Comparative evaluation of ¹⁸F-FLT and ¹⁸F-FDG for detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by the presence of noncaseating granulomas in the involved organs [1]. Although it may involve any organ or system, it most commonly affects the lungs and thoracic lymph nodes, with the cardiovascular system being the third most frequently affected site [1, 2]. Although sarcoidosis has a generally favorable prognosis, 1–5% of patients die of it because of cardiorespiratory complications [1]. Therefore, early and accurate diagnosis and treatment are very important in the management of the disease.

¹⁸F-FDG PET is a well-established functional imaging technique for diagnostic oncologic imaging that provides data on glucose metabolism in lesions [3]. However, the technique allows the visualization not only of malignant cells but also of inflammatory cells [4, 5]. ¹⁸F-FDG PET has been proposed to play a role in the diagnosis and therapeutic monitoring of sarcoidosis including cardiac involvement [6‐25]. The Heart Rhythm Society (HRS) and the Japanese Society of Nuclear Cardiology (JSNC) recommend using ¹⁸F-FDG PET for diagnosis of cardiac sarcoidosis [26, 27]. However, assessing inflammatory lesions in cardiac sarcoidosis using this modality can be challenging because ¹⁸F-FDG accumulates in normal myocardium, namely physiological uptake [11, 12]. Some of the main methods proposed for inhibiting increased ¹⁸F-FDG uptake in myocardial physiological cells include heparin injection, prolonged fasting, and dietary carbohydrate restriction before the ¹⁸F-FDG PET scan [11]. However, myocardial ¹⁸F-FDG uptake may be observed even under these conditions.

3′-Deoxy-3′-¹⁸F-fluorothymidine (¹⁸F-FLT) has been investigated as a promising PET tracer for evaluating tumor proliferative activity [28]. Zhao and colleagues in experimental rat studies reported that ³H-FLT uptake in granuloma was comparable to that in the tumor, whereas ³H-FLT uptake in turpentine oil-induced inflammation was significantly lower than that in the tumor [29]. ³H-FLT may accumulate in chronic granulomatous lesions with proliferative inflammation [29]. One case study of a patient with sarcoidosis showed mild ¹⁸F-FLT uptake and intense ¹⁸F-FDG uptake in lymph nodes [30]. To our knowledge, a previous report from our group was the first to describe positive findings on ¹⁸F-FLT PET/CT in a sarcoidosis patient with cardiac involvement [31]. In contrast to ¹⁸F-FDG, ¹⁸F-FLT uptake in the normal myocardium is low even in the absence of prolonged fasting or imposition of a special diet prior to imaging.

Limited information is available regarding the use of ¹⁸F-FLT in sarcoidosis. There have been no systematic studies, except the two case reports mentioned above [30, 31]. This prompted us to undertake the present study in which the uptake of ¹⁸F-FLT and ¹⁸F-FDG was compared in the evaluation of cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis.

In the present study of 20 patients with sarcoidosis, the detectability of cardiac and extra-cardiac thoracic involvement using ¹⁸F-FLT PET/CT was comparable to that using ¹⁸F-FDG PET/CT. In particular, for evaluation of cardiac involvement, there was no inconclusive ¹⁸F-FLT PET/CT scan that required any special diet prior to imaging.

