Ann Nucl Med DOI 10.1007/s12149-014-0806-0

OTHERS

Recommendations for 18F-fluorodeoxyglucose positron emission tomography imaging for cardiac sarcoidosis: Japanese Society of Nuclear Cardiology Recommendations Yoshio Ishida • Keiichiro Yoshinaga • Masao Miyagawa • Masao Moroi • Chisato Kondoh Keisuke Kiso • Shinichiro Kumita



Received: 26 December 2013 / Accepted: 6 January 2014 Ó The Japanese Society of Nuclear Medicine 2014

Introduction Sarcoidosis is a systemic granulomatous disease that forms epithelioid cell granuloma (accompanied by infiltration of inflammatory cells) without caseous necrosis in organs throughout the body, including the lungs, lymph nodes, skin, eyes, heart, and muscles. Generally there is a good prognosis for spontaneous resolution of sarcoidosis; however, for cardiac-involvement sarcoidosis, the prognosis is extremely poor, and careful management is required. The most common cause of death from sarcoidosis is cardiac complications of the disease, and therefore early detection and treatment of these are very important in the management of cardiac-involvement sarcoidosis. Guidelines for the diagnosis of cardiac sarcoidosis were first published by Hiraga et al. [1] in 1992 (Table 1). These guidelines were modified by the joint committee of the

Committee for diagnosis of cardiac sarcoidosis using 18F-FDG PET, Japanese Society of Nuclear Cardiology.

Japan Society of Sarcoidosis and Other Granulomatous Disorders and the Japanese College of Cardiology in 2006 (Table 2) [2]. These modified guidelines stipulate the following: a histopathological or clinical diagnosis of sarcoidosis in organs other than the heart is essential, and the following cases should be diagnosed as cardiac sarcoidosis: (1) cases histopathologically diagnosed as positive for cardiac sarcoidosis on the basis of myocardial biopsy (histopathologically diagnosed group) and (2) cases with clinical findings indicating characteristic cardiac abnormalities including principal and secondary signs and symptoms (clinically diagnosed group) (Tables 1, 2). In the histopathologically diagnosed group, the positivity rate for detection of cardiac sarcoidosis may be low owing to sampling errors in myocardial biopsy. Hence, in actual clinical settings, the number of cases in the clinically diagnosed group is higher than in the histopathologically diagnosed group. Upon diagnosis of cardiac sarcoidosis, it is important to determine the disease activity to develop a treatment strategy, assess severity, predict prognosis, and

Y. Ishida Department of Cardiology, Kaizuka City Hospital, Kaizuka, Japan

C. Kondoh Department of Diagnostic Radiology, Tokyo Women’s Medical University, Tokyo, Japan

K. Yoshinaga (&) Department of Molecular Imaging, Hokkaido University Graduate School of Medicine, Kita15 Nishi7, Kita-Ku, Sapporo, Hokkaido 060-8638, Japan e-mail: [email protected]

K. Kiso Department of Radiology, National Cardiovascular Research Centre Hospital, Suita, Osaka, Japan

M. Miyagawa Department of Radiology, Ehime University Graduate School of Medicine, Matsuyama, Japan

S. Kumita Department of Radiology, Nihon Medical University Graduate School of Medicine, Sendagi, Tokyo, Japan

M. Moroi Department of Cardiology, Toho University Ohashi Hospital, Tokyo, Japan

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Ann Nucl Med Table 1 Guidelines for diagnosis of cardiac sarcoidosis from the Japanese Ministry of Health and Welfare [1] Histologic diagnosis group

Cardiac sarcoidosis is diagnosed when histologic analysis of operative or endomyocardial biopsy specimens demonstrate epithelioid granuloma without caseating granuloma

Clinical diagnosis group

In patients with histologic diagnosis of extracardiac sarcoidosis, cardiac sarcoidosis is diagnosed when item (a) and one or more of items (b–e) are present

Criteria

(a) Right bundle branch block, left-axis deviation, atrioventricular block, ventricular tachycardia, premature ventricular contraction ([grade 2 in Lown’s classification), or abnormal Q or ST-T changes on ECG or Holter ECG

Table 2 Guidelines for diagnosis of CS (2006) [2] Histologic diagnosis group

Cardiac sarcoidosis is confirmed when endomyocardial biopsy specimens demonstrate noncaseating epithelioid cell granulomas with histological or clinical diagnosis of extracardiac sarcoidosis

Clinical diagnosis group

Although endomyocardial biopsy specimens do not demonstrate noncaseating epithelioid cell granulomas, extracardiac sarcoidosis is diagnosed histologically or clinically and satisfies the following conditions and more than 1 in 6 basic diagnostic criteria 1.2 or more of the 4 major criteria are satisfied 2.1 of the 4 major criteria and 2 or more of the 5 minor criteria are satisfied

