REVIEW URRENT C OPINION
Advances in imaging of cardiopulmonary involvement in sarcoidosis Vasilis Kouranos a, David M. Hansell b, Rakesh Sharma c, and Athol U. Wells a
Purpose of review To highlight recent advances of imaging modalities with focus on interstitial lung disease, pulmonary vascular disease and cardiac involvement of sarcoidosis. The contribution of key imaging features to the assessment of disease activity and their impact in the prognostic evaluation and management of sarcoidosis are also described. Recent findings Imaging plays a central role in the management of patients with sarcoidosis, particularly in the diagnosis and monitoring of disease activity. The correlation of the severity and extent of organ involvement with inflammatory activity helps guide the clinician in determining the optimal treatment strategy for the patient and may also provide prognostic information. The emergence of cardiac MRI and fluoro-deoxyglucose positron emission tomography has enabled an improved understanding of the pathophysiology of sarcoidosis, particularly in relation to cardiac involvement and pulmonary vascular manifestations. Summary In many patients with pulmonary sarcoidosis, a confident diagnosis can be made based on clinical and imaging features, without the need for histological sampling. In cardiac sarcoidosis, advanced imaging modalities have an increasing role in the identification of active disease, risk stratification and optimal management. Keywords cardiac sarcoidosis, FDG-PET/computed tomography, HRCT scan, imaging, pulmonary hypertension
INTRODUCTION A historical consensus statement on sarcoidosis indicates that diagnosis requires the presence of noncaseating granulomas in various tissue biopsies, supported by compatible clinical and radiological findings and the exclusion of other causes of granulomatous inflammation [1]. However, the updated world association of sarcoidosis and other granulomatous diseases organ assessment instrument concluded that in the absence of histological confirmation, sarcoidosis organ involvement is highly probable when supported by specific imaging features [2 ]. Recent imaging studies have focused on: identifying specific phenotypes; assessing the severity and extent of the organ involvement and quantifying linkages with inflammatory disease activity; and examining their prognostic value. Pulmonary involvement is the most common manifestation of sarcoidosis and, thus, interstitial lung disease is a frequent source of histological confirmation of the diagnosis and the most common determinant of treatment requirements [1]. However, respiratory symptoms may also be related &
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to pulmonary vascular involvement: pulmonary hypertension is common in patients with major exercise intolerance and is often fatal [3]. Cardiac sarcoidosis is often overlooked as a cause of exertional dyspnea and has been a major recent focus of clinical research. The purpose of this review is to highlight recent advances in imaging modalities with regard to cardiopulmonary involvement, including interstitial lung disease, pulmonary vascular disease and cardiac involvement.
PULMONARY INVOLVEMENT The diagnosis of sarcoidosis is often straightforward when typical chest radiographic changes are a
Interstitial Lung Disease Unit, bDepartment of Radiology and Department of Cardiology, Royal Brompton Hospital, London, UK
c
Correspondence to Professor Athol U. Wells, Consultant Physician, Royal Brompton Hospital, London SW3 6NP, UK. Tel: +44 207 351 8327; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:538–545 DOI:10.1097/MCP.0000000000000195 Volume 21 Number 5 September 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Imaging of cardiopulmonary Kouranos et al.
KEY POINTS There is a growing consensus that specific imaging features in key organs in a compatible clinical setting may be diagnostic in the absence of histological confirmation. Advanced imaging techniques (MRI and FDG-PET) are more sensitive than historical diagnostic criteria in the identification of cardiac sarcoidosis. Recent data indicate that advanced imaging techniques are likely to increase the accuracy of risk stratification in cardiac sarcoidosis. An easily applicable HRCT-based staging system may increase the accuracy of risk stratification data in pulmonary sarcoidosis.
