The role of PET in the management of sarcoidosis.

PURPOSE OF REVIEW: PET has emerged as method to determine the location and extent of disease activity in sarcoidosis. As most clinicians do not routinely utilize PET in the management of sarcoidosis, an understanding of the imaging technique is needed to comprehend the impact that PET abnormalities have on diagnosis, prognosis, and treatment. RECENT
FINDINGS: Although PET can detect inflammation because of sarcoidosis throughout the body, it is most often utilized for the diagnosis of cardiac sarcoidosis for which it may provide information about prognosis and adverse events. Whenever PET is combined with cardiac magnetic resonance (CMR), clinicians may be able to increase the diagnostic yield of imaging. Furthermore, PET abnormalities have the potential to be utilized in the reduction or augmentation of therapy based on an individual's response to treatment. Although various biomarkers are used to monitor disease activity in sarcoidosis, an established and reproducible relationship between PET and biomarkers does not exist.
SUMMARY: PET has the potential to improve the diagnosis of sarcoidosis and alter treatment decisions but prospective trials are needed to define the role of PET while also standardizing the performance and interpretation of the imaging modality.

INTRODUCTION

The hallmark of sarcoidosis is granulomatous inflammation because of a dysregulated response of the immune system [1]. Once initiated, the resultant organ damage is dependent upon the intensity and duration of the persistent granulomatous inflammation. Given that the lungs are affected in about 90% of individuals, the pulmonary system garners much attention but sarcoidosis is a multisystem disease [2,3]. With the potential to damage any organ system, identifying and localizing active inflammation in different systems can direct management. PET has emerged as a tool to detect inflammation in patients with sarcoidosis that may not be easily recognized by physical examination or methods of assessment currently used in clinical practice [4]. In this current opinion, we hope to present the role of PET in the diagnosis and treatment of sarcoidosis, the advantages and drawbacks of PET, and outline areas of further research.

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INTRODUCTION TO PET IMAGING, TRACERS AND PREPARATION

PET is an imaging modality that utilizes radiotracers to visualize areas of the body with increased metabolic activity. The radiotracer is composed of a positron emitting isotope that is complexed to a specific target protein in the body. PET is combined with computed tomography (PET/CT) to produce a three-dimensional mapping of the organs. Although a full review of the list of radiotracers used in PET imaging is beyond the scope of this opinion, there are a few relevant to the field of sarcoidosis that warrant brief discussion. Fluorodeoxyglucose (FDG) and gallium are two such radiotracers, which have different target proteins. Macrophages and CD4 T-lymphocytes express facilitative glucose transporters on the cell membrane that allow substrates, such as FDG to enter the cells that contribute to the granulomatous inflammation of sarcoidosis [5]. Review of 13 studies that utilized FDG-PET or FDG-PET/CT in biopsy-proven sarcoidosis demonstrated a sensitivity that ranged from 89 to 100% for detecting active inflammation from sarcoidosis [6]. The second radiotracer, gallium, has multiple isotopes. In a prospective observational study of 39 patients with a diagnosis of sarcoidosis, PET with 68Ga identified active disease in 92% of symptomatic but only 16% of asymptomatic patients [7]. To complete imaging, gallium must be injected 48–72 h prior to image acquisition, which is inconvenient for patients and requires greater exposure to radiation. Additionally, the interobserver variability during interpretation leads to varied sensitivity (14–90%) and specificity depending on the imaging findings [8,9]. Although clinicians do not often choose a certain radiotracer, it is worth mentioning that FDG-PET has been shown to be superior at detecting both pulmonary and extrapulmonary activity of sarcoidosis [10]. Clinicians should appreciate that based on expert opinion, the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) endorse FDG PET/CT as a major indication for the diagnosis of sarcoidosis [11].

The most important use of PET in sarcoidosis is for management of cardiac disease. A major barrier for PET/CT to be effective in identifying disease is that normal myocardium takes up FDG as well. The SNMMI recommends high-fat (>35 g) and low-carbohydrate (<3 g) meals the day before the study with fasting for 4–12 h prior to PET/CT to achieve myocardial suppression of FDG uptake [12]. A 24 h diet restriction has shown mixed results with anywhere from 24.5 to 41.7% of individuals having an indeterminate PET/CT result [13,14▪▪]. When a high-fat, high-protein, and low-carbohydrate diet was extended to 72 h prior to the PET/CT scan, the indeterminate rate was 3.6% [15]. A ketogenic diet for 72 h combined with a 3-day overnight fast prior to PET/CT resulted in more complete myocardial suppression, less indeterminate scans, and higher agreement between PET/CT reviewers [14▪▪]. Intravenous lipid emulsion (100 ml) 3 h prior to PET/CT led to higher rates of complete myocardial suppression of FDG uptake as compared with controls [16▪▪]. The combination of intravenous heparin (50 IU/kg), low-carbohydrate diet, and 12-h fast demonstrated a higher rate of complete myocardial suppression compared with the same diet combination with lower doses of intravenous heparin (15 IU/kg) [17▪▪]. Although myocardial suppression is followed to ensure high yield of PET for cardiac sarcoidosis, the exact protocol varies without one universal standard.

