Abstract
Objective:
Pulmonary hypertension (PH) is an underdiagnosed condition associated with poor survival and increased post-operative mortality in lung cancer. CT-based parameters of pulmonary artery enlargement are strong predictors of PH. We used these parameters to investigate pulmonary artery enlargement in lung and oesophageal cancer.
Methods:
Consecutive patients with lung cancer (n = 100) or oesophageal cancer (n = 100) undergoing staging 18F-fluodeoxyglucose PET/CT were retrospectively identified. The transverse diameter of the main pulmonary artery (mPA) and ascending aorta, and the pulmonary artery-to-ascending aorta (PA:A) ratio were obtained. Abnormal values were defined following the Framingham Heart Study cohort.
Results:
Lung cancer patients had a significantly increased mPA diameter compared to the oesophageal cancer patients (males: 27.29 ± 0.39 vs. 25.88 ± 0.24 mm, females: 26.10 ± 0.28 vs. 24.45 ± 0.18 mm). Similarly, a significantly increased proportion of these patients had an abnormal mPA diameter (males: 35.1% vs 12.5%, females: 32.6% vs 10.7%). Lung cancer patients also had a significantly higher PA:A ratio (males: 0.83 ± 0.01 vs. 0.79 ± 0.008, females: 0.85 ± 0.01 vs. 0.79 ± 0.009), with a larger proportion having an abnormal PA:A ratio (males: 24.6% vs 11.1%, females: 27.9% vs 14.3%).
Conclusion:
Simple measurements of mPA diameter and PA:A ratio reveal that lung cancer patients exhibit increased rates of pulmonary artery enlargement compared to oesophageal cancer patients.
Advances in knowledge:
This study demonstrates there is an increased prevalence of pulmonary enlargement in lung cancer, easily detected on routine staging scans, holding implications for further work-up and risk stratification.
Introduction
Pulmonary hypertension (PH) is a progressive disease that is typically diagnosed late, resulting in very poor prognosis and high mortality associated with right heart failure. The prevalence of PH in lung cancer remains poorly studied, despite having important implications for disease management. PH is a major contraindication for pulmonary resection, the mainstay of treatment for early-stage lung cancer.1,2 In patients undergoing resection, PH is an independent risk factor associated with poor outcomes, including increased post-operative complications and mortality.3,4
Although right heart catheterisation (RHC) remains the gold standard for the diagnosis of PH, RHC is a highly invasive procedure that has recognised complications and can delay the definitive management of lung malignancy. Echocardiography is frequently used as a non-invasive alternative. However, this modality is user-dependent and has suboptimal accuracy, particularly in the context of diffuse lung disease.
Multiple studies have established that two CT-based parameters, the mean pulmonary artery (mPA) diameter and the pulmonary artery-to-ascending aorta (PA:A) ratio, are robust predictors of the presence of PH, and strongly correlate with haemodynamic measurements on echocardiography and RHC.5–8 mPA enlargement reflects the increased pulmonary arterial pressure occurring in the disease process in PH, whereas PA:A ratio provides an internal normalisation and corrects for anthropomorphic factors. Despite their predictive value, no studies to date have assessed these parameters to determine whether lung cancer patients exhibit pulmonary artery enlargement on routine staging scans. Furthermore, enlarged mPA and PA:A ratios were listed as an established tool suggestive of PH at the sixth World Symposium on Pulmonary Hypertension.9
18F-fluorodeoxyglucose PET/CT (18F-FDG PET/CT) is increasingly used for the staging of lung cancer, with the National Institute of Clinical Excellence (NICE) guidelines currently recommending this modality for all patients who are suitable for curative treatment.10 This creates the potential for the routine measurement of parameters that may guide further work-up and management in this high-risk patient group. The aim of this study was to investigate the prevalence of pulmonary artery enlargement in patients with lung cancer, compared to patients with oesophageal cancer and the Framingham Heart Study cohort, using PET/CT-based measurements of mPA diameter and PA:A ratio.