associated with a compatible clinical picture. The traditional view is that histological confirmation is always required except in patients presenting with Lofgren’s syndrome [4]. However, there is a growing consensus that in many cases, a biopsy is redundant after consideration of clinical, radiological and epidemiological features [5]. On chest radiography, bilateral, symmetrical hilar and paratracheal lymphadenopathy and/or parenchymal involvement with reticular and nodular changes are the main diagnostic features [6]. High-resolution computed tomography (HRCT) is an important diagnostic tool with a higher sensitivity and specificity than radiography [7,8]. There is no overall consensus on whether routine HRCT is warranted at presentation when the chest radiograph is abnormal. HRCT adds value when chest radiographic appearances are atypical and when pulmonary disease is extensive (and there is a need to exclude mycetoma formation). However, in some centers, routine baseline HRCT is performed in order to allow HRCT to be used in monitoring disease progression, although this use of HRCT has not been formally validated. Enlarged bilateral and symmetric hilar and mediastinal lymph nodes are seen on computed tomography (CT) in approximately 90% of patients; [9,10]. Calcification of these lymph nodes is relatively common and depends on the disease duration (in 40–50% of patients with long-standing sarcoidosis). The pattern of calcification is initially focal and soft (‘icing’ sugar pattern differentiates sarcoidosis from tuberculosis) but over time becomes denser and tends to be bilateral [11]. Parenchymal involvement is usually expressed with micronodular lesions [12–15]. Nodules most commonly measure 2–5 mm but the confluence of
granulomas may result in large nodules or masses which are found in 15–25% of patients, predominately in the upper lobes and peribronchovascular regions. There is considerable variation in micronodular distribution. Although typically perilymphatic, nodules often aggregate in subpleural regions and commonly involve interlobular septa, although nodular septal thickening is seldom extensive. Occasionally, the nodules may be small and result in a diffuse miliary pattern. Extensive microscopic granulomas may result in ground glass opacities or areas of peribronchial consolidation, usually superimposed on a background of nodular pattern or fibrosis. Sarcoidosis presents with a fibrotic phenotype in approximately 20% of patients, manifesting as linear opacities, traction bronchiectasis and architectural distortion on HRCT [16]. Fibrosis most commonly involves upper lobe peribronchovascular regions with an abnormal central conglomeration of perihilar bronchi and vessels associated with masses of fibrous tissue. Subpleural honeycombing occurs in a small percentage of patients involving mainly the upper and middle lobes, unlike idiopathic pulmonary fibrosis [17]. Fibro-bullous destruction may result in large cystic spaces, sometimes complicated by mycetoma formation [18,19]. Patterns of airway involvement include traction bronchiectasis, mosaic attenuation and isolated tracheobronchial abnormalities [20]. Nodules opacities are almost always reversible, whereas honeycombing, architectural distortion and traction bronchiectasis are indicative of irreversible disease [21–23]. However, HRCT is not helpful in predicting outcome in fibrotic disease: baseline findings have not been shown to distinguish between progressive disease and longterm stability. Figures 1–6 illustrate the characteristic HRCT images in sarcoidosis patients. There is great interest in the use of fluoro-deoxyglucose positron emission tomography (FDG-PET) in the diagnosis of sarcoidosis given its high sensitivity in detecting inflammatory activity within lymph nodes and thoracic and extrathoracic locations [24–35]. FDG-PET may provide valuable information in patients with suspected sarcoidosis by revealing sites suitable for histological confirmation. In two studies, FDG-PET showed areas of inflammation which was not evident on concurrent HRCT [31,32]. Overall, FDG-PET is considered to be more sensitive than other pulmonary imaging modalities, including HRCT, in the detection of inflammation [33–35]. This attribute may have particular utility in patients with advanced fibrotic lung disease, in which it is challenging to identify residual disease activity that might benefit from immunomodulation [35–37].
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FIGURE 1. Typical upper lobe predominant nodules of sarcoidosis. In the right upper lobe, some nodules in the periphery have coalesced to form a mass-like opacity. There are no CT features of supervening fibrosis. CT, computed tomography.
FIGURE 3. Focal area of consolidation in the left lower lobe with a few scattered background nodules. This so-called ‘air space’ form of sarcoidosis tends to be an early presentation of the disease and is highly reversible. It may sometimes be difficult to distinguish from mass-like granulomatous fibrosis (as in Figure 5).
FDG-PET signal has been correlated with bronchoalveolar lavage cell cytology and serum inflammatory markers [26–31,33]. Strong associations have been reported between PET positivity and
FIGURE 2. Delicate nodular thickening of several interlobular septa, most obvious anteriorly, in a patient with sarcoidosis. This pattern may occasionally be difficult to distinguish from lymphangitic infiltration. There are no CT features of established fibrosis. CT, computed tomography. 540
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FIGURE 4. A relatively uncommon CT manifestation of pulmonary sarcoidosis is diffuse ground glass opacification with no ancillary features. The exact pathologic correlate of this entirely nonspecific CT pattern has not been established in the context of sarcoidosis, but it probably reflects diffuse granulomatous and lymphocytic infiltration of alveolar walls. CT, computed tomography. Volume 21 Number 5 September 2015
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Imaging of cardiopulmonary Kouranos et al.
FIGURE 5. CT section through the mid-zones showing the typical distribution of fibrosis in chronic sarcoidosis. The dense opacification containing a distorted air bronchogram ‘streams’ off the hila and the fibrosis often trends posteriorly, as in this case. CT, computed tomography.