ROLE OF PET IN THE DETECTION OF CARDIAC SARCOIDOSIS

Detection and management of cardiac sarcoidosis, a high-risk phenotype of sarcoidosis, remains enigmatic. Advanced cardiac imaging, such as PET and cardiac magnetic resonance (CMR), has a major role in the management of cardiac sarcoidosis [3]. Although sarcoidosis can affect any component of the cardiac system, FDG uptake can localize the inflammation to chambers of the heart. Pathologic uptake of FDG has been shown to occur in the left ventricle (LV) in approximately 24% of individuals undergoing PET/CT for concern of cardiac sarcoidosis [18▪▪]. The basal region is the most commonly involved area (91%), followed by the middle region (35.8%) and the apical region (11.9%) of the LV [19▪▪] (Fig. 1). The rate of abnormal metabolic activity in the right ventricle is not as clearly described but was noted in 9% individuals who underwent PET/CT [18▪▪]. Right ventricular disease and biatrial disease activity appears to be more common in individuals being evaluated for cardiac sarcoidosis as compared with those without a known history of sarcoidosis [20].

FIGURE 1

Axial and coronal views of PET scan in patient with cardiac sarcoidosis. Methods: this is an original PET image from the authors’. Results: panel a shows disease activity in the left apical (SUV of 22.6) and septum (SUV of 21.6). Panel b shows a reduction in SUV after treatment (SUV 4.2 and 5.7 respectively). Panel c shows apical and septal disease in the coronal view.

Finding an association between abnormal PET and prognosis may allow clinicians to alter treatment prior to the onset of major adverse cardiac events. Metabolic abnormalities on PET had an association with the adverse events of death and ventricular tachycardia. The associations were strongest when the FDG uptake was paired with a perfusion abnormality by rubidium perfusion but focal right ventricular uptake was independently associated with death or ventricular tachycardia [21]. To further support the observation that the location of FDG uptake may provide clues to which individuals are prone to adverse events, a review of 137 patients undergoing PET/CT for concern for cardiac sarcoidosis, demonstrated that right ventricular abnormality on PET/CT was associated with a significantly higher rate of cardiovascular events whereas pathologic LV FDG uptake was not [18▪▪].

Quantitative analysis of standardized uptake values (SUV) act as an indicator of disease activity but EANM/SNMMI guidelines state that SUV has not been validated in cardiac sarcoidosis [11]. Although SUV has not been vigorously studied, a threshold of 4.0 has been shown to have a sensitivity of 97.3% and a specificity of 83.6% [22]. SUV may be helpful in not only diagnosing cardiac sarcoidosis but also predicting, which patients are at risk of developing cardiac complications from sarcoidosis. In a review of 67 patients undergoing PET/CT, visually identified diseased segments had a maximum SUV (SUVmax) of 5.4 and a mean SUV of 4.9. SUVmax, mean SUV, and LV ejection fraction on gated rest PET perfusion scan were shown to be associated with the number of cardiac events (ventricular tachycardia, automatic implantable cardioverter-defibrillator placement, complete heart block, pacemaker placement, atrial fibrillation, and New York Heart Association class III/IV heart failure, cardiac-related hospitalization) to occur after performance of the scan [19▪▪]. This is supported by a recent study that showed patients who developed a reduced LV ejection fraction, ventricular tachycardia or experienced death had a statistically significant higher SUVmax [18▪▪]. Overall, the role of PET is promising for management and prognostication of cardiac sarcoidosis and further studies will hopefully improve the evidence base.