Methods
Patients
Consecutive patients who referred for 18F-FDG PET/CT staging of lung cancer at our institution between January 2014 and December 2015 were retrospectively identified. Patients were eligible for inclusion if the tumour was >3 cm in diameter (i.e., staged T2 or above following the eighth edition of the International Association for the Study of Lung Cancer TNM staging). Exclusion criteria included masses causing direct anatomical distortions of the measured vessels, congenital heart disease and interstitial lung disease, all of which have been shown to confound the measurement of pulmonary artery diameter.11
Consecutive patients that underwent 18F-FDG PET/CT for biopsy proven oesophageal carcinoma during the same period were selected as the comparison group. Identical exclusion criteria were applied. For both groups, PET/CT was only performed in patients where there was an intention for radical treatment. Ethical approval was waived by the local Institutional Review Board as this was a retrospective image analysis study.
18F-FDGPET/CT imaging protocol
PET/CT imaging was performed on a GE Discovery 690 or a 710 PET/CT system with 64-slice CT systems (GE Healthcare, Milwaukee, USA). The CT was performed using a pitch of 0.984, 120 kV, auto mA with a noise index of 25. Following established protocols for PET/CT acquisition, respiration was not suspended, with the imaging study performed during tidal respiration. CT images were reconstructed at a slice thickness of 2.5 mm and analysed using soft tissue windows (window width, 400 HU; window centre, 40 HU).
CT-based measurements
The CT component of the scans was examined for pulmonary artery enlargement with blinding of clinical information using Hermes Hybrid Viewer (Hermes Medical Solutions,Stockholm, Sweden). The transverse axial diameter of the mPA and the ascending aorta were measured at the level of the bifurcation of the mPA when right and left pulmonary arteries were of the same size, using the same image for both measurements (Figure 1). The PA:A ratio was calculated by dividing the mPA diameter by the ascending aortic diameter. Interobserver variability was determined using measurements from two blinded reviewers in a random sample of 60 patients.
Figure 1.
Measurement of the transverse axial diameter of the main pulmonary artery (mPA) and ascending aorta (A) in patients with normal (a) and abnormally high (b) values.
Statistical analysis
Data are expressed as means with standard error (SE) for continuous variables and as frequencies or percentages for categorical variables. The mean mPA diameter, ascending aortic diameter and PA:A ratio between the lung cancer group and the oesophageal cancer group were compared using multivariate analysis of variance. Cut-off points used were 29 mm (males) and 27 mm (females) for abnormally high mPA diameter, and 0.9 (both males and females), for abnormally high PA:A ratio, as previously defined by the reference cohort in the Framingham Heart Study, consisting of 3171 healthy individuals and constituting the largest study population to date.12 The relationship between mPA and PA:A ratio with age was determined using sex-specific Pearson correlation. Intra- and inter-observer variation of categorical data were expressed using Cohen's κ coefficient. The strength of agreement for the κ coefficient was interpreted following the standards proposed by Landis and Koch: 0 = poor, 0.01–0.20 = slight, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = substantial, and 0.81–1 = almost perfect. All tests were two-sided and a P value < 0.05 was considered significant. All statistical analyses were performed with STATA Statistical Software (Release 12, StataCorp LLC, College Station, USA).
Results
Patient characteristics
100 consecutive patients with lung cancer and 100 consecutive patients with oesophageal cancer who underwent staging PET/CT scans during the study period who met the inclusion criteria. Baseline demographical and radiological characteristics are summarised in Table 1. All cases were technically satisfactory, with no significant image blurring or motion artefacts. There were no significant differences between the lung and oesophageal cancer groups in terms of age, BMI or ascending aortic diameter. The differences in the sex composition between both groups reflect the increased male preponderance of oesophageal carcinoma, and the male-to-female ratio for this condition in our study approximates the ratio found in the underlying UK population (72:28 vs 67:33).10
Table 1.
Baseline patient characteristics
| Characteristics | Lung Cancer Group (n = 100) |
Oesophageal Cancer Group (n = 100) |
|---|---|---|
| Age (years) | 71.44 ± 1.26 | 68.01 ± 1.08 |
| Sex | ||
| Male (%) | 57 | 72 |
| Female (%) | 43 | 28 |
| BMI (kg/m2) | 25.7 ± 0.62 | 26.2 ± 0.56 |
| mPA diameter (mm) | 26.76 ± 0.35 | 25.50 ± 0.23 |
| Aortic diameter (mm) | 32.15 ± 0.37 | 32.42 ± 0.29 |
| PA:A ratio | 0.83 ± 0.01 | 0.79 ± 0.008 |
A, ascending aorta; BMI, body mass index; PA, pulmonary artery; mPA, main pulmonary artery.
Data are expressed as mean ± SE.