interleukin-2 receptor (sIL-2R) levels and angiotensin-converting enzyme, especially in a population of patients with persistent disabling symptoms [26,28]. In several reports, a significant reduction of FDG uptake after the initiation or modification of treatment in sarcoidosis patients has been observed [25,31,34,38,39]. Teirstein et al. [31] demonstrated that improvements of symptoms, conventional imaging findings and physiological data paralleled the therapy-related decrease in SUVmax as seen on the PET scans in most patients, including three patients with radiographic stage IV. Traditionally, the Scadding system has been used to stage sarcoidosis [40] (0: no abnormalities, I: hilar and mediastinal lymph node enlargement without parenchymal abnormality, II: hilar and mediastinal lymph node enlargement with parenchymal abnormality, III: parenchymal abnormality alone and IV: advanced fibrosis with evidence of reticulation and architecture distortion). However, although this system provides average statements of outcome in large patient cohorts, utility is limited by major variability in outcome within individual stages. Recently, an easily applicable HRCT staging system has been developed using split sample testing in over 500 patients evaluated at a referral center [41 ]. The composite physiologic index (previously validated in idiopathic pulmonary fibrosis) [42] and two HRCT variables (the extent of fibrosis and main pulmonary artery diameter to ascending aorta diameter ratio) were integrated to separate patients into low-risk and high-risk groups. In the validation cohort, patients in the high-risk group had a much higher mortality (hazard ratio 5.89, P < 0.0001). However, the utility of this system has yet to be tested in the wider group of sarcoidosis patients not seen at expert centers. Pulmonary hypertension is often regarded as rare in sarcoidosis, a truism that applies to the general sarcoidosis population. In a Japanese cohort, the prevalence of pulmonary hypertension was less than 6%, based on echocardiography (which, on average, tends to overstate pulmonary artery systolic pressures) [43]. By contrast, in two studies, 47.2 and 73.8%, respectively, of sarcoidosis patients with chronic exercise intolerance had pulmonary hypertension on right heart catheterization [44,45]. Pulmonary hypertension in sarcoidosis is not necessarily due to advanced lung disease: in one study, pulmonary hypertension was not associated with CT findings of fibrosis in 32% of patients with no CT findings of pulmonary fibrosis [46]. Pulmonary hypertension is suspected on CT when the diameter of the main pulmonary artery is greater than 29 mm or when the ratio of the diameters of the main pulmonary artery to the ascending aorta is &&
FIGURE 6. Coronal CT reformat of a patient with chronic sarcoidosis showing severe fibrobullous disease in the contracted upper lobes. There is a mycetoma in a cavity at the right apex with adjacent pleural thickening. Note the typical bilateral punctate calcifications in hilar nodes. CT, computed tomography.
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greater than 1 [47,48]. CT may provide useful information about vascular manifestations of sarcoidosis including extrinsic compression of pulmonary arteries or veins by enlarged lymph nodes, pulmonary veno-occlusive disease or direct involvement of vessel walls and pulmonary vasoconstriction [3,19]. Veno-occlusive disease presumably results from obstruction of interlobular septal veins by intramural granulomas or perivascular fibrosis and is suspected on CT by the presence of extensive septal thickening which is more frequent and extensive than in patients with idiopathic pulmonary hypertension [49,50]. Other common CT findings in pulmonary veno-occlusive disease include ground glass opacities, multiple small centrilobular nodules and areas of consolidation [50].
CARDIAC INVOLVEMENT Clinical evidence of cardiac involvement is present in only 5% of patients with sarcoidosis. However, postmortem studies indicate that subclinical involvement is present in 20–30%. This discrepancy is related to the lack of gold standard diagnostic criteria, the inaccuracy of symptoms, ECG and echocardiography in the detection of cardiac sarcoidosis and the occurrence of sudden cardiac death as primary manifestation of cardiac involvement [51–53]. Myocardial biopsy has a low sensitivity due to the patchy distribution of the granulomas [52,54 ]. Effectively, this precludes a requirement for histological confirmation in the diagnosis of isolated cardiac sarcoidosis. Japanese Ministry of Health and Welfare [JMHW] diagnostic criteria have been in use since 1993-latest update in 2006, but are relatively insensitive for detecting cardiac involvement and are imprecise in the risk stratification of patients, compared with cardiac magnetic resonance imaging (CMR) or PET [55,56,57 ,58 ,59, 60 ,61–66]. It is clear that imaging plays a critical role in both the diagnosis and the management of cardiac sarcoidosis and a recent consensus statement on diagnosis of cardiac sarcoidosis suggested that CMR and cardiac PET are the noninvasive diagnostic tests of choice for cardiac sarcoidosis [2 ,54 ]. Attempts have been made in a number of studies to identify the exact prevalence of cardiac sarcoidosis based on the above imaging modalities [53,55,56, 57 ,58 ]. However, in clinical practice, neither test can yet be viewed as a reference standard. It is appropriate to integrate the tests with the clinical presentation of patients, especially when the diagnosis is challenging. CMR is a highly accurate modality of evaluating cardiac morphology and function. However, the major role of CMR in the diagnosis of cardiac &
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&
