Thoracic Complications in Behçet's Disease: Imaging Findings

Behçet's disease (BD) causes vascular inflammation and necrosis in a wide range of organs and tissues. In the thorax, it may cause vascular complications, affecting the aorta, brachiocephalic arteries, bronchial arteries, pulmonary arteries, pulmonary veins, capillaries, and mediastinal and thoracic inlet veins. In BD, chest radiograph is commonly used for the initial assessment of pulmonary symptoms and complications and for follow-up and establishment of the response to treatment. With the advancement of helical or multislice computed tomography (CT) technologies, such noninvasive imaging techniques have been employed for the diagnosis of vascular lesions, vascular complications, and pulmonary parenchymal manifestations of BD. CT scan (especially, CT angiography) has been used to determine the presence and severity of pulmonary complications without resorting to more invasive procedures, in conjunction with gadolinium-enhanced three-dimensional (3D) gradient-echo magnetic resonance (MR) imaging with the subtraction of arterial phase images. These radiologic methods have characteristics that are complementary to each other in diagnosis of the thoracic complications in BD. 3D ultrashort echo time (UTE) MR imaging (MRI) could potentially yield superior image quality for pulmonary vessels and lung parenchyma when compared with breath-hold 3D MR angiography.


Introduction
BD is a chronic, systemic inflammatory disease of unknown origin [1][2][3][4]. A clinical triad of oral ulcers and genital ulcers and uveitis is characteristic of the disease.
is triple symptom complex was first described by the Turkish dermatologist Hulusi Behçet in 1937 [5]. Clinical manifestations additional to this triad were described later including involvement of the skin, joints, large vessels, lung, brain, and gastrointestinal and genitourinary tracts (Table 1) [4,[6][7][8]. e variability of clinical manifestations in addition to specific histological or laboratory findings may cause the difficulty in diagnosis [8].
ere are no specific diagnostic laboratory tests or histopathologic findings. us, the diagnosis of the disease is made on the basis of the criteria proposed by the International Study Group for Behçet's disease in 1990 (Table 2) [9]. Immunopathological findings suggest that the main underlying pathology in the patients suffering from Behçet's disease is vasculitis affecting the small and large pulmonary arteries [3,4,8]. In comparison with the conventional radiological techniques, helical CT or multislice CT (MSCT) is the preferred imaging modality in the diagnostic procedures related to the investigation of thoracic involvements in BD [8,10,11]. Undoubtedly, the need for conventional radiology has diminished with the increasing utility of CT scan. However, CT scans in association with magnetic resonance imaging (MRI) and MR angiography (MRA) or MR venography may prove useful in obtaining detailed thoracic findings of BD [12][13][14].
In this study we review the clinical and imaging findings of BD.

Clinical Findings
BD has a very wide spectrum of clinical features and it has a chronic course with unstable exacerbations and remissions [15]. Hemoptysis is the most common clinical manifestation of pulmonary involvement [3,8,[16][17][18][19][20]. is finding is a poor prognostic sign, leading to death in 30% of patients, in 80% within two years [14,18]. Other clinical problems may include dyspnea, pleuritic chest pain, cough, malaise, fever, and weight loss [3,16,18,19]. Pulmonary artery aneurysms can be fatal due to perforation to the adjacent bronchus [3,[18][19][20] or it may be the result of the development of in situ thrombosis related to the active vasculitis [3,8,19]. In BD, mediastinal involvement with mediastinal fibrosis might be initiated by chronic relapsing systemic vasculitis. Patients with mediastinal fibrosis and superior vena cava (SVC) thrombosis present with signs or symptoms related to obstruction or compression of vital mediastinal structures such as central airways, axillar, subclavian and brachiocephalic veins, and SVC [21,22]. Cardiovascular manifestations have been reported in 7-46% of cases with BD and mortality occurs in up to 20% of those patients with marked vascular involvement [23,24]. Sporadic cases of endocarditis, myocarditis, pericarditis, acute myocardial infarction, aortic aneurysm, ventricular thrombosis, congestive cardiomyopathy, and valvular dysfunction have been reported [23,25].

