Visual Abstract
Abstract
Erdheim–Chester disease (ECD) involves multiple organs and tissues and has diverse manifestations, which makes it difficult to distinguish lesions caused by ECD from those caused by other diseases. Variable degrees of fibrosis are present in ECD. Therefore, we conducted a prospective cohort study to explore the ability of 68Ga fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT to detect lesions in ECD patients. Methods: Fourteen patients diagnosed with ECD, as confirmed by histology, were included in this study. For every patient, 68Ga-FAPI PET/CT and 18F-FDG PET/CT were conducted within 1 wk. The positive rate and SUVmax of the lesions in the involved organs were compared between the examinations. Results: The most commonly involved organs were bone (100%), heart (57.1%), lung (57.1%), kidney (42.9%), and peritoneum or omentum (35.7%); other common manifestations were intracranial infiltration (50%) and cutaneous infiltration (35.7%). 68Ga-FAPI PET/CT detected 64 of 67 lesions in 14 patients, whereas 18F-FDG PET/CT detected 51 of 67 lesions (P = 0.004). The SUVmax for 68Ga-FAPI PET/CT was significantly higher than the SUVmax for 18F-FDG PET/CT of the heart (4.9 ± 2.4 vs. 2.8 ± 1.2, respectively; P = 0.050), lung or pleura (6.8 ± 4.9 vs. 3.1 ± 1.3, respectively; P = 0.025), peritoneum or omentum (5.7 ± 3.6 vs. 2.8 ± 1.7, respectively; P = 0.032), and kidney or perinephric infiltration (4.9 ± 1.2 vs. 2.9 ± 1.1, respectively; P = 0.009). Conclusion: The detectivity of 68Ga-FAPI PET/CT is superior to that of 18F-FDG PET/CT. Moreover, 68Ga-FAPI PET/CT has a better image contrast and higher SUVmax for lesions in multiple organs including the heart, lungs, peritoneum, and kidneys. 68Ga-FAPI PET/CT is a promising tool to assess pathologic features and disease extent in ECD patients.
Erdheim–Chester disease (ECD) is a type of histiocytosis that involves multiple organs and has diverse manifestations. The incidence of ECD is relatively low, with approximately 1,000 cases reported in the literature. The occurrence of ECD is related to the mutation of the mitogen-activated protein kinase pathway and BRAF-V600E (1–3), and agents targeting the BRAF-V600 mutation are approved for the treatment of ECD. The mutation of certain genes results in the dysfunction of histiocytes, which then produce profibrotic and inflammatory chemokines (4). Histopathology of ECD shows variable degrees of fibrosis and inflammatory cell infiltration in most cases.
As clinical manifestations and disease severity differ among patients depending on the location and extent of lesions, it is difficult to distinguish lesions caused by ECD from lesions caused by other diseases with similar manifestations. Meanwhile, the outcome of ECD patients is significantly affected by the extent of the disease; therefore, it is important to identify the involved organs. 18F-FDG PET/CT may help with the diagnosis and is recommended for use in all patients affected by ECD to evaluate disease extent and severity (5). Apart from performing a whole-body scan in 1 examination, 18F-FDG PET/CT has the advantage that it can collect metabolic and anatomic information at the same time, so it is more suitable than anatomic imaging in the evaluation of ECD patients. Previous studies have demonstrated the value of 18F-FDG PET/CT in assessing patients with ECD (6–9). Kirchner et al. used 18F-FDG PET/CT as well as anatomic imaging to evaluate ECD patients and found that 18F-FDG PET/CT was better at identifying disease sites and that anatomic imaging provided better anatomic details (6). Young et al. evaluated 18F-FDG PET/CT in ECD patients, concluding that 18F-FDG PET/CT could help with the diagnosis and treatment of ECD patients (7). Several clinical trials have used 18F-FDG PET/CT to assess baseline conditions and the treatment response of patients with ECD (8,9).