sarcoidosis lies in the identification of late gadolinium enhancement [LGE], which is indicative of fibrosis in the myocardium, and edema on T2-weighted imaging, suggestive of myocardial inflammation. Although the typical pattern of LGE in cardiac sarcoidosis is a focal and nonischemic (nontransmural pattern involving the subepicardial and/or mid-myocardial walls), more extensive infiltration and patterns of subendocardial or transmural LGE (mimicking ischemic heart disease pattern) have been described [59]. Other CMR features that have been described include aneurysm formation, valvular involvement and pericardial thickening, with or without an effusion. Extensive cardiac involvement may lead to congestive heart failure. The definition of the accuracy of CMR in the diagnosis of cardiac sarcoidosis is hampered by the lack of a reference standard. However, in a study of 62 patients with suspected cardiac sarcoidosis, CMR had a sensitivity of 100% and specificity of 78% against JMHW criteria [55]. The highlighted sensitivity of CMR was validated by more accurate prognostication. CMR may also be used to identify patients at higher risk of death or ventricular tachycardia. Although CMR findings have been categorized as positive or negative in most studies, patients who have a greater extent of LGE (>20% of left ventricle mass) were more likely to have adverse events and were less likely to have an improvement in their left ventricular function in one report [60 ]. In a study of 155 patients with systemic sarcoidosis, myocardial LGE was the best independent predictor of potentially lethal events [56]. CMR has several limitations as the geometry of the scanner is not tolerated by patients with claustrophobia and renal impairment (estimated glomerular filtration rate less than 30 ml/kg/min) and the presence of metallic materials within the body, including conventional devices are considered as contraindications. Historically, nuclear imaging techniques such as gallium-67 scintigraphy have been used to evaluate cardiac inflammation. However, newer techniques have demonstrated superiority with higher diagnostic accuracy [61]. FDG-PET has become the standard of care for nuclear imaging evaluation of cardiac inflammation, quantifying hypermetabolic inflammatory activity within the myocardium, using an 18 h fasting protocol designed to suppress normal myocardial glucose uptake. The manifestations of cardiac sarcoidosis on FDG-PET imaging typically include focal or focalon diffuse hypermetabolic activity in any location of the myocardium. In a meta-analysis of seven studies and 164 patients, Youssef et al. [62] reported a high diagnostic accuracy for FDG-PET (89% sensitivity and 78% specificity) against JMHW. In our center, &&
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we perform resting myocardial perfusion scans (MPSs) in patients undergoing cardiac PET. Resting MPS can be extremely useful when interpreting FDG-PET images [63]. In earlier disease, isolated FDG uptake may be seen. As disease progresses, perfusion defects become apparent, usually reflecting fibrosis but occasionally indicative of microvascular compression caused by severe inflammation. Patients with burnt out disease may exhibit profuse defects with little or no FDG uptake. When a perfusion metabolism mismatch coexists with areas of increased FDG, it may be necessary to rule out obstructive coronary disease. In two studies assessing cardiac sarcoidosis, FDG-PET along with resting MPS patients with positive scans had an increased rate of death or ventricular tachycardia, even after adjusting for left ventricular ejection fraction (LVEF), clinical criteria and the presence of extra-cardiac active disease [57 ,58 ]. Increased FDG uptake in the right ventricle, seen less frequently, is associated with an adverse prognosis [57 ,64]. Osborne et al. [65] showed that anti-inflammatory treatment results in a significant reduction in the volume and extent of myocardial inflammation, with variable improvement in cardiac function. Recently, quantitative interpretation of FDG uptake has included the volume of inflammation and integrated volume intensity [58 ,65]. Such measures are most useful when comparing scans in order to follow response to treatment, but may also enhance the standardization of interpretation among centers. Specific recommendations regarding the optimal multimodality imaging strategy are essential. The majority of published data include use of either CMR or PET with MPS. Any approach should take into account the strengths and limitations of each institution, including imaging capabilities and experience. SDC 1–3, http://links.lww.com/COPM/ A15 illustrate characteristic CMR and FDG-PET images in sarcoidosis patients as well as an example of the multimodality approach in suspected cardiac sarcoidosis. There are data to suggest that cardiac symptoms (chest pain, palpitations and syncope/ presyncope), ECG/Holter monitor abnormalities (atrio-ventricular block, right bundle branch block, Q waves and ventricular tachycardia) and echocardiographic abnormalities (LVEF20% of total left ventricular mass). 61. Langah R, Spicer K, Gebregziabher M, Gordon L. Effectiveness of prolonged fasting 18f-FDG PET-CT in the detection of cardiac sarcoidosis. J Nucl Cardiol 2009; 16:801–810.
62. Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012; 53:241–248. 63. Skali H, Schulman AR, Dorbala S. 18F-FDG PET/CT for the assessment of myocardial sarcoidosis. Curr Cardiol Rep 2013; 15:352. 64. Manabe O, Yoshinaga K, Ohira H, et al. Right ventricular (18)F-FDG uptake is an important indicator for cardiac involvement in patients with suspected cardiac sarcoidosis. Ann Nucl Med 2014; 28:656–663. 65. Osborne MT, Hulten EA, Singh A, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014; 21:166–174. 66. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18F-fluoro-2deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008; 35:933–941.