Major criteria

(b) Abnormal wall motion, regional wall thinning, or thickening, or dilatation of LV on UCG (c) Perfusion defect on 201Tl myocardial scintigram or abnormal accumulation on 67Gacitrate or 99mTc-pyrophosphate myocardial scintigram (d) Abnormal intracardiac pressure, low cardiac output, or abnormal wall motion or depressed ejection fraction of LV (e) Interstitial fibrosis or cellular infiltration over moderate grade in endomyocardial biopsy even if findings are nonspecific

tailor steroid therapy. Nuclear imaging is useful in detecting inflammation. Gallium 67 (Ga-67) imaging has been used for this purpose, but Ga-67 imaging has low diagnostic sensitivity owing to its low image resolution. Given this circumstance, F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been used to diagnose cardiac sarcoidosis. 18F-FDG PET is able to visualize not only cancer lesions but also inflammation lesions as having positive 18F-FDG uptake. Thus, 18F-FDG PET has been applied in diseases such as vasculitis, arteriosclerotic vascular disease, and sarcoidosis. Recent studies have shown that FDG uptake in both cancer cells and inflammation cells (evidenced through enhanced glucose metabolism) is attributable to increased levels of glucose transporters GLUT1 and GLUT3 in the cell membrane. When 18F-FDG PET is used to diagnose cardiac sarcoidosis, it is important to determine whether FDG uptake in lesions can be detected separately from physiological FDG uptake in the cardiac muscle since the cardiac muscle itself uses glucose as an energy source. Myocardial glucose use is enhanced in the presence of increased blood glucose and insulin levels and decreased blood free fatty acid levels after a meal. In contrast, it is suppressed as free fatty acid levels in the blood increase during a continued fasting state (glucose-fatty-acid cycle). This suppression is

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(a) Advanced atrioventricular block (b) Basal thinning of the interventricular septum (c) Positive

67

gallium uptake in the heart

(d) Depressed ejection fraction of the left ventricle (\50 %) Minor criteria

(a) Abnormal ECG findings: ventricular arrhythmias (ventricular tachycardia, multifocal or frequent PVCs), CRBBB, axis deviation or abnormal Q-wave (b) Abnormal echocardiography: regional abnormal wall motion or morphological abnormality (ventricular aneurysm, wall thickening) (c) Nuclear medicine: perfusion defect detected by 201thallium or 99mtechnetium myocardial scintigraphy (d) Gadolinium-enhanced CMR imaging: delayed enhancement of myocardium (e) Endomyocardial biopsy: interstitial fibrosis or monocyte infiltration over moderate grade

CMR cardiac magnetic resonance, CRBBB complete right bundle branch block, CS cardiac sarcoidosis, ECG electrocardiogram, PVC premature ventricular contraction

mediated by GLUT4, a glucose transporter, through a mechanism different from that associated with cancer and inflammatory cells. Hence, separately visualizing the increased FDG uptake in lesions through GLUT1/GLUT3 is possible if GLUT4 is used to suppress myocardial 18FFDG uptake.This suppression of physiological 18F-FDG uptake in the cardiac muscle is the key factor in cardiac sarcoidosis diagnosis, and various methods are proposed. 18 F-FDG PET has been shown to have a higher detection rate of cardiac sarcoidosis than does Ga-67 imaging. There has been no assessment through a large-scale clinical study because cardiac sarcoidosis is a relatively rare disease. However, there is no doubt that the capability to diagnose cardiac sarcoidosis has been improved through the use of 18 F-FDG PET. Under the revised medical insurance coverage effective April 2012, the Japanese health insurance system approved insurance reimbursement for 18F-FDG

Ann Nucl Med

PET use to detect inflammation sites in cardiac sarcoidosis. This approval has led to the need for a more detailed assessment of the clinical value of 18F-FDG PET. However, attention should be paid to the stipulation that 18FFDG PET use is approved only for detection of inflammation sites in cardiac sarcoidosis patients. The stipulation mandates that in patients diagnosed with cardiac sarcoidosis according to established guidelines [2], 18F-FDG PET may be used to assess lesion distribution. However, the use of FDG PET to diagnose patients with suspected cardiac sarcoidosis is not covered by the health ministry’s insurance reimbursement. The Japan Society of Sarcoidosis and other Granulomatous Disorders is currently updating its guidelines for the diagnosis of cardiac sarcoidosis and would probably add positive 18F-FDG PET findings as one of the criteria for the diagnosis of cardiac sarcoidosis. Such a move would be in conflict with the current conditions for insurance reimbursement and would necessitate further discussion regarding amendment of the guidelines. Taking this opportunity to discuss the Japanese Ministry of Health, Labor, and Welfare’s insurance reimbursement, the Japanese Society of Nuclear Cardiology has decided to develop guidelines regarding the basic 18F-FDG PET procedure, on the assumption that FDG PET will be widely used in the diagnosis of cardiac sarcoidosis.

