AL[18F]-NOTA-FAPI-46 and [18F]FDG PET/CT in Detecting Postoperative Recurrence and Metastasis of Papillary Thyroid Cancer: A Head-to-Head Comparative study

AL[18F]-NOTA-FAPI-46 and [18F]FDG PET/CT in Detecting Postoperative Recurrence and Metastasis of Papillary Thyroid Cancer: A Head-to-Head Comparative study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article AL[18F]-NOTA-FAPI-46 and [18F]FDG PET/CT in Detecting Postoperative Recurrence and Metastasis of Papillary Thyroid Cancer: A Head-to-Head Comparative study Taisong Wang, Rui Zhang, Na Sun, Lijuan Shen, Wenli Qiao, Qingqing Huang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8736306/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Postoperative monitoring of papillary thyroid cancer (PTC), especially in cases of biochemical recurrence or radioiodine-refractory disease, remains challenging. Although 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) is widely used, its sensitivity is suboptimal, particularly for lesions with low metabolic activity or small metastases. Fibroblast activation protein (FAP), expressed in the tumor stroma, has emerged as a promising target. This study aimed to compare the diagnostic efficacy of Al [¹⁸F]-NOTA-FAPI-46([¹⁸F]FAPI-46) and [¹⁸F]FDG PET/CT in detecting recurrence and metastasis in postoperative PTC patients. Results [¹⁸F]FAPI-46 PET/CT demonstrated significantly higher sensitivity (82.3% vs. 29.4%, P = 0.022) and accuracy (78.3% vs. 30.4%) than [¹⁸F]FDG PET/CT for detecting lymph node metastases, with fewer false-positive cases (2 vs. 4). However, [¹⁸F]FAPI-46 showed three false-positive bone lesions (SUVₘₐₓ: 7.7–7.9), likely due to benign fibroproliferative changes. In patients with metastasis, serum stimulated thyroglobulin (sTg) levels were significantly elevated (79.1 ± 51.1 ng/mL vs. 33.9 ± 36.5 ng/mL, P = 0.044), with an optimal diagnostic threshold of 25.9 ng/mL (AUC = 0.862). [¹⁸F]FAPI-46 PET/CT identified occult metastases in cases with elevated sTg and clarified false-positive [¹⁸F]FDG findings. Conclusions [¹⁸F]FAPI-46 PET/CT shows superior performance over [¹⁸F]FDG PET/CT in diagnosing lymph node metastases in postoperative PTC patients and effectively distinguishes metastatic from reactive lymph nodes. Caution is warranted for false-positive bone lesions, emphasizing the need for correlation with CT morphology. [¹⁸F]FAPI-46 [¹⁸F]FDG PET/CT Papillary thyroid cancer Recurrence Metastasis Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Papillary thyroid cancer (PTC) is the most common endocrine malignancy, and its incidence has been steadily increasing worldwide. While most patients have an excellent prognosis after total thyroidectomy followed by radioiodine therapy, postoperative monitoring for recurrence or metastasis is critical, particularly in intermediate to high-risk cases. Biochemical recurrence, characterized by elevated serum thyroglobulin (Tg) or anti-Tg antibody levels, poses a diagnostic challenge, as conventional imaging modalities, including neck ultrasound, computed tomography (CT)and diagnostic radioiodine whole-body scan (Rx-WBS), may fail to localize the disease[ 1 , 2 ]. According to current guidelines from the American Thyroid Association (ATA), 2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) is recommended in patients with suspected recurrence or metastasis when radioiodine imaging is negative[ 3 ]. However, the sensitivity of [¹⁸F]FDG PET/CT is suboptimal in certain scenarios, such as in the presence of low Tg levels, small metastatic deposits, or well-differentiated tumors with low metabolic activity. Reported false-negative rates range from 8% to 21.1%[ 4 ], underscoring the need for more accurate imaging techniques. In recent years, fibroblast activation protein (FAP), a type II transmembrane serine protease highly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma, has emerged as a promising target for oncologic imaging. FAP-specific inhibitors (FAPIs), particularly those labeled with gallium-68 (e.g., [⁶⁸Ga]FAPI-46), have demonstrated superior tumor-to-background ratios compared to [¹⁸F]FDG in various cancers, including thyroid cancer[ 5 – 7 ]. Studies have shown that [⁶⁸Ga]FAPI PET/CT outperforms [¹⁸F]FDG in detecting lymph node, pleural, and bone metastases in radioiodine-refractory differentiated thyroid cancer [ 8 , 9 ]. Although most clinical studies have used ⁶⁸Ga-labeled FAPI tracers, the use of fluorine-18 offers practical advantages, including a longer half-life (110 minutes) that facilitates centralized production and distribution, as well as potentially higher image resolution due to lower positron energy[ 10 ]. [¹⁸F]FAPI-04 PET/CT has been used in detection of recurrent lesions in differentiated thyroid cancer[ 11 ]. However, head-to-head comparisons between [¹⁸F]FAPI-46 and [¹⁸F]FDG PET/CT in postoperative PTC patients are lacking. This study aims to directly compare the diagnostic performance of [¹⁸F]FAPI-46 and [¹⁸F]FDG PET/CT in detecting postoperative recurrence and metastasis in PTC patients, using a composite reference standard including histopathology, imaging follow-up, and clinical outcome. The findings may help refine imaging strategies for metastasis and recurrence and pave the way for future theranostic applications of FAPI-targeted radionuclide therapy[ 12 – 14 ]. Methods Study design The study received approval from the Clinical Research Ethics Committee of Shanghai General Hospital, Shanghai Jiaotong University School of Medicine (2021 − 113) and was conducted in accordance with the 1964 Helsinki Declaration for ethical standards. Informed written consent was obtained from all of these enrolled patients. A prospective evaluation was carried out on 18 consecutive patients diagnosed with PTC referred to our clinic between September 2022 and June 2023 for postoperative 131 I therapy, guided by histopathological risk factors suggesting a potential increase in tumor aggressiveness. The inclusion criteria for patients were as follows: (1) posttotal thyroidectomy duration exceeding one month; (2) two-week low-iodine diet preparation, and discontinuation of levothyroxine tablets for three weeks resulting in a serum TSH level ≥ 30 mIU/L; (3) Patients underwent [ 18 F]FDG PET/CT and [ 18 F]FAPI-46 PET/CT within one week before treatment. The exclusion criteria for patients included inability or reluctance to provide informed consent, the presence of a secondary cancer or chronic inflammation, and pregnancy or lactation. PET/CT imaging protocols [ 18 F]FAPI-46 tracers were synthesized in the Department of Nuclear Medicine Shanghai General Hospital, Shanghai Jiaotong University School of Medicine. The synthesis process is as follows: A quantity of 2–10 GBq of [18F] fluoride, generated by a MINITRACE Cyclotron (GE, USA) in 2.5 mL of water was subsequently trapped on a preconditioned anion exchange cartridge (Waters Plus QMA Light cartridge, preconditioned with 5 mL of saline and 10 mL of water). The [18F] fluoride was then eluted with 0.3 mL of saline. For the labeling reaction, the eluate was mixed with AlCl3 (24 µL, 2 mM), Potassium hydrogen phthalate (65µL, 2 mM), NOTA-FAPI-46 (26 µL, 4 mM) and anhydrous MeCN (300 µL). The mixture was incubated at 95°C for 15 minutes. Upon cooling to ambient temperature, the reaction mixture was diluted with 5 mL of water and passed through a preconditioned C18 cartridge (Waters Oasis HLB Plus Light cartridge, preconditioned with 5 mL of ethanol and 10 mL of water) to remove unreacted [18F] fluoride. This cartridge was subsequently washed with 10 mL of water and dried with nitrogen gas. The radiolabeled product was then eluted using 1 mL of ethanol, followed by a 10 mL wash with 0.9% NaCl solution. The final eluate was filtered through a 0.22 µm sterile Millipore filter into a sterile vial. The final drug product solution was evaluated through a quality control. [ 18 F]FDG tracers were ordered from Shanghai Atomsun Pharmaceutical Co., Ltd. The PET scans, using two radio-labelled tracers, were applied with at least a 24-hour interval for each patient in our cohort. All patients underwent PET/CT imaging via a PET/CT system (uMI780, United Imaging Medical). For [ 18 F]FDG PET/CT, patients were asked to fast for 6 hours. Their blood glucose levels were measured to ensure that they were within the reference range (3.9–6.1 mmol/L). No special preparation is