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Advances in imaging of cardiopulmonary involvement in sarcoidosis Vasilis Kouranos a, David M. Hansell b, Rakesh Sharma c, and Athol U. Wells a
Purpose of review To highlight recent advances of imaging modalities with focus on interstitial lung disease, pulmonary vascular disease and cardiac involvement of sarcoidosis. The contribution of key imaging features to the assessment of disease activity and their impact in the prognostic evaluation and management of sarcoidosis are also described. Recent findings Imaging plays a central role in the management of patients with sarcoidosis, particularly in the diagnosis and monitoring of disease activity. The correlation of the severity and extent of organ involvement with inflammatory activity helps guide the clinician in determining the optimal treatment strategy for the patient and may also provide prognostic information. The emergence of cardiac MRI and fluoro-deoxyglucose positron emission tomography has enabled an improved understanding of the pathophysiology of sarcoidosis, particularly in relation to cardiac involvement and pulmonary vascular manifestations. Summary In many patients with pulmonary sarcoidosis, a confident diagnosis can be made based on clinical and imaging features, without the need for histological sampling. In cardiac sarcoidosis, advanced imaging modalities have an increasing role in the identification of active disease, risk stratification and optimal management. Keywords cardiac sarcoidosis, FDG-PET/computed tomography, HRCT scan, imaging, pulmonary hypertension
INTRODUCTION A historical consensus statement on sarcoidosis indicates that diagnosis requires the presence of noncaseating granulomas in various tissue biopsies, supported by compatible clinical and radiological findings and the exclusion of other causes of granulomatous inflammation [1]. However, the updated world association of sarcoidosis and other granulomatous diseases organ assessment instrument concluded that in the absence of histological confirmation, sarcoidosis organ involvement is highly probable when supported by specific imaging features [2 ]. Recent imaging studies have focused on: identifying specific phenotypes; assessing the severity and extent of the organ involvement and quantifying linkages with inflammatory disease activity; and examining their prognostic value. Pulmonary involvement is the most common manifestation of sarcoidosis and, thus, interstitial lung disease is a frequent source of histological confirmation of the diagnosis and the most common determinant of treatment requirements [1]. However, respiratory symptoms may also be related &
www.co-pulmonarymedicine.com
to pulmonary vascular involvement: pulmonary hypertension is common in patients with major exercise intolerance and is often fatal [3]. Cardiac sarcoidosis is often overlooked as a cause of exertional dyspnea and has been a major recent focus of clinical research. The purpose of this review is to highlight recent advances in imaging modalities with regard to cardiopulmonary involvement, including interstitial lung disease, pulmonary vascular disease and cardiac involvement.
PULMONARY INVOLVEMENT The diagnosis of sarcoidosis is often straightforward when typical chest radiographic changes are a
Interstitial Lung Disease Unit, bDepartment of Radiology and Department of Cardiology, Royal Brompton Hospital, London, UK
c
Correspondence to Professor Athol U. Wells, Consultant Physician, Royal Brompton Hospital, London SW3 6NP, UK. Tel: +44 207 351 8327; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:538–545 DOI:10.1097/MCP.0000000000000195 Volume 21 Number 5 September 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Imaging of cardiopulmonary Kouranos et al.
KEY POINTS There is a growing consensus that specific imaging features in key organs in a compatible clinical setting may be diagnostic in the absence of histological confirmation. Advanced imaging techniques (MRI and FDG-PET) are more sensitive than historical diagnostic criteria in the identification of cardiac sarcoidosis. Recent data indicate that advanced imaging techniques are likely to increase the accuracy of risk stratification in cardiac sarcoidosis. An easily applicable HRCT-based staging system may increase the accuracy of risk stratification data in pulmonary sarcoidosis.
associated with a compatible clinical picture. The traditional view is that histological confirmation is always required except in patients presenting with Lofgren’s syndrome [4]. However, there is a growing consensus that in many cases, a biopsy is redundant after consideration of clinical, radiological and epidemiological features [5]. On chest radiography, bilateral, symmetrical hilar and paratracheal lymphadenopathy and/or parenchymal involvement with reticular and nodular changes are the main diagnostic features [6]. High-resolution computed tomography (HRCT) is an important diagnostic tool with a higher sensitivity and specificity than radiography [7,8]. There is no overall consensus on whether routine HRCT is warranted at presentation when the chest radiograph is abnormal. HRCT adds value when chest radiographic appearances are atypical and when pulmonary disease is extensive (and there is a need to exclude mycetoma formation). However, in some centers, routine baseline HRCT is performed in order to allow HRCT to be used in monitoring disease progression, although this use of HRCT has not been formally validated. Enlarged bilateral and symmetric hilar and mediastinal lymph nodes are seen on computed tomography (CT) in approximately 90% of patients; [9,10]. Calcification of these lymph nodes is relatively common and depends on the disease duration (in 40–50% of patients with long-standing sarcoidosis). The pattern of calcification is initially focal and soft (‘icing’ sugar pattern differentiates sarcoidosis from tuberculosis) but over time becomes denser and tends to be bilateral [11]. Parenchymal involvement is usually expressed with micronodular lesions [12–15]. Nodules most commonly measure 2–5 mm but the confluence of