¹⁸F-FDG PET has been used in sarcoidosis including cardiac involvement for diagnosis and therapeutic monitoring [6‐25]. ¹⁸F-FDG PET sensitivity was reported as 97–100% for detecting extra-cardiac thoracic sarcoidosis [6‐8], which is similar to the result of the present study (100%). A systematic review using ¹⁸F-FDG PET for detecting cardiac sarcoidosis indicated relatively high sensitivity (79–100%), which is also comparable to that of the present study (85%), but low specificity (38–100%) [9]. The present study showed a high specificity (100%). This may be attributable to inconclusive scans (diffuse pattern) that were considered negative. The reported specificity of ¹⁸F-FDG PET in diagnosing cardiac sarcoidosis has been varied and relatively low compared with the sensitivity [9]. One possible reason for this low specificity and high variability may be the non-specific uptake of ¹⁸F-FDG in the normal myocardium caused by incompletely suppressed glycolytic metabolism [9]. Some studies have shown that an 18-h fast enhanced the quality of myocardial imaging with sufficient suppression of physiological uptake [10, 11]. In the present study, although patients fasted for 18 h prior to their ¹⁸F-FDG PET/CT scan, 4/20 scans did not show complete suppressing of physiological ¹⁸F-FDG uptake. Soussan et al. reported that ¹⁸F-FDG PET/CT after a high-fat and low-carbohydrate diet was a sensitive tool for the diagnosis of active cardiac sarcoidosis [15]. However, the diffuse pattern or focal uptake in the papillary muscle even under such dietary stipulations was still observed in 7/30 controls and 13/58 sarcoidosis patients [15]. A recent review by Osborne et al. reported that the available literature supported use of a high-fat, no-carbohydrate diet for at least two meals with a fast of 4–12 h prior to ¹⁸F-FDG PET imaging and suggested that isolated fasting for less than 12 h and supplementation with food or drink just prior to imaging should be avoided [37]. Ambrosini et al. reported cardiac FDG uptake regardless of the preparation before PET/CT, suggesting that even a meal rich in fat followed by 12 h of fasting, may not be sufficient to completely suppress physiological FDG uptake [16]. Despite the proper preparation, inadequate suppression of physiological uptake in myocardium can sometimes be experienced. More easily applicable and standardized preparation protocols should be established to sufficiently suppress physiological ¹⁸F-FDG uptake in the normal myocardium. Another possible reason for the low specificity observed in other studies is that myocardial ischemia and heart failure may also produce focally or heterogeneously increased ¹⁸F-FDG uptake not related to sarcoidosis. ¹⁸F-FDG PET may also visualize acute myocardial inflammation to suggest active myocarditis [38]. A meta-analysis for pulmonary lesion diagnosis reported that ¹⁸F-FLT showed better results compared with ¹⁸F-FDG in ruling out inflammation-based lesions [39]. A positive ¹⁸F-FDG PET finding in both cardiac and extra-cardiac regions is not specific to sarcoidosis.

An ideal radiopharmaceutical for imaging cardiac sarcoidosis should have no background uptake by normal myocardial cells and not be dependent on patient diet. ¹⁸F-FLT PET has no physiological uptake in the myocardium and does not require patients to adhere to prolonged fasting and/or a special diet prior to imaging. However, the uptake of ¹⁸F-FLT in sarcoidosis has not been elucidated yet. Zhao et al. developed a rat model of granuloma characterized by epithelioid cell granuloma formation and massive lymphocyte infiltration around the granuloma, histologically similar to sarcoidosis [29]. They showed that ³H-FLT uptake in the granuloma was comparable to that in the tumor, as in the case of ¹⁸F-FDG, although the level of ³H-FLT uptake was lower than that of ¹⁸F-FDG [29]. Sarcoidosis is suggested to be a granulomatous disease with high-turnover characteristics [30]. From an in vitro study using ³H-thymidine, there appear to be mostly low-turnover reactions, with occasional granulomas showing high-turnover characteristics, within the lymph node of a patient with sarcoidosis [40]. Active sarcoidosis may be a granulomatous disease with high-turnover characteristics, which could account for the increased ¹⁸F-FLT uptake in the present study. One case study of a patient with sarcoidosis showed a mild ¹⁸F-FLT uptake and intense ¹⁸F-FDG uptake in the involved lymph nodes [30]. In the present study, uptake of ¹⁸F-FLT in the involved lesions was also significantly lower than that of ¹⁸F-FDG. To the best of our knowledge, with the exception of two sporadic case reports [30, 31], the present study is the first investigation of ¹⁸F-FLT PET/CT undertaken for the detection of sarcoidosis. ¹⁸F-FLT may be a potentially useful tracer to combine with ¹⁸F-FDG in the detection of sarcoidosis, especially cardiac sarcoidosis.