FDG PET Guidelines in the diagnosis of cardiac sarcoidosis Preparation: method for suppressing physiological myocardial 18F-FDG uptake in normal cardiac muscle Over 90 % of fasting myocardial energy metabolism is fatty acid metabolism. Most of the remaining 10 % of metabolism involves other substances including glucose [3, 4]. However, fasting myocardial glucose metabolism varies among individuals, and in some cases, myocardial 18FFDG uptake is observed even under fasting conditions. This discrepancy means it is difficult to apply 18F-FDG PET for myocardial inflammation imaging. Therefore, some groups have evaluated methods of suppressing

myocardial physiological glucose use (18F-FDG uptake). Currently, the following three methods are considered to be effective approaches. Pre-18F-FDG PET fasting time In order to accurately diagnose cardiac sarcoidosis, it is essential to produce a state with high FDG uptake in a myocardial lesion and no uptake in the normal myocardium. In addition, it is necessary to administer the 18F-FDG and perform 18F-FDG PET image acquisition under fasting conditions [5]. However, optimum fasting time for the diagnosis of cardiac sarcoidosis has not been established. In its guidelines for oncology diagnosis, the European Association of Nuclear Medicine recommends fasting for at least 6 h in order to suppress 18F-FDG uptake in normal tissues [6]. Similarly, the Society of Nuclear Medicine and Molecular Imaging (USA) guidelines recommend at least 4–6 h of fasting for oncology diagnosis using18F-FDG PET/computed tomography (CT) [7]. The guidelines of the Society of Nuclear Medicine and Molecular Imaging (U.S.A.) recommend 6–12 h fasting before glycemic load calculation in myocardial viability diagnostic testing by 18 F-FDG PET/CT [8]. Generally, the guidelines indicate that a fasting duration of less than 6 h is insufficient. On the basis of the above guidelines, a diagnosis of cardiac sarcoidosis is also considered to require a fasting duration of at least 6 h. In an early study on the diagnosis of cardiac sarcoidosis, a fasting duration of 5 h was applied [9], and many studies published since 2004 have adopted a fasting duration of over 12 h (Table 3). A report that reviewed five previously published papers shows a diagnostic sensitivity of 91 % and specificity of 75.5 % in the diagnosis of cardiac sarcoidosis using 18F-FDG PET [5]. A meta-analysis by Youssef et al. [10] showed a diagnostic sensitivity of 89 % and specificity of 78 % in the diagnosis of cardiac sarcoidosis by 18F-FDG PET. Most of the papers reviewed in the above two reports discussed fasting conditions in excess of 12 h. Attention is paid to the high sensitivities, while the low specificity and high variability are also highlighted especially by the second meta-analysis. The

Table 3 Fasting time for FDG PET/CT Author

Year

Pt (n)

Fasting time (h)

Foods

Sensitivity (%)

Yamagishi et al. [9]

2003

17

[5

Not specified

82

Okumura et al. [28]

2004

22

[12

Not specified

100

Specificity (%) N/A 91

Ishimaru et al. [21]

2005

32

[12

Not specified

100

82

Ohira et al. [22]

2008

21

[12

Not specified

88

39

Langah et al. [11] Tahara et al. [29]

2009 2011

76 12

[18 [12

Not specified Not specified

85 100

90 97

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Ann Nucl Med Table 4 Preparation of foods FDG PET/CT Author

Year

Pt (n)

Patients

Fasting time

Meal preparation

Lum et al. [12]

2002

69

Chest malignant tumor

Overnight fast

Low carbohydrate

Cheng et al. [13]

2010

63

Malignant tumor

[6 h

Low carbohydrate

15 h Williams et al. [16]

2008

161

Wykrzykowska et al. [14]

2009

32

Harisankar et al. [17]

2011

110

Malignant lymphoma

3–6 h

Low carbohydrate and high fat

12 h fasting

Low carbohydrate and high fat (20.8 g)