Combining PET with cardiac magnetic resonance

A systematic review investigated the role of PET or PET/CT in the diagnosis of cardiac sarcoidosis . After evaluating 17 studies, a pooled sensitivity and specificity of 0.84 and 0.83 was noted [23]. It remains that PET is an imperfect tool for the detection of cardiac sarcoidosis . Evaluation of 118 consecutive patients referred for PET/CT with rubidium perfusion scan because of concern for cardiac sarcoidosis demonstrated that 60% of patients had abnormal imaging findings [21]. By combining PET with CMR, it may be possible to increase the diagnostic yield. The role of combined PET after CMR was evaluated in 107 consecutive patients referred for evaluation of known or suspected cardiac sarcoidosis. Fifty three percent of patients were found to have probable or highly probable cardiac sarcoidosis by CMR (>50% likelihood of having cardiac sarcoidosis). When PET was integrated with CMR, 32 (29.9%) of participants were reclassified to a higher likelihood classification. Twelve patients were reclassified as highly probable cardiac sarcoidosis (>90% likelihood), five of which experienced adverse events on follow-up evaluation [24]. Whenever CMR and PET abnormalities are both present, mortality and adverse events were significantly increased [25]. Clinicians must exercise caution when comparing PET and CMR findings as the two are not always consistent. Only 11% of patients were found to have concordant positive findings consistent with cardiac sarcoidosis on both CMR and PET [26]. PET and CMR may provide important different information in these patients. Abnormal enhancement on CMR could indicate inflammation or scarring whereas abnormal PET uptake is indicative of inflammatory activity. Whenever combined, this information can be useful in the management of patients with cardiac sarcoidosis (anti-inflammatory therapy, device placement, etc.).

ROLE OF PET IN ASSESSING PULMONARY SARCOIDOSIS

Although chest radiograph is the first imaging test used for the evaluation of sarcoidosis, staging by the Scadding criteria is subjective and does not correlate to activity on PET/CT [27]. A more detailed imaging technique is high-resolution CT (HRCT) of the chest. Parenchymal consolidations, lymphadenopathy, intraparenchymal nodules, septal and nonseptal lines, and pleural thickening on HRCT have been found to be associated with increased FDG uptake [28] (Fig. 2). Most individuals with fibrosis had persistent abnormalities on PET beyond the expected uptake of FDG in fibrotic areas that is because of increased glucose metabolism of fibroblasts. Despite this finding, a threshold SUV that distinguishes active disease from fibrosis is yet to be determined to the authors’ knowledge. Few studies have compared the value of HRCT versus PET/CT for the diagnosis of sarcoidosis. Although HRCT and PET/CT can detect abnormalities at similar rates, concordant findings for disease activity were present in only 46% of reviewed imaging [29]. The benefit of PET over HRCT is the ability of PET to identify ongoing inflammation from ‘burnt-out’ sarcoidosis and can assist in management planning.

FIGURE 2

Pulmonary parenchymal changes because of sarcoidosis on computed tomography and corresponding PET findings. Methods: this is an original PET image from the authors. Results: the top image was obtained from computed tomography and shows parenchymal architectural changes while the bottom image shows increase FDG uptake by PET in the corresponding location.

ROLE OF PET IN EXTRATHORACIC SARCOIDOSIS

Although PET has been primarily used to identify cardiac sarcoidosis , it is a whole-body imaging technique and can identify other organ involvement in sarcoidosis (Fig. 3). The role of PET in the diagnosis of extrathoracic sarcoidosis is described by small retrospective evaluations, case series, and case reports. Of the 165 PET/CT scans that were negative for cardiac sarcoidosis, 34% were found to have extrathoracic disease. The extrathoracic lesions were in the bone (9%), liver (12%), spleen (11%), extrathoracic lymph nodes (21%), and cutaneous locations (3%) [30]. These findings are incidental but are important for assessment of disease burden, correlation of symptoms, signs, and laboratory abnormalities for individualized management of the patient.

FIGURE 3

FDG-PET findings in multisystem sarcoidosis. Methods: this is an original PET image from the authors. Results: the image on the left demonstrated FDG uptake in the heart while the image on the right reveals multisystem disease involving the liver, spleen, right acetabular bone, and lymph nodes in the low cervical, supraclavicular, mediastinal, and hilar regions. Both images are from the same individual at different rime intervals of the disease course.