Imaging Findings
3.1. Chest Radiograph. Chest radiograph is the first choice in imaging technique to demonstrate the pulmonary signs and symptoms of BD [14]. Pulmonary artery aneurysms (PAAs) appear as a hilar enlargement or as round, lobular opacities on chest radiographs. ese lesions resemble hilar mass lesions. Chest radiographs are also useful for the detection of hilar enlargement, which may develop due to PAAs [8,14]. Chest radiograph can show the clinical effectiveness of immunosuppressive treatment and findings related to response to the treatment in early period during follow-up [26]. Radiograph may be normal or may show indirect signs such as mediastinal widening [10,14].

Angiography.
Contrast studies of the arteries and veins are the standard method in diagnosing vascular lesions and vascular complications in BD and for evaluating their response to medical therapy. If a source of bleeding in the bronchial artery is suspected, it may be controlled via embolization techniques during arteriography [12,14,27]. However, venous puncture, intravenous infusion, rapid injection of a large quantity of contrast medium, or insertion of vascular catheters may initiate the formation of thrombosis or aneurysm. Moreover, an aneurysm may develop at the site of the arterial puncture [3,10,14]. In the literature, following angiography for the demonstration of vascular lesions has been reported as being severely hazardous (in 70% in patients) [16,18]. Surgical repair carries a high risk because of the presence of massive hemoptysis. us, arterial embolization with catheter angiography is advocated as alternative life-saving method for treatment of PAAs in BD with massive, life-threating hemoptysis [28].

Computed Tomography (CT).
Helical CT (spiral CT) or MSCT is an important imaging technique in demonstrating the entire thoracic manifestations in BD [10,11,29]. Twodimensional and 3D reformatted chest CT images have been suggested as the most appropriate imaging techniques because contrast-enhanced CT scans can provide a surgical road map of contrast-filled lumen of major or mediastinal arteries, mediastinal and thoracic inlet veins, and segmental and larger pulmonary arteries [11,12,14]. When compared with contrast-enhanced CT, it has been reported that helical CT phlebography is superior to contrast-enhanced CT for showing of thrombi and for determining the degree of obstruction. Although CT phlebography shows the site and the extent of obstruction for visualizing collateral pathways, it has been reported that this technique is insufficient to diagnose the cause of obstruction [30]. Major technical   [31]. MSCT or MDCT, with its multiplanar and 3D imaging, depicts mediastinal widening and identifies superimposed thrombosis, severity of SVC obstruction, and the level and extent of venous obstruction [32]. e CT diagnosis of SVC obstruction includes lack of opacification of SVC, intraluminal filling defect or severe narrowing of the SVC, and visualization of collateral vascular channels [32].
In addition, CT scan examinations (especially, CT angiography) can detect and locate aneurysms and central or segmental pulmonary thromboemboli. CT scans can also identify the origin of aneurysm and its anatomic relationships with the adjacent structures and the pulmonary artery. Moreover, it is useful in determining the need for intervention and the optimum surgical approach [12,33]. CT is significantly more accurate than angiography in the assessment of intraluminal thrombi, wall calcification, and extraluminal disease [33]. Furthermore, angiography could not demonstrate pulmonary aneurysms if they are completely thrombosed [34]. Consequently, CTangiography also provides excellent vascular images with only a small quantity of contrast medium and may be used as an alternative to venography and angiography [10,14].