¹⁸F-sodium fluoride (NaF) similarly has little myocardial uptake and is not dependent on patient preparation in terms of diet or insulin status similar to ¹⁸F-FLT. Recently, Weinberg et al. investigated ¹⁸F-NaF PET/CT for detection of cardiac sarcoidosis in three patients [41]. However, they reported that ¹⁸F-NaF may not be able to effectively image active inflammation due to cardiac sarcoidosis unlike ¹⁸F-FDG [41]. Gormsen et al. investigated the feasibility of ⁶⁸Ga-DOTA-NaI-octreotide (DOTANOC) PET/CT, compared with ¹⁸F-FDG PET/CT, for the detection of cardiac sarcoidosis [36]. They showed that the diagnostic accuracy of ⁶⁸Ga-DOTANOC in diagnosing cardiac sarcoidosis was 100% although 11/19 ¹⁸F-FDG scans were rated as inconclusive despite prolonged pre-scan fasting [36]. To date, there have been few studies using newer radiopharmaceuticals other than ¹⁸F-FDG for evaluation of sarcoidosis.

Limitations of the present study include a small sample size and retrospective design. Only 9 patients were diagnosed histologically, while none of those with cardiac sarcoidosis were diagnosed histologically by endomyocardial biopsy. Generally, endomyocardial biopsy shows lower sensitivity due to the heterogeneous distribution of the noncaseating granulomas that are characteristic of the disease. Given the limited sensitivity of myocardial biopsy, the revised guidelines 2006 [27], 2015 [32], and 2016 [33] have been used as the diagnostic standard. An important limitation of this study is the lack of significant dietary preparation with high-fat and low-carbohydrate meals prior to the ¹⁸F-FDG PET studies. Further studies to compare the ¹⁸F-FLT PET and ¹⁸F-FDG PET with such a dietary preparation will be needed and are currently underway. Unfortunately, in the present study, no data on whole-body scanning were available. Teirstein et al. reported that whole-body scan with ¹⁸F-FDG PET was particularly useful for detecting unsuspected extra-thoracic sarcoidosis [42]. They concluded that whole-body ¹⁸F-FDG PET was useful mainly in the detection of occult sites for biopsy and in the assessment of the presence of residual activity in patients with fibrotic pulmonary sarcoidosis, which may help to decide whether to continue or cease steroid therapy [42]. We did not compare PET imaging and myocardial perfusion imaging. Although ¹⁸F-FLT PET/CT could detect cardiac and extra-cardiac thoracic sarcoidosis as well as ¹⁸F-FDG PET/CT, uptake of ¹⁸F-FLT in lesions was significantly lower than that of ¹⁸F-FDG. The lower level of uptake probably increases the detection limit, making it more difficult to visualize lesions. Pathology findings seen in sarcoidosis range from inflammatory cell infiltration, edema, noncaseating granuloma formation, and fibrotic changes to scarring [43]. Of these, ¹⁸F-FDG PET has limited ability to depict fibrous regions [24]. To date, no study has reported this issue using ¹⁸F-FLT PET. The combined use of ¹⁸F-FDG, ¹⁸F-FLT, other PET tracers, and other imaging modalities such as magnetic resonance imaging might be helpful in the diagnosis and staging of cardiac sarcoidosis. Additional large prospective studies are needed to determine the clinical usefulness of ¹⁸F-FLT PET/CT in patients with sarcoidosis.

¹⁸F-FDG PET can monitor the disease activity of sarcoidosis including cardiac involvement, during and after steroid therapy [7, 16‐22]. However, elevations in serum glucose and insulin levels due to steroid therapy may adversely affect ¹⁸F-FDG uptake in target organs including the heart and reduce test specificity [5, 17]. This may preclude accurate assessment of the effects of steroids using ¹⁸F-FDG PET. Although ¹⁸F-FLT PET might be useful for avoidance of such misleading evaluations, the role of ¹⁸F-FLT PET in steroid therapy monitoring has not been evaluated so far. Further prospective studies involving a larger number of patients will be required to determine the clinical usefulness of ¹⁸F-FLT PET in the diagnosis and monitoring the effects of steroid therapy in patients with sarcoidosis.

Based on the results of this preliminary study in a small patient sample, ¹⁸F-FLT PET/CT seems to be as effective as ¹⁸F-FDG PET/CT in detecting cardiac and extra-cardiac thoracic involvement in patients with newly diagnosed sarcoidosis, although uptake of ¹⁸F-FLT in the lesions was significantly lower than that of ¹⁸F-FDG. However, since ¹⁸F-FLT PET/CT requires neither prolonged fasting nor a special diet prior to imaging, it may be a more convenient technique for evaluation of cardiac involvement in sarcoidosis.