CORRELATION OF PET WITH BIOMARKERS

Ideally, there would exist a single serological, physiological or imaging marker, which has sufficient sensitivity and specificity for diagnosis, prognosis, severity, and medication response. However, the exact pathophysiology of sarcoidosis has been elusive with no single pathognomonic finding that can pinpoint the diagnosis or prognosis. Nevertheless, serological and imaging findings are correlated, which suggest that measuring various serological biomarkers can complement PET [31]. A prospective study, which enrolled 30 patients with untreated sarcoidosis measured various biomarkers including soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), ACE, and urine calcium in addition to splenic FDG uptake on PET and found that there was a significant linear correlation between sIL-2R and SUVmax on PET [32]. It has also been shown that a reduction in absolute peripheral CD4+ T-lymphocyte count is associated with increased PET activity and possibly serves as a proxy for inflammatory activity [33]. A less commonly known laboratory marker, serum chitotriosidase, was found to be significantly correlated with PET activity whereas no correlation was found with ACE [34].

Being able to correlate PET results with data from pulmonary function test (PFT) could allow clinicians to monitor progression of disease. PFT results do not allow clinicians to differentiate between irreversible parenchymal damage or reversible inflammation. Multiple measurements are often needed to assess trends to ensure that declines are related to disease activity rather than changes in technique or effort. Individuals with parenchymal lung disease on PET will likely have a decline in gas exchange if the disease is not treated. And intuitively, when individuals with parenchymal disease receive therapy, vital capacity, forced expiratory volume in 1 s (FEV1), and the diffusion capacity of carbon monoxide (DLCO) improve significantly [35]. In patients undergoing treatment with infliximab, the change in the SUVmax after starting therapy has been shown to correlate with the change in forced vital capacity (FVC) and FEV1 but not with DLCO [36].

Additional studies are needed to provide evidence on the utility of biomarkers before performing or supplementing PET to determine the impact of biomarkers on the management of sarcoidosis.

ROLE OF PET IN TREATMENT DECISIONS

Determining when and how to treat a patient with sarcoidosis is challenging and depends on a combination of impairment of patient's quality of life and the potential for organ damage. PET may potentially be used to initiate treatment, monitor response, and modify treatment (Fig. 4). Positive findings on PET/CT have been shown to lead to increasing doses of corticosteroids and the initiation of methotrexate [37]. SUVmax has been shown to decrease once therapy is enacted, which also coincided with statistically significant improvement in self-reported symptoms [38]. Findings observed on PET have long-term implications, as the treatment for sarcoidosis involves medications, which can cause immunosuppression, metabolic, and other side effects. Tailoring doses to the appropriate level allow for effective treatment while minimizing these unnecessary consequences. A subset of patients who have reduced FDG uptake on follow-up PET can have immunosuppression reduced or even discontinued [39].

FIGURE 4

Consecutive FDG-PET scans in patient with multisystem sarcoidosis. Methods: this is an original PET image from the authors’. Results: this figure shows three consecutive FDG-PET performed in a patient with progressively more aggressive therapy for sarcoidosis.

Pulmonary fibrosis is an independent predictor of mortality in patients with sarcoidosis [40▪▪]. In select patients, treatment of pulmonary disease because of sarcoidosis can lead to an improvement in lung function [41]. Pulmonary fibrosis, the result of persistent inflammation from sarcoidosis, represents inactive tissue but there can be co-existent active inflammatory activity in these area [27,28]. This is extremely useful in cases of advanced pulmonary sarcoidosis where identification of inflammatory activity leads to alteration of management (and possibly prognosis by preventing further fibrosis from ongoing inflammation) [28].

Data on the appropriate time interval for follow-up assessment and the role of PET-guided therapy is scarce. This latter is of particular importance in cardiac sarcoidosis , for which PET is the major method of assessing treatment response [42].

LIMITATIONS AND FUTURE DIRECTIONS

Although PET has a satisfactory sensitivity and specificity for identifying inflammation because of sarcoidosis, the current state of the literature is composed mostly of retrospective investigations. Prospective trials are needed to strengthen the role of PET in management of sarcoidosis. These trials should investigate a connection between PET findings and practical clinical outcomes. These studies have the potential to set a standard for preparation and interpretation of PET as well which is currently lacking. The importance of abnormal PET results in context of an asymptomatic patient needs more evidence base to support or withhold treatment. These results would make further studies, collaboration, and patient management more efficient.

CONCLUSION

At present, the primary role of PET is to diagnose cardiac sarcoidosis but PET may potentially be used to identify multisystem disease. PET can provide clinicians with valuable information regarding prognosis of cardiac sarcoidosis. With more research, PET may be utilized to monitor therapy efficacy. More prospective trials are necessary to determine how to optimize and when to apply PET.

Acknowledgements

The acknowledgements are limited to the three authors of this opinion.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.