Suspected coronary artery disease Malignant tumor

4 h prior to high fat diet

greatest cause of low specificity and high variability seems to be physiological 18F-FDG uptake in normal myocardium. Hence, a minimum of 12 h of fasting is needed, but even this condition is likely insufficient. Recently, Langah et al. [11] examined an 18-h fasting condition, and they reported a diagnostic sensitivity of 85 % and specificity of 90 % in the diagnosis of cardiac sarcoidosis using 18F-FDG PET. This study indicated that with 18 h of fasting preparation there was an improvement in specificity. It was also reported that the 18F-FDG myocardial-to-blood pool ratio decreased more significantly under the 18-h fasting condition than under a shorter fasting condition. On the basis of the above-mentioned reports, the Japanese Society of Nuclear Cardiology recommends the following pre-18F-FDG PET/CT fasting conditions: Recommendations: fasting time for 18F-FDG PET/CT in diagnosis of cardiac sarcoidosis The pre-FDG PET/CT fasting time needs to be at least 12 h. The pros and cons of further prolongation of fasting time will be the subject of future investigation. Precautions It is essential to estimate blood glucose levels before 18F-FDG PET/CT studies. According to the 18F-FDG PET/CT guidelines for oncologic diagnosis or cardiac viability studies provided by the Society of Nuclear Medicine and Molecular Imaging (USA), FDG PET/CT should be performed on the day after the blood glucose level is controlled if the fasting blood glucose level is 150–200 mg/dL [5]. In accordance with the above guidelines, our Society considers 18F-FDG PET/CT to be unsuitable for patients with poorly controlled blood glucose levels. Dietary modification prior to FDG-PET/CT The dietary modification makes it possible to make fatty acid metabolism exceed glucose metabolism and suppress glucose metabolism in myocardium. Changing to a specific diet is as effective as changing the fasting time to suppress

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myocardial physiological 18F-FDG uptake [5]. An attempt has been made to have patients follow a low-carbohydrate diet alone or a low-carbohydrate diet with the addition of a high-fat diet before 18F-FDGPET/CT (Table 4). In an attempt to improve diagnostic accuracy in assessing intrathoracic cancer, Lum et al. recommended carbohydrate withdrawal the night before 18F-FDG PET/ CT. Thus, they were able to significantly suppress physiological 18F-FDG uptake in the entire myocardium [12]. Moreover, in a randomized study in patients with cancer, it was reported that the ingestion of a low-carbohydrate diet resulted in significantly reduced 18F-FDG uptake in the entire myocardium [maximum standardized uptake value (SUVmax)] [13]. Currently there is no report on whether following a low-carbohydrate diet contributes to an improvement in diagnostic accuracy for cardiac sarcoidosis. However, following a low-carbohydrate diet is simple, clinically applicable, and recommended as a method contributing to the accurate diagnosis of cardiac sarcoidosis. In the low-carbohydrate diet, the carbohydrate content is less than 5 g per meal [5, 13, 14]. Ohira et al. [5] provide a sample low-carbohydrate menu. On the other hand, it is known that taking fatty acids suppresses myocardial glucose metabolism [15]. Williams et al. at Beth Israel Deaconess Medical Center attempted a test procedure in which they had patients follow a lowcarbohydrate diet the night before undergoing 18F-FDG PET/CT and a high-fat diet 3–6 h before undergoing 18FFDG -PET/CT. It was reported that this method produced a significant reduction in 18F-FDG uptake in the entire myocardium (SUVmax) [14, 16]. Other researchers also reported that, in comparison with 12-h fasting alone, the above method resulted in significantly suppressed 18F-FDG uptake in the normal myocardium [17]. In this case, the high-fat diet 4 h before administration of FDG consisted of 20.8 g of fat and 1.2 g of carbohydrate (caloric intake of 265 kcal). However, Cherg et al. [13], as mentioned earlier, reported that no significant decrease in myocardial 18FFDG uptake was achieved in the group in which a high-fat diet was followed, as compared with the over-12-h-fasting-

Ann Nucl Med

only group. Currently there is no established view on the advantage of a high-fat diet.

not currently an established method. Future study including the development of an appropriate protocol will be required.

Recommendations: diet modification prior to 18F-FDG PET/CT for the diagnosis of cardiac sarcoidosis

Precautions Pre-18F-FDG PET/CT heparin administration is, as a rule, contraindicated in patients with a known bleeding tendency. Care should be taken to prevent the occurrence of heparin-induced thrombocytopenia (HIT). The incidence of HIT has been reported to vary from 0.5 to 5 % [23] according to patient background, but a metaanalysis showed an HIT incidence of 2.6 % [24].

1.

2.

3.

Because over-12-h fasting alone will lead to unstable myocardial 18F-FDG uptake, it is also important to consider diet modification the night before undergoing 18 F-FDG PET/CT. It is recommended that patients follow a low-carbohydrate diet the night before undergoing 18F-FDG PET/CT. In this case, the carbohydrate content should be less than 5 g. Following a high-fat diet 3–6 h before administration of 18F-FDG PET/CT was also reportedly useful. However, the usefulness of this approach has yet to be established. This method will be the subject of future investigation.

