radiography in order to rule out thoracic aneurysms.
Lung cancer. The oncological history was recorded for each patient including histological tumour type and tumour stage at time of first diagnosis according to TNM (13) and Union for International Cancer Control (UICC) (14) classification. Treatment modalities such as chemotherapy, radiotherapy, treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors or surgical treatment were also recorded.
Follow-up. All patients with either AAA and/ or LC were followed over a median of 16.5 months (95%CI=15.0-19.0). Follow-up was performed at regular visits at our oncological outpatient departments. Clinical events were confirmed by review of the corresponding medical records in our electronic Hospital Information System, contact with the general practitioner or the treating hospital.
Statistical analysis. Data are presented as mean±standard deviation. Continuous parameters were compared using a two-tailed Student's t-test for parametric and Mann–Whitney U-test for non-parametric variables. Categorical variables were compared with the χ2 or Fischer's exact test.
All results were considered statistically significant when p<0.05. Analyses were performed with Statistical 1 Package for Social Sciences (SPSS for windows 14.0, Chicago, IL, USA) and GraphPad Prism 8.0 (Graphpad Software, Inc., San Diego, CA, USA).
Results
Of 614 patients meeting the inclusion criteria, 601 patients were enrolled. There was a high prevalence of LC (29 patients, 4.8%), with a significant proportion of new diagnoses (21 patients, 3.5%). AAA were detected in 50 patients (8.3%), whereof newly diagnosed in 14 patients (2.3%). In addition, 9 out of 50 patients with AAA also had LC (18.0%), with an incidence of 12.0% (6 of 50).
Prevalence and incidence of AAA and LC are depicted in Figure 1.
Patients with AAA only (n=41) were compared with patients with LC only (n=20) and patients with both AAA and LC (n=9) (Figure 2A). Patients with AAA only were on average 5 years older than patients with LC (79.0±6.6 vs. 73.9±6.8, p=0.006) and had a higher rate of cardiorenal comorbidities. This was particularly obvious in coronary artery disease (CAD) (both CAD in general and three vessel disease specifically) and CKD, which was also reflected in corresponding differences in comedication, with higher use of betablocker and angiotensin receptor blocking agents (ARB) in the AAA group. Patients with an AAA received significantly more often statins and platelet inhibition or anticoagulant therapy in comparison to patients with LC only. While hypertension was more common in patients with AAA only, however without statistical significance [AAA only 38 (92.7%) vs. LC only 15 (75.0%), p=0.06], there were no differences regarding other shared risk factors, such as history of smoking, COPD or diabetes.
Detailed results are displayed in Table I. Figure 3 shows a CT reconstruction of a patient with both AAA and a pulmonary mass, that later turned out to be a LC. The LC was a preoperative accidental finding.
LC characteristics. Of 29 patients with LC, 21 (72.4%) were newly diagnosed during hospital stay, with an incidence of 12.0% (6 of 50) in patients with AAA. According to the histological findings, adenocarcinoma constituted the main entity with 15 cases (51.7%), followed by seven patients with squamous cell carcinoma (24.1%) and five (17.2%) with small cell LC (SCLC). Two patients (6.9%) were classified as unspecified non-small cell LC (NSCLC) due to inconclusive histological findings. At the time of study inclusion only two patients (6.9%) had a localized tumour (UICC stage II), one third (9 patients, 31.0%) were classified as having locally advanced (UICC stage III) cancer and 16 patients (55.2%) suffered from stage IV disease. One patient had an adenocarcinoma in situ. Characteristics of 29 patients with LC including tumour stages are shown in Table II. LC therapy included conventional chemotherapy, radiotherapy or combined radiochemotherapy, surgical treatment and drug treatment with tyrosine kinase inhibitors (e.g. erlotinib, afatinib) or immune checkpoint inhibitors (e.g. nivolumab, pembrolizumab).
Prevalence and incidence of abdominal aortic aneurysm and lung cancer. AAA: Abdominal aortic aneurysm; LC: lung cancer; n: number.
Mortality. Patients with AAA and/ or LC (n=70) were followed over a median of 16.5 months (95%CI=15.0-19.0). Follow-up was available in 98.6%, as one patient declined further treatment and contact. Of these 70 patients, a total of 14 (20.0%) died.
A total of 11 of the 29 patients with LC died (37.9%) while of the 50 patients with an AAA, a total of 6 died during follow-up (mortality rate of 12%). Three of these deaths occurred in the group of the 9 patients with both diagnoses (mortality rate 33.3%). The highest mortality was found in patients with LC only (8 of 20, 40.0%), followed by patients with both AAA and LC (3 of 9, 33.3%), while patients with AAA only had the lowest mortality rate (3 of 41, 7.3%). All deaths in patients with LC were classified as cancer-related. Of the three deaths in the AAA only group one death was due to metastatic prostate cancer, another due to sepsis and the third to perioperative cardiovascular complications after surgery of a popliteal artery aneurysm, which was then classified as cardiovascular. Given the limited number of patients, we did not perform a competing risks survival analysis. Follow-up results are depicted in Figure 2B.