CT measurements of mPA and PA:A ratio
Patients with lung cancer had a significantly higher mPA diameter compared to the oesophageal cancer group (26.76 ± 0.35 mm vs 25.50 ± 0.23 mm, p = 0.003; mean ± SE). This difference persisted after adjusting for sex, with both males and females with lung cancer exhibiting larger mPA sizes (males: 27.29 ± 0.39 mm vs 25.88 ± 0.24 mm,p = 0.01; females: 26.10 ± 0.28 mm vs 24.45 ± 0.18 mm, p = 0.01; mean ± SE). Furthermore, when compared to predefined sex-specific cut-off values, a higher proportion of lung cancer patients of both sexes had an abnormally high mPA diameter compared to the Framingham Heart Study reference cohort (males: 35.1% vs 12.5%,p = 0.002; females: 32.6% vs 10.7%, p = 0.002) (Figure 2).
Figure 2.
Mean main pulmonary artery (mPA) diameter (a) and pulmonary artery-to-ascending aorta (PA:A) ratio (c) in lung cancer vs oesophageal cancer. Proportion of patients with abnormally high mPA diameter (b) (>29 mm in males >27 mm in females) and abnormally high PA:A ratio (d) (>0.9 in males and females) in lung cancer vs oesophageal cancer. *p < 0.05. Data are expressed as mean ± SE.
The overall mean PA:A ratio was also significantly higher in lung cancer patients (0.83 ± 0.01 vs. 0.79 ± 0.008, p = 0.0006;mean ± SE), with both males and females exhibiting higher PA:A ratios compared to the oesophageal cancer group (males: 0.83 ± 0.01 vs. 0.79 ± 0.008, p = 0.02; females: 0.85 ± 0.01 vs. 0.79 ± 0.009, p = 0.03; mean ± SE). Similarly, a larger percentage of the study group had an abnormally high PA ratio (males: 24.6% vs 11.1%, p = 0.003; females: 27.9% vs 14.3%,p = 0.003) (Figure 2).
The Cohen’s κ values for intra-observer and inter-observer agreement were 0.93 and 0.91 for mPA diameter and 0.92 and 0.88 for PA:A ratio, respectively, indicating almost perfect agreement.
Correlation between mPA and PA:A ratio with age
Correlation analysis between mPA and age detected a positive but weak correlation between mPA diameter and age (males: r = 0.15, p = 0.03; females: r = 0.13,p = 0.04), and between aortic diameter and age (males: r = 0.31, p = 0.01; females: r = 0.12, p = 0.04). On the other hand, a negative but weak correlation between PA:A ratio and age was found in males (r=–0.14,p = 0.03) but not in females (r = 0.02, p = 0.4) (Figure 3).
Figure 3.
Correlation between age and mPA diameter, aortic diameter, and PA:A ratio. The vertical dotted lines indicate the cut-off values for abnormally high mPA diameter and PA:A ratio in males (black) and females (grey).
Discussion
PH is an insidious condition associated with a poor median survival of 2.8 years, reflecting its late diagnosis.13 In the context of lung cancer, PH is a contraindication to pulmonary resection and a predictor of poor prognosis.4 Despite its significance, the prevalence of PH in lung cancer has been poorly studied, and PH remains underdiagnosed, especially in at-risk populations.14 PH is the most common cause of pulmonary artery enlargement, and numerous studies have validated mPA diameter and PA:A ratio as robust predictors of the presence of this condition in both healthy and respiratory disease cohorts.
To our knowledge, this is the first study to investigate pulmonary artery enlargement using staging PET/CT scans in lung or oesophageal cancer, although a study performed on a cohort of smokers undergoing lung cancer screening found a greater prevalence of increased mPA and PA:A than in the general population.15 Our findings suggest that pulmonary artery enlargement is highly prevalent in staging lung cancer patients, being present in 35.1% of males and 32.6% of females. Furthermore, these patients have increased rates of abnormally high PA:A ratio, found in 24.6% of males and 27.9% of females, indicating that these differences are largely independent of anthropomorphic factors such as age, sex, height or body surface area.