granulomas may result in large nodules or masses which are found in 15–25% of patients, predominately in the upper lobes and peribronchovascular regions. There is considerable variation in micronodular distribution. Although typically perilymphatic, nodules often aggregate in subpleural regions and commonly involve interlobular septa, although nodular septal thickening is seldom extensive. Occasionally, the nodules may be small and result in a diffuse miliary pattern. Extensive microscopic granulomas may result in ground glass opacities or areas of peribronchial consolidation, usually superimposed on a background of nodular pattern or fibrosis. Sarcoidosis presents with a fibrotic phenotype in approximately 20% of patients, manifesting as linear opacities, traction bronchiectasis and architectural distortion on HRCT [16]. Fibrosis most commonly involves upper lobe peribronchovascular regions with an abnormal central conglomeration of perihilar bronchi and vessels associated with masses of fibrous tissue. Subpleural honeycombing occurs in a small percentage of patients involving mainly the upper and middle lobes, unlike idiopathic pulmonary fibrosis [17]. Fibro-bullous destruction may result in large cystic spaces, sometimes complicated by mycetoma formation [18,19]. Patterns of airway involvement include traction bronchiectasis, mosaic attenuation and isolated tracheobronchial abnormalities [20]. Nodules opacities are almost always reversible, whereas honeycombing, architectural distortion and traction bronchiectasis are indicative of irreversible disease [21–23]. However, HRCT is not helpful in predicting outcome in fibrotic disease: baseline findings have not been shown to distinguish between progressive disease and longterm stability. Figures 1–6 illustrate the characteristic HRCT images in sarcoidosis patients. There is great interest in the use of fluoro-deoxyglucose positron emission tomography (FDG-PET) in the diagnosis of sarcoidosis given its high sensitivity in detecting inflammatory activity within lymph nodes and thoracic and extrathoracic locations [24–35]. FDG-PET may provide valuable information in patients with suspected sarcoidosis by revealing sites suitable for histological confirmation. In two studies, FDG-PET showed areas of inflammation which was not evident on concurrent HRCT [31,32]. Overall, FDG-PET is considered to be more sensitive than other pulmonary imaging modalities, including HRCT, in the detection of inflammation [33–35]. This attribute may have particular utility in patients with advanced fibrotic lung disease, in which it is challenging to identify residual disease activity that might benefit from immunomodulation [35–37].
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FIGURE 1. Typical upper lobe predominant nodules of sarcoidosis. In the right upper lobe, some nodules in the periphery have coalesced to form a mass-like opacity. There are no CT features of supervening fibrosis. CT, computed tomography.
FIGURE 3. Focal area of consolidation in the left lower lobe with a few scattered background nodules. This so-called ‘air space’ form of sarcoidosis tends to be an early presentation of the disease and is highly reversible. It may sometimes be difficult to distinguish from mass-like granulomatous fibrosis (as in Figure 5).
FDG-PET signal has been correlated with bronchoalveolar lavage cell cytology and serum inflammatory markers [26–31,33]. Strong associations have been reported between PET positivity and
FIGURE 2. Delicate nodular thickening of several interlobular septa, most obvious anteriorly, in a patient with sarcoidosis. This pattern may occasionally be difficult to distinguish from lymphangitic infiltration. There are no CT features of established fibrosis. CT, computed tomography. 540
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FIGURE 4. A relatively uncommon CT manifestation of pulmonary sarcoidosis is diffuse ground glass opacification with no ancillary features. The exact pathologic correlate of this entirely nonspecific CT pattern has not been established in the context of sarcoidosis, but it probably reflects diffuse granulomatous and lymphocytic infiltration of alveolar walls. CT, computed tomography. Volume 21 Number 5 September 2015
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Imaging of cardiopulmonary Kouranos et al.
FIGURE 5. CT section through the mid-zones showing the typical distribution of fibrosis in chronic sarcoidosis. The dense opacification containing a distorted air bronchogram ‘streams’ off the hila and the fibrosis often trends posteriorly, as in this case. CT, computed tomography.