Magnetic Resonance Imaging (MRI).
A review of the clinical and radiology literature has shown that MRI and MRA can be used to detect the exact localization of the aneurysm of the aorta, brachiocephalic arteries, and PAAs, as well as changes in the vessel walls, mural thrombus, and thrombus within the aneurysms [12,14]. However, a few studies suggest that MRI is less sensitive than helical CT for the detection of small aneurysms in the lungs [20,35].
rombosis or the obstruction of the central veins is an important cause of morbidity or mortality in patients with benign or malignant conditions. Several investigators [36][37][38] have advocated that MRI and 3D gadolinium-enhanced MR venography with the subtraction of arterial phase images can be successfully used in the evaluation of thoracic veins and obstructions of the central veins. In a study by Akpolat et al. [13], it has been reported that MRI and MRA can demonstrate not only the arterial lesions but also the venous occlusions in the central and peripheral veins in BD patients. However, the advantages and limitations of MR examinations have been well described in [37]. Because no contrast agent is needed to image flowing blood, MR examination can be performed safely in patients with allergic to iodinated contrast media or in those for whom such media are contraindicated medically. Gadolinium-based contrast agents include risk of nephrotoxicity in patients with renal insufficiency and pregnant patients or in patients in whom intravenous access cannot be obtained. In these patients alternative imaging techniques such as noncontrast MR venography (phase contrast MRA) can be used to evaluate the venous lesions [39][40][41]. Some researchers [42][43][44] have advocated that free-breathing 3D radial ultrashort echo time (UTE) MRI can be used in both detection of lung parenchymal lesions (e.g., emphysema and fibrosis) and pulmonary vascular pathologies (e.g., pulmonary emboli) simultaneously. According to the literature reports, several types of thoracic complications associated with BD have been described in the literature [10,11].

Systemic Arterial Manifestations.
e entire arterial tree can be involved in BD. Although vascular involvement is noted in only 25% of all affected patients, it is the most common cause of mortality in BD [10,14,18]. BD associated with lesions in the large vessels is referred to as 'vasculo-BD' or 'angio-BD' [4,10]. e most frequent site of systemic arterial involvement is the thoracic aorta, brachiocephalic arteries, subclavian artery ( Figure 1) abdominal aorta, and peripheral arteries. Involvement of visceral vessels occurs rarely. e arterial lesions are aneurysm, stenosis, complete occlusion, and pseudoaneurysms [14,45,46]. Arterial occlusions or stenosis may be asymptomatic or associated with ischemic symptoms, depending on the site of involvement and collateral circulation. e pathogenesis of the arterial lesions is thought to be related to vasa vasorum and arterial wall vasculitis [47]. Differential diagnosis of the vascular lesions includes Takayasu's arteritis, connective tissue disease, ankylosing spondylosis, Reiter's disease, and Burger disease [46,47].

Pulmonary Artery Involvement.
Pulmonary artery involvement causes pulmonary artery aneurysm (PAA), one of the most important complications of BD, and pulmonary artery thrombosis (PAT) with or without PAA [17,[48][49][50]. In a large series of 2500 patients performed retrospectively by Seyahi et al. [50] pulmonary artery involvement (PAI) was identified in 47 patients. %72 of the 47 patients (n � 34) were identified with PAA including 8 patients associated with PAT and the rest of the patients (n � 13, 28%) presented with isolated PAT. PAA has a particularly poor prognosis and a high mortality rate [20,51]. Hemoptysis in varying degrees is the most common and predominant clinical manifestation [8,20,52]. It can be life threating when PAA is ruptured and the worst prognostic sign in BD [18,20,48,51]. Moreover, PAA is associated strongly with thrombophlebitis [3,53]. PAA or PAI associated with lung lesions such as nodules, consolidations, and cavitary lesions occurs [48,49]. Pathologic findings suggest that arterial involvement of BD may result from neutrophilic vasculitis, which affects the vasa vasorum [54]. e arterial involvement in BD resembles those of Takayasu's arteritis, including aneurysm formation and arterial occlusion [54]. However, in BD sudden hilar enlargement or intraparenchymal round opacities on the chest radiograph or chest CT scan can present pulmonary artery aneurysm [8,14]. PAAs may be single (Figures 2-4) or multiple unilateral or bilateral ( Figure 5). ese lesions may be occluded totally or partially by thrombus (Figures 2, 4, 5). rombosed aneurysms cause ischemia or infarction in pulmonary parenchyma [8,20]. In BD hemoptysis can also be misdiagnosed as pulmonary thromboembolism (PTE) and this condition could be mistakenly attributed to PTE and inappropriate anticoagulation may prove fatal [3,51]. Hemoptysis, the most frequent symptom in BD, is also caused by lung cancer, bronchiectasis, and various infectious diseases such as lung tuberculosis and fungal infections.
ese diseases must be included in the differential diagnosis [48]. Some studies also suggest that PAAs may show clinical and radiological regression with corticosteroid and immunosuppressive treatment [14,52,55]. In another study, it has been reported that aneurysms or thrombosis may disappear or regress in about 70% of the cases with only immunosuppressive treatment [50,52]. However, the exact mechanism of this regression remains unknown [55]. Although there are reports of successful treatment results and regression of aneurysm with immunosuppressive treatment, mortality rate is still 26% [48,49]. In BD thrombosis of the pulmonary arteries is usually in situ thrombosis secondary to vasculitis. rombi being organized are firmly adherent to the vascular lumens [20,51,56]. Although deep vein thrombosis is common in BD, PTE is uncommon [20,57]. Hughes-Stovin syndrome (HSS) is characterized by the findings of thrombophlebitis and multiple pulmonary and/ or bronchial aneurysms [58]. Behçet's disease is also associated with combination of these lesions. ere is a significant overlap between the clinical, radiological, and histopathological findings of HSS and BD. Particularly pulmonary involvement is indistinguishable between two vasculitides [58]. In BD, the diagnosis is made on the basis of the criteria published in 1990 by the International Study Group for Behçet's disease [5]. ere exist evident similarities between the vascular manifestations of BD and HSS. However the exact pathophysiology of both vasculitides remains unclear [58].