Heparin preadministration Following intravenous administration of unfractionated heparin, blood free fatty acid levels increase [18]. The increased blood free fatty acid levels suppress myocardial glucose metabolism and skeletal muscle glucose metabolism [19, 20]. On the basis of these findings, a heparin preadministration method was developed for 18F-FDG PET in the diagnosis of cardiac sarcoidosis. Blood free fatty acid levels increase rapidly following heparin administration, and the protocol for intravenous administration of heparin 15 min before FDG administration has been adopted [21]. Nuutilla et al. [20] reported that the administered dose of heparin was 4,700 IU, although patients’ body weights were unknown. Ishimaru et al. administered heparin at a dose of 50 IU/kg [21, 22]. There has been no report examining the relationship between the dose of heparin and the suppression of myocardial 18F-FDG uptake. Regarding the inhibitory effect of heparin preadministration on myocardial 18F-FDG uptake, a study of 30 healthy subjects by Ishimaru et al. showed that myocardial 18 F-FDG uptake was not fully suppressed (14 cases, 47 %), with the observation of diffuse myocardial uptake. Heparin preadministration was considered to produce the suppression effect only in some patients [21]. Heparin preadministration is considered to be theoretically appropriate, and some reports suggest the usefulness of heparin preadministration in the diagnosis of cardiac sarcoidosis. However, it is not an established method. Future studies and the development of an appropriate protocol will be required. Recommendations: pre-18F-FDG PET/CT heparin administration in the diagnosis of cardiac sarcoidosis This is

18

F-FDG PET: 18F-FDG dose, administration, and scan protocol

18

F-FDG administration dose

The ‘‘18F-FDG PET, PET/CT Practice Guidelines 2012’’ of the Japanese Society of Nuclear Medicine, September 2012, stipulate the method for 18F-FDG PET/CT in the diagnosis of cardiac sarcoidosis [25]. These guidelines recommend that an 18F-FDG dose range from 111 to 259 MBq (2–5 MBq/kg) for 3D data collection and from 185 to 444 MBq (3–7 MBq/ kg) for 2D data collection. The dose should be increased or decreased based on the type of PET/CT equipment to be used and the patient’s age and body weight. The guidelines for ‘‘PET Myocardial Perfusion and Glucose Metabolism Imaging’’ of the Society of Nuclear Medicine and Molecular Imaging (USA) [8] stipulate that the standard dose of 18F-FDG in cardiac PET is in the 185–555 MBq (5–15 mCi) range. With the same equipment, a lower dose is required for PET imaging for 3D data collection than is required for 2D data collection. The main studies on the application of 18F-FDG PET in the diagnosis of cardiac sarcoidosis are listed in Table 5. All methods in these papers met the standard of the Society of Nuclear Medicine and Molecular Imaging (USA). A dose of 555 MBq is considered to be too high considering the sensitivity of recent PET or PET/CT equipment and the reduction of radiation exposure. In Japan, the dose recommended by the guidelines of the Japanese Society of Nuclear Medicine [25] is thought to be more suitable. Recommendations: FDG dose A dose in the range of 111–259 MBq (2–5 MBq/kg) is administered intravenously for 3D data collection, and a dose in the range of 185–444 MBq (3–7 MBq/kg) is administered intravenously for 2D data collection. The dose should be increased or decreased according to the type of equipment to be used and the patient’s age and body weight. 18

F-FDG PET/CT scan protocol

The ‘‘FDG PET, PET/CT Practice Guidelines 2012 [25]’’ of the Japanese Society of Nuclear Medicine stipulate the

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Ann Nucl Med Table 5 Application of FDG PET or PET/CT for the diagnosis of cardiac sarcoidosis: FDG dose, time from FDG administration to scan, acquisition time for cardiac spot images Author

Year

Pt (n)

Scanner

FDG dose

Time between FDG administration to image acquisition (min)

Acquisition time for cardiac spot images

Yamagishi et al. [9]

2003

17

PET

259–370 MBq

50

10 min

Okumura et al. [28]

2004

22

PET

200 MBq

60

Not specified

Ishimaru et al. [21] Langah et al. [11]

2005 2009

32 20

PET PET/CT

185 MBq 555 MBq

45–60 60

Not specified Not specified

Tahara et al. [29]