The fibroblast activation protein inhibitor (FAPI) is a newly introduced agent in molecular imaging that targets the fibroblast activation protein. The fibroblast activation protein is expressed in fibrosis, atherosclerotic plaques, rheumatoid arthritis, ischemic heart tissue, and several solid tumors (10–12). Because fibrosis is a feature of ECD and because chemokines involved in fibrosis are increased in ECD patients (13), 68Ga-FAPI PET/CT may play an important role in the evaluation of ECD. Only 1 case report has depicted the distribution of 68Ga-FAPI in an ECD patient, and that case report demonstrated promising results (14). In this study, we describe 68Ga-FAPI PET/CT findings in a prospectively enrolled ECD cohort. Moreover, we compare the results between 68Ga-FAPI PET/CT and 18F-FDG PET/CT, which is widely recognized in ECD evaluation, to determine the utility of 68Ga-FAPI PET/CT.
MATERIALS AND METHODS
Study Design and Patient Population
This was a prospective observational cohort study approved by the ethics committee of Peking Union Medical College Hospital. Written consent was obtained for each patient. Patients diagnosed with ECD between December 2019 and May 2021 were considered for inclusion in this study. The inclusion criteria were patients who were diagnosed with ECD by pathology and who consented to be included in this study. Patients were excluded if they were unable to finish the examinations or were pregnant or breastfeeding. Included patients were referred to the department of nuclear medicine in our hospital to undergo 18F-FDG PET/CT and 68Ga-FAPI PET/CT, which were conducted within 1 wk for the same patient.
Image Acquisition
FAPI was labeled with 68Ga manually before injection. First, Ga3+ was obtained through a 68Ge/68Ga generator, and the pH of the solution was adjusted between 3.5 and 4.0 for further reaction. Second, FAPI-04 was added to the solution with Ga3+, which was then heated to 100°C for 10 min. After that, the mixture was purified through a Sep-Pak C18 Plus Light cartridge (Waters Corp.) to obtain the final 68Ga product, which was filtered through a 0.22-μm Millex-LG filter (EMD Millipore) before injection. Patients waited for 60 min for radiotracer uptake before the scan.
18F was generated through an 11-MeV cyclotron (CTI RDS 111; Siemens), and FDG was labeled with 18F in an automated process to synthesize 18F-FDG. Patients fasted for more than 6 h before injection, and blood glucose was monitored to guarantee the quality of the images. Then 18F-FDG was injected at a dose of 5.55 MBq/kg, after which patients waited 60 min for uptake.
The images were acquired on PET/CT scanners (Polestar m660 [SinoUnion] or Biograph 64 TruePoint TrueV [Siemens]) after a stable distribution of radiotracers. First, a topogram was obtained to determine the scan range, which was set between the top of the skull and the feet. Then low-dose CT was performed for each patient. The CT images were used to provide anatomic information as well as attenuation correction. Next, the PET images were acquired at a speed of 2 min/bed position. Finally, the images were reconstructed through an ordered-subset expectation maximization, which was set to 8 subsets, 2 iterations, a gaussian filter of 5 mm in full width at half maximum, and a 168 × 168 image size for the Siemens Biograph 64 and 10 subsets, 2 iterations, a gaussian filter of 4 mm in full width at half maximum, and a 192 × 192 image size for the SinoUnion Polestar.
Image Measurement
The acquired PET/CT images were transferred to Medical Image Merge (MIM Software Inc.) for further evaluation. Two experienced nuclear medicine physicians evaluated the PET/CT images to determine the nature of the lesions, and any disagreements were resolved by consensus. Positive lesions were defined by radioactive uptake higher than that in surrounding or contralateral normal tissues. Regions of interest were created for each lesion to obtain the SUVmax of the lesions. For lesions with negative uptake, regions of interest were also created on the basis of localization of other radiologic examinations. If there was more than 1 lesion in a single organ, only the highest SUVmax was recorded.
Statistical Analysis
Qualitative data were presented using frequencies and percentages. Continuous data were displayed as means ± SD if they were normal; otherwise, they would be presented as medians and quartiles. The McNemar test was used to compare the detection rate of the lesions between 18F-FDG PET/CT and 68Ga-FAPI PET/CT. A paired Student t test was used to examine the difference in SUVmax between 18F-FDG PET/CT images and 68Ga-FAPI PET/CT images. P values of 0.05 or lower were considered to be significant. We used SPSS, version 25 (SPSS Inc.), for statistical analyses.