Although higher than some previous reports, our rates are consistent with a 2014 study using echocardiography-derived pulmonary artery systolic pressure (PASP) to estimate the presence of PH after pneumonectomy in lung cancer patients, finding that 37.9% of patients developed mild-to-moderate PH while 3.4% developed severe PH.16 However, the measurements in our study population were conducted immediately prior to potential radical therapy rather than post-operatively. Pulmonary resection leads to increased right heart workload and limits the remaining pulmonary vascular function, and could predispose to PH.
mPA diameter has a sensitivity of 87% and specificity of 89% for detecting PH,17 and the PA:A ratio has been shown to be superior to echocardiography in its predictive value.5 We used the sex-specific cut-off values defined by the largest study to date, the Framingham Heart Study cohort.12 By contrast, previous studies investigating the validity of these metrics have chosen a wide range of cut-off values for mPA diameter (25–33.3 mm) and PA:A ratio (0.86–1), resulting in different discriminatory abilities.5–8 Similarly, the use of sex-specific cut-off values is not always implemented, despite males and females having been shown to exhibit different mPA diameter sizes. This was particularly relevant in our cohort due to the increased male-to-female ratio in the oesophageal cancer group.The population in our study was more disease-specific and homogeneous compared to previous studies, which evaluated these measurements in groups of patients with undefined comorbidities resulting in heterogeneity.
mPA diameter and consequently PA:A ratio can be influenced by technical factors, including measurement method, acquisition and reconstruction protocols, window settings, i.v. contrast and the cardiac cycle. These are likely to account, at least in part, for the discrepancies found in the literature. Considering these limitations and that sensitivity and specificity are high but not perfect, caution should be exercised when interpreting findings of pulmonary artery enlargement on CT. Abnormal findings could be confirmed with echocardiography or, in selected cases, RHC.
In fact, although these CT metrics alone are strong predictors of the presence of PH, their sensitivity and specificity can be increased further when combined with other techniques. One study showed that a composite index of PA:A ratio and echocardiography was more strongly related to mean pulmonary arterial pressure (mPAP) than either measurement alone.6 Other studies have shown an increased predictive value using multivariate modelling in chronic obstructive pulmonary disease (COPD).18 mPA diameter and PA:A ratio have been found to predict the presence of early borderline PH, and correlate with invasive haemodynamic measurements of echocardiography and RHC.6,8,19 These metrics can be rapidly and routinely obtained from staging CT or PET/CT scans, require minimal training, and are highly reproducible, as shown by our almost perfect intra- and inter-observer agreement. Therefore, routine CT-based screening for pulmonary artery enlargement in lung cancer patients has the potential to guide further work-up and stratification for PH.
There are several possible explanations for the increased rates of pulmonary enlargement found in our study. PH is the most common, but not the sole cause of PA enlargement, with other rarer causes including left-to-right shunting, vasculitides and connective tissue diseases.11,20 Tobacco smoking and other toxins are common risk factors for lung cancer and PH,21 and could predispose to both conditions. Similarly, lung cancer patients are at an increased risk of several conditions that are established causes of PH, with the most prominent examples being cardiovascular disease (WHO Group 2 PH) and COPD (WHO Group 3 PH).22,23 In a small proportion of lung cancer cases, PH could also be due to microembolisation.24 Another possibility is that the pulmonary artery enlargement in these patients reflects other processes triggered by the underlying malignancy, such as vascular fluctuations with centralisation of blood flow, hypoxic stress or altered mechanics due to structural changes in elastin and collagen. Although direct involvement of the vessels or anatomical distortion by the tumour are also possible, these were avoided by our exclusion criteria.
Our study had several limitations. First, the study had a single-centre retrospective design. The nature of our regional referral centre meant that limited data were available regarding patient risk factors, such as smoking status and COPD prevalence, and subsequent outcomes. Second, the sample size (n = 200) was relatively small, and patients with advanced lung cancer were probably under represented. These patients are less suitable for radical treatment and therefore less likely to be referred for PET/CT. Nonetheless, our sample size is comparable to other studies performed on patients with COPD and cystic fibrosis, and the population included a range of patients at different stages of lung cancer. Third, we did not analyse the relationship between mPA diameter and PA:A ratio and PASP, since echocardiography or RHC were not performed. However, multiple studies have validated these CT metrics as robust predictors of PASP and PH.5,6,8 Although breathing was not suspended in our study, modern spiral CT protocols are fast, and none of the images were deemed to be technically inadequate due to breathing motion artefact.