2011

12

PET

4.2 MBq/kg

60

Not specified

imaging method as follows: ‘‘Perform emission and transmission scanning (in PET) or CT scanning (in PET/ CT) 45–60 min after FDG administration with PET or PET/CT equipment.’’ On the other hand, the guidelines of the Society of Nuclear Medicine and Molecular Imaging (USA) [8] recommend an interval between 18F-FDG administration and the start of the scan of at least 45 min. FDG uptake in the myocardium increases gradually with time even 45 min after FDG administration, whereas uptake in the blood pool declines [26]. Hence, an even longer interval may be more suitable. The decrease in the radiation count due to the attenuation of 18F with time should also be considered. In many previous studies, imaging started 60 min after 18FFDG administration. It is important to standardize this time interval if 18F-FDG PET and PET/CT imaging are performed repeatedly for a follow-up. Recommendations: imaging method Perform emission and transmission scanning (in PET) or CT scanning (in PET/CT) 60 min after FDG administration with PET or PET/CT equipment. In subsequent imaging tests for comparison, the interval before the start of imaging (about 60 min) should be the same as it was in the previous imaging. Spot cardiac imaging and avoidance of misalignment artifacts After imaging data acquisition, data are transferred to a dedicated workstation for image processing and analysis. In most previous studies on the use of PET in the diagnosis of cardiac sarcoidosis, dedicated PET equipment was used. Up until now, PET/CT equipment has been used mainly in clinical settings. When using PET/CT equipment, it is important to avoid misaligning PET and CT images (see next section). Misalignment generates image artifacts, which hinder comparison in the degrees of uptake among myocardial segments and the analysis of SUV [27]. To prevent this misalignment, it is recommended that spot imaging of the heart with the patient’s arms up be added to systemic PET/CT scan imaging. Elevating the arms

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contributes to the reduction of streak artifacts or beam hardening to the heart. It is advisable to perform spot imaging of the heart by suppressing the movement of the diaphragm through abdominal compression or respiratory synchronization. If the patient has difficulty keeping arms up, keeping arms in front of the body as much as possible would be recommended. Doing so makes it possible to prevent the vertebral column and the arms, which are high X-ray absorbers, from being in the same straight line on the X-ray projection, thus reducing streak artifacts or beam hardening. According to the guidelines of the Society of Nuclear Medicine and Molecular Imaging (USA) [8], the data acquisition time is 10–30 min, depending on the type of PET/CT equipment and 18F-FDG dose. The combination of respiratory synchronization and electrocardiographic synchronization is recommended if the PET/CT scanner allows it. With the dose of 18F-FDG based on the guidelines of the Japanese Society of Nuclear Medicine, a cardiac spot imaging time could be 10 min, which is considered to be sufficient. Themes of future studies could include the combined use of respiratory synchronization and electrocardiographic synchronization, optimum time of asynchronous cardiac spot imaging, and differences in SUV in the heart between spot images and systemic images. Figure 1 shows a typical imaging protocol. Recommendations: cardiac spot imaging In PET/CT imaging, it is important to avoid misalignment between CT and PET images. Spot imaging of the heart with the patient’s arms elevated (duration of about 10 min) is recommended in addition to conventional systemic imaging. The adoption of respiratory synchronization and electrocardiography synchronization is also expected to be useful. Image processing and image interpretation Image processing Attenuation correction PET scanners use transmission data for attenuation correction. PET scanner systems use radiation from an external source. On the other hand, PET/

Ann Nucl Med Fig. 1 18F-FDG PET/CT imaging protocol

CT scanners use CT images for attenuation correction. However, since CT data are obtained in a shorter timeframe than are PET data, misalignment due to the patient’s breathing and body movement can occur. Respirationsynchronization CT imaging (expiratory phase) makes it possible to avoid respiratory misalignment. However, imaging equipment that has respiratory synchronization is currently limited. When misalignment between PET and CT images is suspected, reference to original images without CT attenuation correction may be useful. A pacemaker lead, in particular an implantable cardioverter defibrillator (ICD) lead, may affect CT images. This metal artifact causes excessive attenuation correction. Thus, care should be exercised in interpreting the images [25, 26]. Image reconstruction (short axis, long axis, and horizontal long axis) Previous reports show that image reconstruction of myocardial tomography images was performed by oblique tomography (short axis, vertical long axis, and horizontal long axis images) [9, 10, 21, 22, 28–30]. However, if myocardial 18F-FDG uptake is completely suppressed, it is difficult to perform such oblique tomography. In this case, axial chest tomography imaging (transverse, coronary, and sagittal tomographic imaging) is used [3]. In oblique tomography, the central heart axis has to be set appropriately. The orientations of a reconstructed left ventricular short-axis image, a left ventricular vertical long-axis image, and a left ventricular horizontal long-axis image are shown in Fig. 2. Bull’s-eye map display It is useful to use a Bull’s-eye map display on the basis of myocardial circumferential profile analysis of left ventricular short-axis images (display in polar coordinates) in confirming abnormal uptake distribution. This is also helpful for comparing images acquired

Fig. 2 Image reconstruction

using other modalities such as myocardial perfusion singlephoton emission computed tomography (SPECT) imaging with 18F-FDG PET/CT images. Care should be taken in creating a Bull’s-eye map display as follows: 1.

2.

3.

The myocardial trace should be accurate. If 18F-FDG uptake is localized in the lesion site, other normal myocardium does not have positive 18F-FDG uptake. Thus, it should be difficult to trace myocardium. If the Bull’s-eye map display is used for comparison with other images (SPECT image, etc.), it is advisable to use the same workstation or algorithm. Whether the Bull’s-eye map display is accurate should be confirmed through comparison with myocardial tomography.

