In this prospective study, FLT-PET demonstrated excellent imaging and diagnostic properties for the evaluation of extra-cardiac sarcoidosis, as well as CS. FLT-PET was able to detect multiple NS lesions in a single subject with known neural involvement.
Limitations inherent in cardiac FDG-PET imaging are well-known and include extensive patient preparation, variable success in suppression of myocardial activity, and the existence of normal patterns of myocardial uptake complicating the interpretation of studies (10). In particular, interpretation of the various cardiac uptake patterns is associated with only moderate inter-observer agreement (17). Due to high, non-suppressible physiological uptake seen in the central nervous system (CNS), FDG-PET plays very little role in the evaluation of NS, with the extant literature limited to case reports. Because of these limitations, there is a need for a radiotracer which can accurately assess not only the lung parenchyma and lymph nodes, but also the myocardium and CNS, without the need for extensive patient preparation.
FLT offers multiple advantages, especially for the assessment of CS and NS. In particular, lack of physiological myocardial uptake obviates the need for extensive patient preparation resulting in increased patient convenience, and decreased risk of non-diagnostic studies due to patient non-compliance with pre-imaging preparation instructions. Unlike FDG, there are no known normal variants demonstrating non-pathological myocardial FLT uptake, simplifying cardiac interpretation while lowering the risk of false-positive studies. In particular, our subject with a normal variant (i.e. lateral wall FDG uptake) had an unremarkable cardiac FLT study. In our subject with NS, both FLT and FDG were able to detect paraspinal lesions; however, only FLT adequately demonstrated intracalvarial disease, due to a lack of background cerebral uptake. The high concordance in the distribution of lesions seen on FLT and FDG at key sites (i.e. heart, CNS, lung parenchyma), as well as for the overall number of organs involved, suggests a comparable performance to FDG disease staging. Furthermore, FLT effectively identified small pathological lymph nodes which could be used to identify active sites of disease for diagnostic biopsy. Our study was not designed to determine the utility of FLT lung uptake as a therapeutic target; however, one would expect that, in order to duplicate the success of FDG in this respect, there should at least be good concordance between FLT and FDG for the assessment of parenchyma involvement, which was present in our results. Additional studies will be needed to assess the effectiveness of FLT-PET in the assessment of therapeutic response.
Although FLT demonstrates a lower degree of uptake (SUV) in sarcoidosis lesions when compared to FDG, the difference was not clinically significant with lesions demonstrating similar signal to background with both tracers. After correction for background activity (i.e. blood pool) the difference in SUVs was not statistically significant. Linear regression analysis revealed a relatively low degree of correlation between FDG and FLT uptake compatible with our previously reported results (12). This can be attributed to the fact that the degree of FDG uptake is non-specific and reflects all underlying metabolic processes while FLT uptake is specific to proliferative activity.
FLT activity is expected to represent granuloma burden while FDG reflects general inflammatory activity. Differences in uptake mechanisms between FLT and FDG could be useful for disease monitoring and therapy assessment. In particular, we speculate that the specificity of the uptake mechanism of FLT may be particularly well-suited for monitoring response to therapy; however, additional studies are needed.
It is unclear why a single subject (#10) showed discordant myocardial findings (positive on FDG, negative on FLT) while another subject (#8) showed discordant whole-body FLT and FDG findings (positive on FLT, negative on FDG). In both cases, these subjects were undergoing treatment at the time of imaging. It may be that the discordance was related to treatment effects. Also it should be noted that the imaging findings in both cases were subtle and the discordances might be attributable to limited sensitivity (i.e. false-negative) and/or specificity (i.e. false-positive) for either FLT or FDG.
Our results can be compared to those of Norikane et al. (11) who conducted a retrospective study involving 20 subjects with newly diagnosed cardiac sarcoidosis and compared FLT and FDG-PET findings. They found that both FLT and FDG had high accuracy for cardiac and extra-cardiac thoracic sarcoidosis. There are, however, several important differences between our studies. Our study was prospective and used the HRS criteria as gold standard, compared to the JMHW criteria used by Norikane et al. Furthermore, subjects undergoing cardiac evaluation in the Norikane study had a high rate of inconclusive FDG studies (4/20) while all of our subjects’ studies were diagnostic. Also, Norikane limited their imaging to the thorax while we acquired near whole-body images, which enabled us to compare findings in extra-thoracic sarcoidosis (including intracalvarial NS). Importantly, the work by Norikane et al. did not incorporate cardiac perfusion imaging in their analysis – we have previously shown significant associations between the findings on FLT-PET and perfusion imaging (12). Finally, none of their subjects had evidence of NS.
Some limitations of this study should be acknowledged. Our sample size was small, and lack of negative controls prevented us from calculating the accuracy for whole-body sarcoidosis. In order to remedy this, a larger prospective study is underway. In addition, all subjects were referred for suspicion of CS. This subgroup of subjects may not be representative of typical subjects with sarcoidosis and may have influenced the distribution of sarcoidosis lesions we observed in our study. Finally, there was only a single subject with NS, limiting our assessment of the utility of FLT-PET for neural involvement.
In summary, FLT-PET has the ability to accurately detect sarcoidosis lesions, including cardiac and CNS involvement, without the need for extensive patient preparation. Follow-up studies are ongoing in order to confirm these findings.