interleukin-2 receptor (sIL-2R) levels and angiotensin-converting enzyme, especially in a population of patients with persistent disabling symptoms [26,28]. In several reports, a significant reduction of FDG uptake after the initiation or modification of treatment in sarcoidosis patients has been observed [25,31,34,38,39]. Teirstein et al. [31] demonstrated that improvements of symptoms, conventional imaging findings and physiological data paralleled the therapy-related decrease in SUVmax as seen on the PET scans in most patients, including three patients with radiographic stage IV. Traditionally, the Scadding system has been used to stage sarcoidosis [40] (0: no abnormalities, I: hilar and mediastinal lymph node enlargement without parenchymal abnormality, II: hilar and mediastinal lymph node enlargement with parenchymal abnormality, III: parenchymal abnormality alone and IV: advanced fibrosis with evidence of reticulation and architecture distortion). However, although this system provides average statements of outcome in large patient cohorts, utility is limited by major variability in outcome within individual stages. Recently, an easily applicable HRCT staging system has been developed using split sample testing in over 500 patients evaluated at a referral center [41 ]. The composite physiologic index (previously validated in idiopathic pulmonary fibrosis) [42] and two HRCT variables (the extent of fibrosis and main pulmonary artery diameter to ascending aorta diameter ratio) were integrated to separate patients into low-risk and high-risk groups. In the validation cohort, patients in the high-risk group had a much higher mortality (hazard ratio 5.89, P < 0.0001). However, the utility of this system has yet to be tested in the wider group of sarcoidosis patients not seen at expert centers. Pulmonary hypertension is often regarded as rare in sarcoidosis, a truism that applies to the general sarcoidosis population. In a Japanese cohort, the prevalence of pulmonary hypertension was less than 6%, based on echocardiography (which, on average, tends to overstate pulmonary artery systolic pressures) [43]. By contrast, in two studies, 47.2 and 73.8%, respectively, of sarcoidosis patients with chronic exercise intolerance had pulmonary hypertension on right heart catheterization [44,45]. Pulmonary hypertension in sarcoidosis is not necessarily due to advanced lung disease: in one study, pulmonary hypertension was not associated with CT findings of fibrosis in 32% of patients with no CT findings of pulmonary fibrosis [46]. Pulmonary hypertension is suspected on CT when the diameter of the main pulmonary artery is greater than 29 mm or when the ratio of the diameters of the main pulmonary artery to the ascending aorta is &&
FIGURE 6. Coronal CT reformat of a patient with chronic sarcoidosis showing severe fibrobullous disease in the contracted upper lobes. There is a mycetoma in a cavity at the right apex with adjacent pleural thickening. Note the typical bilateral punctate calcifications in hilar nodes. CT, computed tomography.
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Imaging
greater than 1 [47,48]. CT may provide useful information about vascular manifestations of sarcoidosis including extrinsic compression of pulmonary arteries or veins by enlarged lymph nodes, pulmonary veno-occlusive disease or direct involvement of vessel walls and pulmonary vasoconstriction [3,19]. Veno-occlusive disease presumably results from obstruction of interlobular septal veins by intramural granulomas or perivascular fibrosis and is suspected on CT by the presence of extensive septal thickening which is more frequent and extensive than in patients with idiopathic pulmonary hypertension [49,50]. Other common CT findings in pulmonary veno-occlusive disease include ground glass opacities, multiple small centrilobular nodules and areas of consolidation [50].
CARDIAC INVOLVEMENT Clinical evidence of cardiac involvement is present in only 5% of patients with sarcoidosis. However, postmortem studies indicate that subclinical involvement is present in 20–30%. This discrepancy is related to the lack of gold standard diagnostic criteria, the inaccuracy of symptoms, ECG and echocardiography in the detection of cardiac sarcoidosis and the occurrence of sudden cardiac death as primary manifestation of cardiac involvement [51–53]. Myocardial biopsy has a low sensitivity due to the patchy distribution of the granulomas [52,54 ]. Effectively, this precludes a requirement for histological confirmation in the diagnosis of isolated cardiac sarcoidosis. Japanese Ministry of Health and Welfare [JMHW] diagnostic criteria have been in use since 1993-latest update in 2006, but are relatively insensitive for detecting cardiac involvement and are imprecise in the risk stratification of patients, compared with cardiac magnetic resonance imaging (CMR) or PET [55,56,57 ,58 ,59, 60 ,61–66]. It is clear that imaging plays a critical role in both the diagnosis and the management of cardiac sarcoidosis and a recent consensus statement on diagnosis of cardiac sarcoidosis suggested that CMR and cardiac PET are the noninvasive diagnostic tests of choice for cardiac sarcoidosis [2 ,54 ]. Attempts have been made in a number of studies to identify the exact prevalence of cardiac sarcoidosis based on the above imaging modalities [53,55,56, 57 ,58 ]. However, in clinical practice, neither test can yet be viewed as a reference standard. It is appropriate to integrate the tests with the clinical presentation of patients, especially when the diagnosis is challenging. CMR is a highly accurate modality of evaluating cardiac morphology and function. However, the major role of CMR in the diagnosis of cardiac &