Recommendations: image processing and reconstruction 1.

When attenuation correction is conducted using CT images, attention should be paid to the potential

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Ann Nucl Med

2.

3.

occurrence of misalignment due to the patient’s breathing or body motion. Comparison with original 18 F-FDG PET images before attenuation correction is useful. In patients with a pacemaker or an implanted ICD, care should be exercised as a lead could affect CT images since metal induces artifacts and may cause excessive attenuation correction. If myocardial positive 18F-FDG uptake is observed, oblique myocardial tomography imaging could be performed in addition to standard systemic maximum intensity projection (MIP) imaging and axial chest tomography. If there is no myocardial uptake, it is difficult to perform oblique myocardial tomography imaging. A Bull’s-eye map display is useful for the evaluation of uptake location and patterns. It is also helpful for comparison of 18F-FDG images and myocardial perfusion images. However, it is important to ensure that the Bull’s-eye map display is appropriate by comparing it with myocardial tomography images. It is also important to use the same software and algorithm for comparison between the Bull’s-eye map display and other modalities.

1. 2. 3.

Classification into two types of patterns [11]: diffuse and focal. Classification into three types of patterns [10]: none, diffuse, and focal. Classification into four types of patterns [21, 22, 29]: none, diffuse, focal, and focal and diffuse.

If a case shows an 18F-FDG uptake distribution that is focal or that has a focal and diffuse pattern according to classifications 2 and 3, this case is determined to show an abnormal FDG uptake in a sarcoidosis inflammation lesion. On the other hand, cases showing both focal and diffuse FDG uptake distribution patterns in classification 1 are determined to show abnormal FDG uptake. Classification 3 of FDG uptake distribution into four types of patterns, which was proposed by Ishimaru et al. [21], is currently the most frequently adopted determination criteria in Japan. Figure 3 shows its typical patterns. It was reported that when patients with FDG uptake patterns shown in images C and D were determined as being positive for cardiac sarcoidosis, by exclusion of cases with localized uptake in only the lateral wall, FGD PET/CT imaging had a diagnostic capability of 100 % and specificity of 81.5 % [21].

Image interpretation It is recommended that imaging data after attenuation correction should be used. Overall assessment is conducted comprehensively, using systemic MIP images, axial transverse tomography, left ventricular short-axis image, left ventricular vertical long-axis image, left ventricular horizontal long-axis image, and Bull’s-eye map display. Whole-body MIP image (transaxial plane) for systemic disease evaluation Cardiac sarcoidosis is considered to be a systemic disease including involvement of myocardium. Therefore, abnormal 18F-FDG uptake in the lungs, lymph nodes, spleen, liver, muscles, eyes, and skin should be observed using systemic MIP images. However, there are some cases in which such abnormal 18F-FDG uptake is not observed. The presence of sporadic (no lesions except in the heart) cardiac sarcoidosis has been reported [31, 32]. In some cases, visible cardiac involvement depended on the stage of the disease. Abnormal 18F-FDG uptake in the aortic wall (sarcoid vasculitis) can be observed on systemic MIP images. Axial transverse images are helpful in observing the presence of abnormal 18F-FDG uptake in the right ventricular free wall or atrial wall. Diagnostic criteria for cardiac regions with visual assessment Myocardial 18F-FDG uptake distribution observed in cardiac sarcoidosis has been analyzed on the basis of the classification shown below:

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Use of common sites of cardiac sarcoidosis as a reference The base of the ventricular septum is known to be a common site of cardiac sarcoidosis in association with the wall thinning of the ventricular septum detected by echocardiography. Second- or third-degree atrioventricular block is observed in 23–30 % of patients with cardiac sarcoidosis, and it was reported that this preponderance is related to inflammatory cell infiltration into the base of the ventricular septum [33, 34]. Localized FDG uptake in the base of the ventricular septum in patients with atrioventricular block is likely to be at the lesion site. On the other hand, a histopathological examination showed that the left ventricular free wall is also a common site of cardiac sarcoidosis [35]. It was reported that ventricular tachycardia occurs in 23 % of cardiac sarcoidosis patients [33]. If the onset site of monomorphic ventricular tachycardia corresponds to the 18F-FDG positive uptake site, the possibility that it is the site of the lesion increases. Comparison with myocardial perfusion SPECT and myocardial fatty acid metabolism SPECT In some cases, the combined use of myocardial perfusion SPECT with a Tl201- or Tc-99 m-labeled radiopharmaceutical is useful in the determination of inflammation based on 18F-FDG uptake in relation to myocardial tissue disorder images. If 18 F-FDG uptake is consistent with the perfusion abnormality or is in the peripheral zone of the perfusion abnormality, there is likely to be a positive finding. The