RESULTS
Fourteen patients with a diagnosis of ECD, as confirmed by pathology, were included in this study, including 4 men (mean age, 50.0 ± 12.1 y; range, 33–60 y) and 10 women (mean age, 48.5 ± 10.3 y; range, 29–66 y). The characteristics of the 14 ECD patients are summarized in Table 1. Among the 14 patients, 4 of them were newly diagnosed and the other 10 had received previous treatment with interferon-α or a BRAF inhibitor.
Characteristics of ECD Patients
First, we analyzed the involvement of organs. The most commonly involved organs were bone (14/14 patients, 100%), heart (including the pericardium, the right atrial mass, and the periaortic sheathing [8/14 patients, 57.1%]), lung or pleura (8/14 patients, 57.1%), kidney (with or without perinephric infiltration; 6/14 patients, 42.9%), and peritoneum or omentum (5/14 patients, 35.7%); other common processes included intracranial infiltration (7/14 patients, 50%) and cutaneous infiltration (5/14 patients, 35.7%). Other tissues included the maxillary sinus (4/14 patients, 28.6%), perithoracoabdominal aortic sheathing (3/14 patients, 21.4%), orbital mass (3/14 patients, 21.4%), and retroperitoneum (2/14 patients, 14.3%). Moreover, adrenal glands and the pancreas were involved in 1 patient. In 9 patients, 68Ga-FAPI PET/CT discovered more lesions than 18F-FDG PET/CT. The detection rates of 18F-FDG PET/CT and 68Ga-FAPI PET/CT are presented in Table 2. 68Ga-FAPI PET/CT detected 64 of 67 lesions in 14 patients, whereas 18F-FDG PET/CT detected 51 of 67 lesions, indicating that a significant difference existed (P = 0.004). For most organs, 68Ga-FAPI PET/CT revealed more lesions than 18F-FDG PET/CT.
Detectability of 68Ga-FAPI PET/CT and 18F-FDG PET/CT of ECD
Second, we compared the SUVmax of each lesion with 18F-FDG PET/CT and 68Ga-FAPI PET/CT, and the results are displayed in Table 3. The SUVmax on 68Ga-FAPI PET/CT was significantly higher than the SUVmax on 18F-FDG PET/CT for the heart (4.9 ± 2.4 vs. 2.8 ± 1.2, respectively; P = 0.050), lung or pleura (6.8 ± 4.9 vs. 3.1 ± 1.3, respectively; P = 0.025), peritoneum or omentum (5.7 ± 3.6 vs. 2.8 ± 1.7, respectively; P = 0.032), and kidney or perinephric infiltration (4.9 ± 1.2 vs. 2.9 ± 1.1, respectively; P = 0.009). For other organs and tissues, the means of SUVmax on 68Ga-FAPI PET/CT were higher than those on 18F-FDG PET/CT for bones, perithoracoabdominal aortic sheathing, retroperitoneum, cutaneous infiltration, and maxillary sinus, whereas the means of SUVmax were lower on 68Ga-FAPI PET/CT for intracranial infiltration and orbital mass. However, no significant differences were observed for these organs. Maximum-intensity projections of 68Ga-FAPI PET/CT and 18F-FDG PET/CT are displayed in Figure 1.
SUVmax of ECD Involvement on 68Ga-FAPI PET/CT and 18F-FDG PET/CT
Maximum-intensity projections of 68Ga-FAPI PET/CT and 18F-FDG PET/CT in 4 patients. Contrast of lesions is higher in 68Ga-FAPI PET/CT than in 18F-FDG PET/CT. 68Ga-FAPI PET/CT detected lesions in bone (patients 5 and 11), heart (patient 2), lungs or pleura (patient 2), peritoneum or omentum (patient 2), intracranial infiltration (patient 4), and kidneys (patient 5), which were not displayed on 18F-FDG PET/CT.
