Sarcoidosis is a multisystem disorder of unknown etiology, characterized by the formation of non-caseating granulomas in many organs including eye, skin, bone, muscle, nerve system, lymph node, lung, liver, and heart. Although sarcoidosis is generally recognized as having a low mortality rate,1 cardiac involvement could present a life-threatening situation such as conduction disturbance, ventricular tachyarrhythmia, and congestive heart failure.2 In 1992, the Japanese Ministry of Health and Welfare established preceding guidelines for the diagnosis of cardiac sarcoidosis (CS).3 Typical granulomatous myocarditis based on endomyocardial biopsy was determined as histopathologically diagnosed CS. However, endomyocardial biopsy shows the limited sensitivity no better than 30% by sampling errors due to patchy distribution of cardiac granulomas.2,4,5 Sarcoidosis often has been determined by extracardiac biopsy specimens from skin, muscle, and lymph node. While cardiac involvement is clinically apparent in < 5% of all patients with sarcoidosis, over 20% of the patients have been found cardiac granulomas at autopsy.6,7 Therefore, the diagnosis of CS was often a challenging issue for physicians.

In 2006, the joint committee of the Japan Society of Sarcoidosis and Other Granulomatous Disorders and the Japanese College of Cardiology modified the guidelines (Table 1).8 Briefly, the modified guidelines required that a histopathological or clinical diagnosis of sarcoidosis in any organs except the heart is prerequisite for evidence of sarcoidosis. If endomyocardial biopsy is negative, presence of cardiac abnormalities compatible with CS was defined as clinically diagnosed CS (Table 1). Serial electrocardiogram, 24 h Holter monitoring of electrocardiogram, echocardiography, myocardial perfusion scintigraphy, and 67Gallium scintigraphy can be helpful tools for clinically diagnosed CS. Especially, the revised guidelines included a positive 67Gallium uptake in the heart as a major criterion. However, these conventional tools are far from satisfactory for the detection of cardiac involvement.

Table 1 Guidelines for diagnosis of cardiac sarcoidosis (2006)
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With advances in imaging technologies, the molecular targeting approach using 18Fluorine-fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to visualize inflamed tissues and help to identify occult lesions.9,10,11 The shortcomings of the conventional tools stimulated the use of FDG-PET to identify and quantify granulomatous inflammation. The diagnostic approach and assessment of treatment effect in a CS patient using FDG-PET was first reported in 2002.12 Thereafter, FDG-PET has been employed for the assessment of granuloma localization and inflammatory activity in the heart with varying degrees of success to develop a treatment strategy in CS patients.8,13,14,15 It has been demonstrated that the focally increased FDG uptake in the heart indicates inflammatory activity within granulomas.13,14,15 Also, an index of heterogeneity of myocardial FDG uptake can determine the diagnosis of CS and the effect of corticosteroid therapy.8 Further, FDG-PET can identify individuals having a higher risk of future adverse events.16,17 However, some patients may exhibit physiological myocardial FDG uptake on PET imaging under 6-12 h of fasting conditions. Recent studies have revealed that preparation including more than 18 h of long fasting and a low-carbohydrate diet modification prior to FDG-PET scan can reduce myocardial physiological FDG uptake and visualize accurate granulomatous inflammatory activity of CS.18,19,20 In these days, FDG-PET has been widely utilized for the initial diagnosis, assessment of disease activity, and monitoring of treatment response in CS.21

In this issue of the journal, Tuominen et al. report data from a single-center retrospective study that assessed the imaging features of FDG uptake on PET in 137 consecutive patients with suspected CS.22 In the study, 33 (24.1%) patients had pathological cardiac FDG uptake, and 12 (36.4%) of these patients showed FDG uptake in both left and right ventricles (LV and RV). Of the 12 patients, 7 (58.3%) indicated biopsy positive for sarcoidosis such as endomyocardial biopsy or extracardiac biopsy. A positive biopsy finding for sarcoidosis was more seen in patients with pathological uptake in both ventricles than those with only pathological LV uptake (19.0%) (Figure 1: left). Also, 16 (48.5%) of 33 patients with pathological cardiac FDG uptake had abnormal extracardiac FDG uptake. Among them, 8 (50.0%) patients showed biopsy positive for sarcoidosis. A positive biopsy finding for sarcoidosis was more recognized in patients with abnormal extracardiac FDG uptake than those without it (Figure 1: right). In regard to extracardiac uptake sites, FDG uptake in mediastinal and hilar lymph nodes was more often seen in patients with pathological uptake in both ventricles than those with only pathological LV uptake. Pathological uptake in both ventricles may be associated with abnormal uptake in mediastinal and hilar lymph nodes, but not with uptake at other extracardiac sites. Especially, pathological cardiac uptake was stronger in patients having abnormal extracardiac uptake than those without it. The key finding of the study was that pathological uptake in both ventricles and abnormal extracardiac uptake were associated factors that could predict a positive biopsy finding for sarcoidosis. This is noteworthy because it is better to get a histologic proof of granulomatous inflammation for accurately diagnosing CS, which has important prognostic and therapeutic implications to the individual involved. In a previous study by Kandolin et al, FDG uptake in mediastinal lymph nodes was seen in 71.4% of CS patients.23 Another study by Simonen et al showed FDG-avid mediastinal lymph nodes in 66.7% of CS patients.24 Compared to these reports, there were relatively small number of patients with abnormal extracardiac uptake in this study. It may be due to a low proportion of sarcoidosis, which could lead to a selection bias. In any case, metabolically active mediastinal lymph nodes evaluated by FDG-PET can be a candidate for extracardiac biopsy to confirm the histology of sarcoidosis, if no positive endomyocardial biopsy.

Figure 1
figure 1

Biopsy positive rate for sarcoidosis. LV, left ventricle; RV, right ventricle; EC, extracardiac; +, pathological FDG uptake; -, no pathological FDG uptake

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The Heart and Rhythm Society (HRS) has indicated a consensus of the role of FDG-PET for the detection of CS.25 In 2017, the Japanese Circulation Society and its collaborative organizations updated the guidelines for the diagnosis and treatment of CS (Chair: Fumio Terasaki) (Tables 2, 3).26 The updated guidelines have shown that CS patients having positive endomyocardial biopsy findings was diagnosed as the histological diagnosis group and those with negative endomyocardial biopsy findings or not undergoing myocardial biopsy as the clinical diagnosis group. (Tables 2, 3). Of particular note is that strongly suggestive pulmonary or ophthalmic sarcoidosis and meet criteria for cardiac involvement based on the major criteria and the minor criteria (Table 3) are needed for the clinically diagnosed CS in the updated guidelines. Notably, a positive FDG uptake in the heart is included in the major criteria of the updated guidelines. Against the expert consensus statement from the Heart Rhythm Society,25 diagnosing CS without any histologic proof has been possible.26 Cautious interpretation is necessary as not to misdiagnosis.

Table 2 Guidelines for diagnosis of cardiac sarcoidosis (2017)
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Table 3 Criteria for cardiac involvement of sarcoidosis (2017)
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