Future prospective studies using echocardiography or RHC are needed to validate our findings in patients with lung and oesophageal cancer. Similarly, multivariate analyses in larger cohorts could be used to determine whether enlarged mPA diameter and PA:A ratio constitute risk factors predictive of post-operative morbidity and mortality and performance status in this patient group, and also what degree of enlargement appears critical. Although a recent 2019 study showed that PA:A ratios >1 predict poor survival in fibrotic interstitial lung disease, the predictive of these metrics in patients with lung cancer remains undetermined.25
Conclusion
PH is an underdiagnosed condition that carries high mortality and has been associated with poor surgical outcomes in lung cancer patients. With the increasing use of staging PET/CT scans in lung cancer, the mPA diameter and PA:A ratio constitute to be easily assessed and reproducible metrics that could inform management pathways and prognostication. Patients with lung cancer exhibit a higher prevalence of pulmonary artery enlargement than patients with oesophageal cancer, and simple CT-based measurements can be routinely obtained to screen patients and guide further referral and testing for PH.
Contributor Information
Antonio Ji-Xu, Email: antoniojixu@gmail.com.
Yunfei Yang, Email: yunfei.yang94@gmail.com.
Kevin M Bradley, Email: BradleyK2@cardiff.ac.uk.
REFERENCES
- 1.Fee HJ, Holmes EC, Gewirtz HS, Ramming KP, Alexander JM. Role of pulmonary vascular resistance measurements in preoperative evaluation of candidates for pulmonary resection. J Thorac Cardiovasc Surg 1978; 75: 519–24. doi: 10.1016/S0022-5223(19)41235-X [DOI] [PubMed] [Google Scholar]
- 2.Rams JJ, Harrison RW, Fry WA, Moulder PV, Adams WE. Operative pulmonary artery pressure measurements as a guide to postoperative management and prognosis following pneumonectomy. Dis Chest 1962; 41: 85–90. doi: 10.1378/chest.41.1.85 [DOI] [PubMed] [Google Scholar]
- 3.Pierce RJ, Sharpe K, Johns J, Thompson B. Pulmonary artery pressure and blood flow as predictors of outcome from lung cancer resection. Respirology 2005; 10: 620–8. doi: 10.1111/j.1440-1843.2005.00759.x [DOI] [PubMed] [Google Scholar]
- 4.Asakura K, Mitsuboshi S, Tsuji M, Sakamaki H, Otake S, Matsuda S, et al. Pulmonary arterial enlargement predicts cardiopulmonary complications after pulmonary resection for lung cancer: a retrospective cohort study. J Cardiothorac Surg 2015; 10: 113. doi: 10.1186/s13019-015-0315-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Iyer AS, Wells JM, Vishin S, Bhatt SP, Wille KM, Dransfield MT. Ct scan-measured pulmonary artery to aorta ratio and echocardiography for detecting pulmonary hypertension in severe COPD. Chest 2014; 145: 824–32. doi: 10.1378/chest.13-1422 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Devaraj A, Wells AU, Meister MG, Corte TJ, Wort SJ, Hansell DM. Detection of pulmonary hypertension with multidetector CT and echocardiography alone and in combination. Radiology 2010; 254: 609–16. doi: 10.1148/radiol.09090548 [DOI] [PubMed] [Google Scholar]
- 7.Alhamad EH, Al-Boukai AA, Al-Kassimi FA, Alfaleh HF, Alshamiri MQ, Alzeer AH, et al. Prediction of pulmonary hypertension in patients with or without interstitial lung disease: reliability of CT findings. Radiology 2011; 260: 875–83. doi: 10.1148/radiol.11103532 [DOI] [PubMed] [Google Scholar]
- 8.Mahammedi A, Oshmyansky A, Hassoun PM, Thiemann DR, Siegelman SS. Pulmonary artery measurements in pulmonary hypertension: the role of computed tomography. J Thorac Imaging 2013; 28: 96–103. doi: 10.1097/RTI.0b013e318271c2eb [DOI] [PubMed] [Google Scholar]
- 9.Frost A, Badesch D, Gibbs JSR, Gopalan D, Khanna D, Manes A, et al. Diagnosis of pulmonary hypertension. Eur Respir J 2019; 53: 1801904. doi: 10.1183/13993003.01904-2018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.National Institute for Health and Clinical Excellence Lung cancer: diagnosis and management. March 2019. Available from: https://www.nice.org.uk/guidance/ng122 [Accessed March, 2020].