Because some lesions were negative on 18F-FDG PET/CT or 68Ga-FAPI PET/CT and other imaging methods were needed to find the corresponding position of the negative lesions, the selection of the regions of interest may not be accurate because of the mismatch caused by movement of these lesions. Therefore, we repeated the comparison of SUVmax between 18F-FDG PET/CT images and 68Ga-FAPI PET/CT images after excluding lesions with negative 18F-FDG or 68Ga-FAPI uptake. The results are shown in Table 4. The SUVmax of lung or pleura on 68Ga-FAPI PET/CT was 7.9 ± 5.4, and the SUVmax on 18F-FDG PET/CT was 3.4 ± 1.3. Significant differences existed. Kidney or perinephric infiltration had an uptake on 68Ga-FAPI PET/CT (SUVmax, 5.0 ± 1.3) that was significantly higher than that on 18F-FDG PET/CT (SUVmax, 3.0 ± 1.2). For organs including bone, heart, peritoneum or omentum, or retroperitoneum; tissues such as perithoracoabdominal aortic sheathing, maxillary sinus, and orbital mass; and processes including cutaneous infiltration and intracranial infiltration, no significant differences were found between 18F-FDG PET/CT images and 68Ga-FAPI PET/CT images.
SUVmax of ECD Involvement on 68Ga-FAPI PET/CT and 18F-FDG PET/CT After Excluding Lesions with Negative 18F-FDG or 68Ga-FAPI Uptake
DISCUSSION
To the best of our knowledge, few previous studies have explored the use of 68Ga-FAPI PET/CT to evaluate patients with ECD. Due to the relatively low incidence of ECD, large cohort studies with large amounts of evidence are scarce, impeding further improvement in the diagnosis and treatment of ECD patients. According to the literature, the most frequent radiologic abnormalities of ECD patients are osteosclerosis, perinephric stranding, periaortic infiltration, lung parenchyma, pericardial thickening or effusion, retroperitoneal infiltration, and infiltration of the entire thoracoabdominal aorta (15,16). Our results accord with the literature.
ECD often involves multiple organs and systems, and the extent of disease will affect the clinical outcomes of patients. Arnaud et al. found that central nervous system involvement could predict death of ECD patients independently (17). Chazal et al. proved that ECD could result in chronic kidney disease or kidney failure even if patients were well treated (18). Azoulay et al. discovered that cardiac involvement in ECD patients was related to ECD-related clinical complications but not to a lower survival rate (19). Haroche et al. concluded that ECD-related orbital disease could lead to optic nerve signal abnormalities (20). These studies prove that determining the extent of ECD is meaningful in predicting the outcome of patients, indicating the significance of evaluating ECD accurately.
ECD is usually evaluated by conventional anatomic imaging methods such as CT and MRI. These examinations provide valuable information on the evaluation of the disease extent and treatment response. Compared with CT and MRI, PET/CT can obtain a whole-body scan at 1 scan and provide additional biochemical information. Several previous studies have investigated using 18F-FDG PET/CT to evaluate ECD (6,7,21–25), and results from these studies proved the significance of 18F-FDG PET/CT in diagnosis establishment, biopsy guidance, and treatment response evaluation. However, the quality of PET/CT is influenced by many factors, such as blood glucose and temperature. In addition, background uptake of 18F-FDG is high in several organs, which may disguise the presence of lesions if they locate around these organs.
Fibroblast activation protein is a kind of type II transmembrane serine protease that is expressed in abnormal fibroblasts in malignant and nonmalignant conditions (10,12). Previous literature reported an increased uptake of 68Ga-FAPI in diseases leading to fibrosis, including IgG4-related disease, liver cirrhosis, arthritis, tuberculosis, and various kinds of cancers (11,26–32). Because fibrosis is widely present in ECD (13), 68Ga-FAPI PET/CT may be a good imaging tool to evaluate ECD lesions. Our results showed that 68Ga-FAPI PET/CT had an excellent ability to display ECD lesions, and its detection rate is superior to that of 18F-FDG PET/CT. This result, which proves the feasibility of 68Ga-FAPI PET/CT, is promising and may provide more options for the evaluation of ECD patients.