Patients with abdominal aortic aneurysm only, lung cancer only or both diagnoses A. Comparison, B. Follow-up. Abdominal aortic aneurysm; LC: lung cancer; n: number.
Discussion
The present analysis evaluated the prevalence of LC in patients screened for AAA with a cardiovascular high-risk profile. We could hereby reveal the following:
i) a high prevalence of both AAA (8.3%) and LC (4.8%) was found; ii) while the proportion of newly diagnosed AAA was low at 2.3% (without any large AAA), the rate of newly diagnosed LC was significantly higher at 3.5%; iii) LC was diagnosed in 9 out of 50 patients (18.0%) with an AAA; iv) of 70 patients with an AAA and/ or LC, 14 (20.0%) died during follow-up.
In the current discussion on the prognostic benefit of AAA screening (15), it is important to adequately record associated concomitant diseases. Due to common risk factors, a high prevalence of malignant diseases and AAA has also been reported (16-19). In addition, there is also growing evidence that genetics contribute to the development of AAA. Some of the described associated genes are also playing a role in cancer, leading to an increased susceptibility for both diseases (20). In Germany, where this study was performed, the national S3 guideline for the management of AAA highlights that in about every 20th patient who is scheduled for AAA treatment, a malignancy is found as coincidence and the authors recommend thoracic imaging (preferably CT) before further interventions (21). Other screening guidelines for AAA, such as those from the European Society for Vascular Surgery or the US Preventive Services Task Force, do not recommend or contain information in this regard (22-24).
Baseline characteristics of 1) 41 patients with AAA, 2) 20 patients with LC, and 3) 9 patients with both AAA and LC.
Computed tomography reconstruction of a patient with both abdominal aortic aneurysm and lung cancer. A. Overview of the degenerately altered abdominal aorta and supradiaphragmatic mass. B. Overview of right intrapulmonary mass. C. Detailed view of intrapulmonary mass.
We have previously reported that screening of an inpatient high-risk cohort of male patients over the age of 65 years, hospitalized for suspected or known cardiopulmonary disease revealed a high prevalence of AAA with only moderate proportion of new screen-detected AAA (11). While the implementation of national AAA screening programs aims to reduce the number of newly diagnosed AAA in an inpatient setting, there are no population-based screening programs for LC. Current screening recommendations for lung cancer with low-dose CT are limited to individuals at risk aged 55 to 74 years in relatively “good health“ (25), yielding a prevalence of cancer among adults in the United States of 3.9 % in 2015 (26). On the basis of the available data, we cannot answer whether a general screening for LC should be carried out as routine procedure in patients with a distinct cardiovascular risk profile, but performance of thoracic imaging in patients with AAA may also detect noncancerous conditions of the thorax, such as accompanying thoracic aortic aneurysm.
Characteristics of 29 patients with lung cancer, including tumour stages and therapy.
Despite an overlap of 9 patients, the AAA subgroup and the LC subgroup differ noticeably. The aneurysm group is characterized by the classical image of atherosclerosis - higher age, distinct cardiovascular risk profile and CKD (27). There was a comparable proportion of nicotine abuse in patients with AAA and LC, but an association with CAD was found only for AAA and not for LC. In contrast, patients with LC were younger and had fewer comorbidities at the time of the first diagnosis. This leads to the assumption that these patients do not reach the age to evolve their comorbidities but die of cancer before. Recent data indicate that the 5-year survival rate in patients with LC is still very poor, despite improvements in therapy and prevention strategies (30% for localized tumours and 5% for distant disease) (28). In 2019, lung cancer was the leading cause of death from cancer in men and women, accounting for more than 142.000 deaths in the United States, which is approximately 25% of all cancer deaths (7). In an earlier retrospective single-center study, Blochle et al. analyzed the co-existence of AAA and LC diagnoses, based on ICD-10 codes (international statistical classification of diseases and related health problems). Of a total of 2971 inpatients (1875 were diagnosed with LC and 1096 with AAA), they detected 75 patients with both diagnoses, reaching a coprevalence of 6.8% (5). In patients with LC, the overall mortality rate was 96% after 5 years and none of the patients who was diagnosed with both LC and AAA had an aneurysm-related death. Compared to our cohort, mean age was slightly lower (72.1±7.2 years) and patients showed less comorbidities such as CKD, CAD or diabetes. We found an 18% coprevalence of LC in patients with AAA in our cohort. In a recent analysis of 589 patients who underwent AAA repair, Onohara et al. have found an incidence of late-onset malignancy occurrence of almost 3.6% per year, reaching a cumulative incidence of about 40% in 10 years (29). In an earlier study, Valentine et al. have also found a cumulative cancer rate of 40% (within only 5 years) and increased incidence of LC (4). They followed 126 patients with AAA and for comparison 99 patients with peripheral occlusive disease who underwent aortofemoral bypass and 100 patients with herniorrhaphy (4). A total of 51 patients with AAA were diagnosed with cancer (40%), while only 20% of the patients after bypass surgery or herniorrhaphy had a diagnosis of a malignancy. Multivariate analysis could hereby identify the presence of AAA as the strongest independent predictor for the diagnosis of malignancy of which LC was the most common. According to recent data the incidence for LC in patients with AAA and concomitant peripheral occlusive disease is estimated at 2.8% per year (21).