- 11.Raymond TE, Khabbaza JE, Yadav R, Tonelli AR. Significance of main pulmonary artery dilation on imaging studies. Ann Am Thorac Soc 2014; 11: 1623–32. doi: 10.1513/AnnalsATS.201406-253PP [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Truong QA, Massaro JM, Rogers IS, Mahabadi AA, Kriegel MF, Fox CS, et al. Reference values for normal pulmonary artery dimensions by noncontrast cardiac computed tomography: the Framingham heart study. Circ Cardiovasc Imaging 2012; 5: 147–54. doi: 10.1161/CIRCIMAGING.111.968610 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002; 106: 1477–82. doi: 10.1161/01.cir.0000029100.82385.58 [DOI] [PubMed] [Google Scholar]
- 14.Hoeper MM, McLaughlin VV, Dalaan AMA, Satoh T, Galiè N. Treatment of pulmonary hypertension. Lancet Respir Med 2016; 4: 323–36. doi: 10.1016/S2213-2600(15)00542-1 [DOI] [PubMed] [Google Scholar]
- 15.Steiger D, Han D, Yip R, Li K, Chen X, Liu L, et al. Increased main pulmonary artery diameter and main pulmonary artery to ascending aortic diameter ratio in smokers undergoing lung cancer screening. Clin Imaging 2020; 63: 16–23. doi: 10.1016/j.clinimag.2019.11.011 [DOI] [PubMed] [Google Scholar]
- 16.Potaris K, Athanasiou A, Konstantinou M, Zaglavira P, Theodoridis D, Syrigos KN. Pulmonary hypertension after pneumonectomy for lung cancer. Asian Cardiovasc Thorac Ann 2014; 22: 1072–9. doi: 10.1177/0218492314527992 [DOI] [PubMed] [Google Scholar]
- 17.Tan RT, Kuzo R, Goodman LR, Siegel R, Haasler GB, Presberg KW. Utility of CT scan evaluation for predicting pulmonary hypertension in patients with parenchymal lung disease. medical College of Wisconsin lung transplant group. Chest 1998; 113: 1250–6. doi: 10.1378/chest.113.5.1250 [DOI] [PubMed] [Google Scholar]
- 18.Wells JM, Washko GR, Han MK, Abbas N, Nath H, Mamary AJ, et al. Pulmonary arterial enlargement and acute exacerbations of COPD. N Engl J Med 2012; 367: 913–21. doi: 10.1056/NEJMoa1203830 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lange TJ, Dornia C, Stiefel J, Stroszczynski C, Arzt M, Pfeifer M, et al. Increased pulmonary artery diameter on chest computed tomography can predict borderline pulmonary hypertension. Pulm Circ 2013; ; 3: 363–8Apr-Jun. doi: 10.4103/2045-8932.113175 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Shen Y, Wan C, Tian P, Wu Y, Li X, Yang T, et al. CT-based pulmonary artery measurement in the detection of pulmonary hypertension: a meta-analysis and systematic review. Medicine 2014; 93: e256. doi: 10.1097/MD.0000000000000256 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Schiess R, Senn O, Fischler M, Huber LC, Vatandaslar S, Speich R, et al. Tobacco smoke: a risk factor for pulmonary arterial hypertension? A case-control study. Chest 2010; 138: 1086–92. doi: 10.1378/chest.09-2962 [DOI] [PubMed] [Google Scholar]
- 22.Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med 1986; 105: 503–7. doi: 10.7326/0003-4819-105-4-503 [DOI] [PubMed] [Google Scholar]
- 23.Rodríguez LAG, Wallander M-A, Martín-Merino E, Johansson S. Heart failure, myocardial infarction, lung cancer and death in COPD patients: a UK primary care study. Respir Med 2010; 104: 1691–9. doi: 10.1016/j.rmed.2010.04.018 [DOI] [PubMed] [Google Scholar]
- 24.Hibbert M, Braude S. Tumour microembolism presenting as "primary pulmonary hypertension". Thorax 1997; 52: 1016–7. doi: 10.1136/thx.52.11.1016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kogo M, Otsuka K, Morimoto T, Nagata K, Nakagawa A, Tomii K. Pulmonary artery enlargement predicts poor outcome during acute exacerbations of fibrotic interstitial lung disease. Respirology 2019; 24: 777–82. doi: 10.1111/resp.13504 [DOI] [PubMed] [Google Scholar]