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Fig. 3 Diagnostic criteria of myocardial 18F-FDG PET/CT imaging. MIP images and transverse myocardial images. a None :without focal myocardial 18F-FDG uptake. This pattern is considered to be negative. b Diffuse: definite diffuse FDG uptake in the entire left ventricular wall without localized high 18F-FDG uptake. This 18FFDG uptake distribution pattern generally does not indicate an abnormality. It is histopathologically known that the myocardial sarcoidosis lesion is not diffuse but localized. c Focal: with localized FDG uptake in the left ventricular wall. This finding is considered to be positive for cardiac sarcoidosis. However, it is required to exclude other heart diseases that show localized 18F-FDG uptake (e.g. ischemic heart diseases and hypertrophic cardiomyopathy). 18FFDG uptake in the lateral wall region was reported even in healthy subjects [38, 39]. Other researchers [21, 22] reported that localized 18 F-FDG uptake in this region does not indicate positivity for cardiac sarcoidosis. Reports presented at recent academic conferences have

pointed out that localized 18F-FDG uptake in the anteroseptal base and diffuse uptake in the entire circumference of the heart base could be physiological myocardial uptake. Therefore, this remains a controversial issue. Care should be exercised in assessing the findings of 18F-FDG uptake in these regions. Some researchers consider that comparison of these false-positive findings with myocardial perfusion images will be useful for differential diagnosis. d Focal on diffuse: some strong 18F-FDG uptake with diffuse myocardial uptake of 18FFDG. This finding generally indicates positivity for cardiac sarcoidosis. However, it requires careful interpretation because it has been reported that cases with such FDG uptake potentially included falsepositive ones [29]. In some patients with cardiac dysfunction and those with cardiac failure, diffuse myocardial 18F-FDG uptake is sometimes observed under fasting conditions. Hence, the determination of findings is often difficult in these patients

diagnostic capability of myocardial perfusion SPECT in the diagnosis of cardiac sarcoidosis is hardly high with a sensitivity of 40–65 % [36, 37]. However, myocardial perfusion SPECT is expected to be applied for the staging of the disease because it provides data on the state of myocardial tissue disorder. Myocardial fatty acid metabolism SPECT with I-123 beta-methyl-iodophenyl pentadecanoic acid (BMIPP) is also considered to be useful in determining the progression of myocardial tissue disorder; however, currently there is no available evidence of such usefulness.

left ventricular cardiac muscle into 13 segments. Patients with cardiac sarcoidosis showed higher myocardial SUV than did healthy subjects. The diagnostic capability on the basis of the above criterion had a sensitivity of 100 % and specificity of 91 % [28]. Tahara et al. divided the left ventricular cardiac muscle into 17 segments and obtained SUV in each segment. The coefficient of variance of over 0.18 is regarded as positive for cardiac sarcoidosis. This had a high diagnostic capability of sensitivity of 100 % and specificity of 97 % [29]. Regarding the use of SUV in the diagnosis of cardiac sarcoidosis, there are problems that remain to be solved. These include unstandardized SUV calculation software and differences in measurement values depending on imaging equipment and imaging conditions.

Use of standardized uptake value The usefulness of a standardized uptake value (SUV), a quantitative index of FDG uptake, has not been assessed in depth in patients with cardiac sarcoidosis. SUV is defined by dividing postattenuation-corrected uptake radioactivity, measured using a PET camera, by radioactivity per kg of the patient’s body weight. In cardiac sarcoidosis, the high SUV in the FDG uptake site has been reported, consistent with visual determination of the site [28]. Okumura et al. divided the

Recommendations: image interpretation 1.

It is recommended that abnormal 18F-FDG uptake in organs other than the heart be observed using systemic MIP imaging and axial transverse imaging.

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3.

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F-FDG uptake in the left ventricular myocardium is classified into four patterns. The findings of ‘‘focal’’ and ‘‘focal and diffuse’’ patterns are considered to be positive findings of cardiac sarcoidosis. However, it is essential to exclude ischemic cardiac disease and hypertrophic cardiomyopathy. These diseases may trigger localized 18F-FDG uptake. Since myocardial perfusion SPECT imaging is useful for confirming positive 18F-FDG PET findings and disease staging in relation to the myocardial impairment site, the combined use of 18F-FDG PET/CT and myocardial perfusion SPECT is advisable. Measurement of SUV will possibly be useful for the improvement of diagnostic capability and quantitative disease activity.

Conflict of interest

None.

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Recommendations for (18)F-fluorodeoxyglucose positron emission tomography imaging for cardiac sarcoidosis: Japanese Society of Nuclear Cardiology recommendations.

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