Another advantage of 68Ga-FAPI PET/CT is high image contrast and low background activity due to the absence of the fibroblast activation protein in normal tissues. In contrast, normal uptake of 18F-FDG is present in many organs, and an elevation of 18F-FDG uptake could be caused by numerous physiologic and pathologic conditions. In our study, SUVmax on 68Ga-FAPI PET/CT was significantly higher than SUVmax on 18F-FDG PET/CT for heart, lung or pleura, peritoneum or omentum, and kidney or perinephric infiltration. This result demonstrates a higher contrast of lesions on 68Ga-FAPI PET/CT. In addition, the means of SUVmax on 68Ga-FAPI PET/CT were higher than those on 18F-FDG PET/CT for bones, perithoracoabdominal aortic sheathing, retroperitoneum, cutaneous infiltration, and maxillary sinus. Although no significance was reached for these organs between 68Ga-FAPI PET/CT and 18F-FDG PET/CT, this could be caused by a small sample size.
Previous literature reported that central nervous system and cardiac involvement indicate a worse outcome (17,19). Therefore, identifying lesions involving the heart and central nervous system is significant for optimizing treatment and predicting outcome. 18F-FDG uptake of myocardium varies among patients, whereas normal myocardium barely takes up 68Ga-FAPI, so 68Ga-FAPI PET/CT can contribute to identifying cardiac involvement in ECD patients. Regarding intracranial infiltration, a high background uptake of 18F-FDG in brain tissue could interfere with the observation of lesions. Although the SUVmax was higher on 18F-FDG PET/CT, the lesions were more obvious on 68Ga-FAPI PET/CT.
A promising application of 68Ga-FAPI PET/CT is its potential to reflect the histology of lesions. Inflammation and fibrosis are typical features of ECD and may cause organ damage. According to Ohara et al. (33), the pathologic features of different lesions are different even in the same patient, and a discrepancy of histology can influence radiologic images. 68Ga-FAPI PET/CT and 18F-FDG PET/CT are effective tools to evaluate the extent of fibrosis and inflammation, respectively. Therefore, we can speculate that the combination of 68Ga-FAPI PET/CT and 18F-FDG PET/CT may be used in areas such as disease progression assessment, treatment response evaluation, and outcome prediction.
This research has several limitations. First, because of the low incidence of ECD, it is difficult to recruit patients, causing a small sample size for this study. Although the results indicate differences between 18F-FDG PET/CT and 68Ga-FAPI PET/CT in multiple organs, a statistically significant result could not be reached in most cases. Further studies with a larger sample size are needed to verify the value of 68Ga-FAPI PET/CT. Moreover, this study includes not only newly diagnosed patients but also treated patients, and treatment may influence the tracer uptake. Further studies may be necessary to investigate the effect of treatment on 68Ga-FAPI PET/CT and 18F-FDG PET/CT for ECD patients, which reflects the value of these diagnostic tools on efficiency evaluation. In addition, just as a reconstruction method has an influence on image quality, a higher detection rate may be obtained in another reconstruction method. Finally, although the existence of ECD was confirmed for every included patient through pathology, we could not obtain the pathologic results for every suspected lesion.
CONCLUSION
In this study, we explored the use of 68Ga-FAPI PET/CT and 18F-FDG PET/CT for the evaluation of ECD patients. Our results showed that 68Ga-FAPI PET/CT can detect more lesions than 18F-FDG PET/CT. Moreover, 68Ga-FAPI PET/CT has a better image contrast and higher SUVmax for lesions in multiple organs, including the heart, lungs, peritoneum, and kidney. 68Ga-FAPI PET/CT is a promising tool to assess the extent of disease in ECD patients.
DISCLOSURE
This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (2022-I2M-JB-001). No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Is 68Ga-FAPI PET/CT valuable for the evaluation of ECD patients?
PERTINENT FINDINGS: This prospective observational cohort study revealed that 68Ga-FAPI PET/CT detects more lesions in ECD patients than does 18F-FDG PET/CT. 68Ga-FAPI PET/CT has a higher SUVmax for lesions in the heart, lungs, peritoneum, and kidneys.
IMPLICATIONS FOR PATIENT CARE: 68Ga-FAPI PET/CT is a promising tool to assess pathologic features and extent of disease in ECD patients.
Footnotes
Published online Jul. 20, 2023.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication March 7, 2023.
- Revision received April 27, 2023.
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