Involvement of Major Mediastinal Veins and the Superior
Vena Cava. In general, vascular lesions occur in the venous system more frequently than the arterial system. e high frequency of venous involvement and the lower frequency of arterial involvement have been emphasized by different studies [45,48,[59][60][61][62]. However, according to the literature reports in Japanese [63], North American, and European series [64], it has been reported that arterial lesions are more common than venous lesions. ese studies suggest that vascular lesions show differences according to the geographical areas in BD.
ere is no concordance in the literature on the frequency rates of venous lesions. Major vein thromboses, such as superior and inferior vena cava, portal vein, hepatic vein, and dural sinuses, have been reported on up to 30% of the patients [45,50,59]. However, the most commonly venous involved site is the lower extremities followed by the SVC, the IVC, and the upper extremity veins [60,61,65]. In a large series of 2313 patients from Turkey, it has been reported that these venous lesions including jugular, renal, brachiocephalic, and hepatic veins occur less commonly [66]. In BD, SVC syndrome is frequently accompanied with thrombosis in SVC and rarely secondary to mediastinal fibrosis [21,67]. Calamia KT et al. [62,67] have reported that BD is a common cause of SVC syndrome in areas where the disease is common. In another study, Sagdıc et al. [65] have reported that BD is the most common cause of SVC syndrome in Mediterranean countries, after intrathoracic malign lesions. In BD, SVC thrombosis causes characteristic signs and symptoms of SVC syndrome [48,50,68]. Moreover, SVC syndrome due to vasculopathy, without evidence of thrombosis, has been presented as a case report [69]. Patients with SVC syndrome may tolerate clinical caval occlusion for many years compared to that of the malignant intrathoracic tumors. However, the deaths have been described as a result of extensive thrombosis, hemoptysis or other vascular causes, and rarely pulmonary embolus [62,67]. CT diagnosis of SVC syndrome includes lack of opacification of SVC or thoracic inlet and mediastinal veins, an intraluminal filling defect in the SVC, and wall thickening and obliteration of the SVC with accompanying prominent venous collaterals in the area drained by SVC (Figures 6 and  7) [22,32,52]. MRI and gadolinium-enhanced MR venography also show the extent and site of mediastinal and the thoracic inlet venous occlusions and collateral veins [13,[36][37][38]. Chylothorax, chylopericardium, and chylous ascites are rare presenting manifestations of BD. Association of these manifestations and SVC syndrome has been presented as case reports [70,71].