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sarcoidosis lies in the identification of late gadolinium enhancement [LGE], which is indicative of fibrosis in the myocardium, and edema on T2-weighted imaging, suggestive of myocardial inflammation. Although the typical pattern of LGE in cardiac sarcoidosis is a focal and nonischemic (nontransmural pattern involving the subepicardial and/or mid-myocardial walls), more extensive infiltration and patterns of subendocardial or transmural LGE (mimicking ischemic heart disease pattern) have been described [59]. Other CMR features that have been described include aneurysm formation, valvular involvement and pericardial thickening, with or without an effusion. Extensive cardiac involvement may lead to congestive heart failure. The definition of the accuracy of CMR in the diagnosis of cardiac sarcoidosis is hampered by the lack of a reference standard. However, in a study of 62 patients with suspected cardiac sarcoidosis, CMR had a sensitivity of 100% and specificity of 78% against JMHW criteria [55]. The highlighted sensitivity of CMR was validated by more accurate prognostication. CMR may also be used to identify patients at higher risk of death or ventricular tachycardia. Although CMR findings have been categorized as positive or negative in most studies, patients who have a greater extent of LGE (>20% of left ventricle mass) were more likely to have adverse events and were less likely to have an improvement in their left ventricular function in one report [60 ]. In a study of 155 patients with systemic sarcoidosis, myocardial LGE was the best independent predictor of potentially lethal events [56]. CMR has several limitations as the geometry of the scanner is not tolerated by patients with claustrophobia and renal impairment (estimated glomerular filtration rate less than 30 ml/kg/min) and the presence of metallic materials within the body, including conventional devices are considered as contraindications. Historically, nuclear imaging techniques such as gallium-67 scintigraphy have been used to evaluate cardiac inflammation. However, newer techniques have demonstrated superiority with higher diagnostic accuracy [61]. FDG-PET has become the standard of care for nuclear imaging evaluation of cardiac inflammation, quantifying hypermetabolic inflammatory activity within the myocardium, using an 18 h fasting protocol designed to suppress normal myocardial glucose uptake. The manifestations of cardiac sarcoidosis on FDG-PET imaging typically include focal or focalon diffuse hypermetabolic activity in any location of the myocardium. In a meta-analysis of seven studies and 164 patients, Youssef et al. [62] reported a high diagnostic accuracy for FDG-PET (89% sensitivity and 78% specificity) against JMHW. In our center, &&
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Imaging of cardiopulmonary Kouranos et al.
we perform resting myocardial perfusion scans (MPSs) in patients undergoing cardiac PET. Resting MPS can be extremely useful when interpreting FDG-PET images [63]. In earlier disease, isolated FDG uptake may be seen. As disease progresses, perfusion defects become apparent, usually reflecting fibrosis but occasionally indicative of microvascular compression caused by severe inflammation. Patients with burnt out disease may exhibit profuse defects with little or no FDG uptake. When a perfusion metabolism mismatch coexists with areas of increased FDG, it may be necessary to rule out obstructive coronary disease. In two studies assessing cardiac sarcoidosis, FDG-PET along with resting MPS patients with positive scans had an increased rate of death or ventricular tachycardia, even after adjusting for left ventricular ejection fraction (LVEF), clinical criteria and the presence of extra-cardiac active disease [57 ,58 ]. Increased FDG uptake in the right ventricle, seen less frequently, is associated with an adverse prognosis [57 ,64]. Osborne et al. [65] showed that anti-inflammatory treatment results in a significant reduction in the volume and extent of myocardial inflammation, with variable improvement in cardiac function. Recently, quantitative interpretation of FDG uptake has included the volume of inflammation and integrated volume intensity [58 ,65]. Such measures are most useful when comparing scans in order to follow response to treatment, but may also enhance the standardization of interpretation among centers. Specific recommendations regarding the optimal multimodality imaging strategy are essential. The majority of published data include use of either CMR or PET with MPS. Any approach should take into account the strengths and limitations of each institution, including imaging capabilities and experience. SDC 1–3, http://links.lww.com/COPM/ A15 illustrate characteristic CMR and FDG-PET images in sarcoidosis patients as well as an example of the multimodality approach in suspected cardiac sarcoidosis. There are data to suggest that cardiac symptoms (chest pain, palpitations and syncope/ presyncope), ECG/Holter monitor abnormalities (atrio-ventricular block, right bundle branch block, Q waves and ventricular tachycardia) and echocardiographic abnormalities (LVEF20% of total left ventricular mass). 61. Langah R, Spicer K, Gebregziabher M, Gordon L. Effectiveness of prolonged fasting 18f-FDG PET-CT in the detection of cardiac sarcoidosis. J Nucl Cardiol 2009; 16:801–810.
62. Youssef G, Leung E, Mylonas I, et al. The use of 18F-FDG PET in the diagnosis of cardiac sarcoidosis: a systematic review and metaanalysis including the Ontario experience. J Nucl Med 2012; 53:241–248. 63. Skali H, Schulman AR, Dorbala S. 18F-FDG PET/CT for the assessment of myocardial sarcoidosis. Curr Cardiol Rep 2013; 15:352. 64. Manabe O, Yoshinaga K, Ohira H, et al. Right ventricular (18)F-FDG uptake is an important indicator for cardiac involvement in patients with suspected cardiac sarcoidosis. Ann Nucl Med 2014; 28:656–663. 65. Osborne MT, Hulten EA, Singh A, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol 2014; 21:166–174. 66. Ohira H, Tsujino I, Ishimaru S, et al. Myocardial imaging with 18F-fluoro-2deoxyglucose positron emission tomography and magnetic resonance imaging in sarcoidosis. Eur J Nucl Med Mol Imaging 2008; 35:933–941.
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