Problems of management due to concomitant malignancies and AAA have been described (1, 2) and there is no consensus on the best management approach (30). Considering the prognosis of patients with AAA and cancer and regarding the causes of death, cancer related deaths accounted for a third (32%) of late deaths in patients after AAA repair (4). However, more recent data and analyses from health insurance data showed that cardiovascular diseases remain the leading cause of deaths in patients after AAA repair, followed by cancer (29, 31, 32). Therefore, considering late mortality, patients after AAA repair should be under surveillance regarding both cardiovascular diseases and malignancies, with the intention to positively influence the overall prognosis (29). Only then will patients benefit from the AAA repair. In contrast to this, LC is associated with a significantly higher mortality. Upon concurrent existence of LC and AAA, the prognosis is largely determined by the LC (5). As a consequence, interventional treatment of the AAA is only recommended in patients with aneurysm-related symptoms or in asymptomatic patients with aneurysms larger than 7 cm (5, 21).
Our AAA cohort was mainly characterized by the moderate number of newly diagnosed AAA and high prevalence of LC. Nine patients of our cohort were diagnosed with both AAA and LC. Two of these 9 patients had a previously repaired AAA (one with surgical treatment and one with endovascular aortic repair) before the diagnosis of the LC was made. Since we diagnosed neither patients who were symptomatic nor any large aneurysms, the remaining seven patients of our cohort with both diagnoses were treated conservatively regarding their AAA. They are under surveillance with regular ultrasound examinations of the AAA. We hypothesize, however, that the simultaneous presence of an AAA doesn't have any influence on the outcome of patients with LC in our cohort. As most of our AAA patients are still alive, the cumulative incidence of LC is supposed to rise with longer follow-up periods. Here again the question arises as to how patients with AAA should be followed. Valentine tried to take this into account and recommended regular follow-up every three years based on median time to cancer detection (4). However, this recommendation applies to cancer in general and not to lung cancer in particular.
We found different histological subtypes of LC in our study population, with a distribution corresponding approximately to the usual distribution of LC. Adenocarcinoma is the most common tumor entity with a rate about 40%, followed by squamous cell carcinoma with a rate of 30% and SCLC and unspecified NSCLC with a rate of 15% each (33). This is comparable to our observations. The most frequent tumour entity was adenocarcinoma with a rate of more than 50%, followed by squamous cell carcinoma (24.1%), SCLC (17.2%) and NCSCLC (6.9%). At the time of first diagnosis only two patients (6.9%) had a localized tumour (UICC stage II). This is in line to recent data which indicated that circa 80% of LC are diagnosed in an advanced stage with poorer survival (25) and in patients with coexistent AAA, the overall survival correlated closely with the stage of the LC (5, 29).
We found a total mortality of 7.3% (3 of 41 patients) in the AAA only group, while in the LC only group absolute mortality rate was more than five times higher, reaching up to 40% (8 of 20 patients). The prognosis of the patients who were diagnosed with both AAA and LC was slightly better (mortality rate of 33.3%). Patients with both diagnoses showed an advanced age, averaging 75 years. In addition, only one patient suffered from a SCLC, which is associated with a worse prognosis since surgical treatment is rarely an option, as dissemination is usual at diagnosis (34). SCLC mainly affects middle-aged persons (27-66 years) with a history of smoking (35), which might be an explanation for different mortality rates in the group of patients with both AAA and LC and the LC only group.
Limitations
The main limitation is that not all patients with a LC were examined with the same imaging modality, as in contrast to AAA there is no established LC screening, so CT was only performed in the case of another justified indication. Therefore, the actual incidence of LC may have been underestimated. Given the limited number of patients, a competing risks survival analysis was performed. No cost-benefit analysis could be carried out based on the available data. AAA was associated not only with LC but also with other malignancies that were not considered in this analysis.
Conclusion
Male patients with a distinct cardiovascular risk profile, admitted to an emergency department, showed a high prevalence of both AAA and LC. Not only the prevalence, but also the incidence of LC was remarkable. The prevalence of LC among patients with AAA was even higher. In summary, the prognosis of AAA patients largely depends on cardiovascular comorbidities and synchronous or metachronous malignancies. In patients with both AAA and LC the prognosis is largely determined by the LC. Due to common risk factors, the frequent coexistence and the impact on overall prognosis, LC is of particular importance in screening, surveillance and after AAA repair.
Footnotes
Authors' Contributions
All Authors have made substantial contributions to the concept of the study. M.S, G.R. and M.B. conceived the study. R.H., J.B. and E.S. provided data on tumour stages and cancer treatment and performed follow-up visits. T.S. and M.P. collected the data and performed statistical analysis. A.H. and M.S. wrote the manuscript. J.M. and I.A. provided essential scientific input. Evaluation of chest imaging was performed by P.R. All Authors discussed the results and contributed to the final version of the manuscript.
Conflicts of Interest
All Authors of this manuscript certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
- Received May 25, 2020.
- Revision received June 10, 2020.
- Accepted June 11, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