Involvement of the Pulmonary Parenchyma.
In many patients, involvement of pulmonary parenchyma may correlate with pulmonary infections that have been reported in 0.43% of patients with BD [72]. On chest radiograph or CT scans PAAs or PAT associated with ground glass lesions ( Figure 5) nodular infiltrates, consolidations, cavitary lesions, mediastinal lymphadenopathy, pleural and pericardial effusions, and intracardiac filling defects are often found [49,50]. Subpleural nodules ( Figure 5) and consolidations are commonly found during the exacerbations or at the beginning of the disease [50]. However, in a study performed in the early 2002s, Erkan et al. [20] have reported that pulmonary parenchymal findings are nonspecific. Subpleural nodular opacities or triangular opacities in CT scan are generally accepted as a foci of pulmonary hemorrhages and/or infarcts [15]. In recent studies, pulmonary parenchymal lesions such as nodular infiltrates, consolidations, ground glass opacities, and cavitary lesions have also been  [48][49][50]. Pulmonary parenchymal lesions such as organizing pneumonia have been rarely described [26,48,50]. As a result, histopathologic examinations of pulmonary parenchymal lesions are necessary in the differential diagnosis of lung parenchymal lesions [49]. Pleural manifestations of BD include pleural effusions and pleural nodules. Vasculitis of pleura is often difficult to differentiate from parenchymal subpleural lesions. Pleural effusion may be attributed to pulmonary infarction, vasculitis of pleura, or SVC thrombosis [10,14]. In BD patients with prolonged immunosuppressive treatment, bacterial, viral, fungal (Figure 4), and mycobacterial organisms may infect the lungs in a similar manner to that noted in certain types of immunosuppression [73].

4.5.
Involvement of the Heart. Cardiac involvement occurs in 1-6% of BD patients and often is associated with pulmonary arterial and venous involvement [48,73]. Cardiac problems in BD include pericarditis, myocarditis with conducting system findings, endocarditis with valvular regurgitation, intracardiac thrombus (ICT), coronary arteritis, and sinus of Valsalva aneurysms [48,50,74]. However, the authors consider that endomyocardial fibrosis in the right side of the heart is one of the causes of ICT in patients with BD without deep vein thrombus [75]. Most of the ICT in BD are seen in the right side of the heart, but left-sided and multichamber lesions have been also reported [22,74]. e differential diagnosis of intracardiac thrombus should include primary cardiac tumors, such as haemangioma, myxoma, lymphoma, or sarcoma [29,73]. Transesophageal echocardiography (TEE) can help in establishing the diagnosis by demonstrating a heterogeneous and echogenic mass [22]. Contrastenhanced CT may reveal a hypodense mass or a filling defect in the ventricle as well as other thoracic manifestations such as PTE and occlusions of SVC or lung parenchymal lesions. MRI may provide diagnostic information of the ICT within the cardiac chambers and the involvement of the additional vessels or surrounding structures (Figure 8) [20,76].

Conclusion
BD involving the chest can be characterized by aneurysms or occlusions of the aorta and its major branches or pulmonary vascular tree. Venous lesions and SVC syndrome develop after the initial diagnosis of BD in patients within long-term follow-up. CT scan is useful not only in diagnosing vascular involvement or complications but also in detecting pulmonary parenchymal involvement of BD. In comparison with catheter angiography, CT or MRA is less invasive and cost-effective and takes less time and provides diagnostic information that can help determine appropriate clinical management. Moreover, CT, MRI, MRA, and MR  venography are effective imaging modalities for the diagnosis, follow-up, and evaluation of vascular complications in BD patients, without resorting to invasive procedures. Contrast-enhanced MRA (cMRA) shows inferior depiction of the lung parenchyma and may be limited in dyspneic patients due to need for breath-holding. Although gadolinium-based contrast agents are contraindicated in some patients, contrast-enhanced 3D MRA is routinely used for diagnose of thoracic arterial and venous lesions, because of its spatial resolution reliability and potential for multiplanar assessment. Larger patients studies are needed to investigate the clinical utility of free-breathing UTE-MRI. Moreover, UTE-MRI with 3 Tesla MRI system is not more readily available and expensive.

Consent
Written informed consent was obtained from all subjects (patients) in this study. Disclosure e scientific guarantor of this publication is KemalÖdev. is is a retrospective, diagnostic or prognostic, and multicenter study.

Conflicts of Interest
e authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.