required for the [ 18 F]FAPI-46 PET/CT examination. IV doses of [ 18 F]FDG and [¹⁸F]FAPI-46 were 3.7 MBq/kg (0.1 mCi/kg). PET/CT scans were performed approximately 60 minutes after IV administration. The CT scan was performed and acquired according to the following parameters: tube voltage, 120 kV; current, 120 mA; layer thickness, 3.00 mm, layer spacing, 5 mm; pitch, 0.813. The PET scan was then performed in 3D acquisition mode on the same bed as the CT. PET/CT image analysis Two experienced nuclear medicine physicians (SN and SLJ, with over 5 and 10 years of experience, respectively) performed blinded evaluations and delineations of [ 18 F]FAPI-46 and [ 18 F]FDG PET/CT imaging. The evaluation included PET, CT, and fused whole-body images presented in the axial, coronal, and sagittal planes for detailed assessment. A semiquantitative analysis of tracer activity was performed to determine the maximal standardized uptake value (SUVmax) of both [ 18 F]FAPI-46 PET/CT and [ 18 F]FDG PET/CT via software provided by the United Imaging Medical. If the SUVmax value is lower than that of the mediastinal blood pool, it is recorded as not applicable(NA). Reference Standard Given the clinical context of this study, obtaining histopathological confirmation for all suspected lesions was not feasible due to a combination of technical and ethical considerations. Technical challenges included the small size or deep location of some lesions (e.g., subcentimeter lymph nodes or bone changes), which made percutaneous biopsy high-risk or non-diagnostic. Ethically, subjecting patients to invasive procedures for lesions with low pre-test probability or those located in high-risk anatomical areas was not justified, especially when alternative, non-invasive monitoring could provide sufficient diagnostic certainty. Therefore, we employed a composite reference standard, integrating all available clinical, imaging, and follow-up data to adjudicate the final status of each suspected lesion. The reference standard was constructed from the following elements, listed in order of priority: (1) Histopathological confirmation from surgery or biopsy (when available and clinically indicated). (2) Imaging follow-up over a period of at least 6 months. Lesions were monitored using a combination of high-resolution neck ultrasound, diagnostic or post-therapeutic ¹³¹I whole-body scan (Rx-WBS), and cross-sectional imaging (CT or MRI) as clinically appropriate. Lesions were classified as tumor-related (positive) if they demonstrated significant progression in size or number on serial imaging, or unequivocal regression in response to systemic therapy (including radioactive iodine therapy, radiotherapy, targeted therapy, or immunotherapy). Lesions were classified as benign (negative) if they remained stable or regressed spontaneously over the follow-up period without specific anti-tumor therapy, or if their imaging features were conclusively characteristic of a benign process (e.g., reactive lymphadenopathy, benign bone island). (3) Clinical course: and serial serum thyroglobulin (Tg) levels were also considered to support the imaging-based classification. Statistical analysis All statistical analyses were performed using SPSS software (version 25.0; IBM, Armonk, NY, USA). Continuous variables are presented as mean ± standard deviation (SD) if they followed a normal distribution, as assessed by the Shapiro-Wilk test; otherwise, they are presented as median with interquartile range (IQR). Categorical variables are summarized as frequencies and percentages. For comparisons between the metastasis and non-metastasis groups, independent-sample t-tests were used for normally distributed continuous variables. The diagnostic performance (sensitivity, specificity, accuracy) of [¹⁸F]FAPI-46 and [¹⁸F]FDG PET/CT for lymph node metastasis was evaluated against the composite reference standard. The McNemar test was employed to compare the diagnostic accuracy of the two imaging modalities. The maximal standardized uptake value (SUVₘₐₓ) of true-positive lymph nodes between tracers was compared using the paired t-test. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic efficacy of sTg level and [¹⁸F]FAPI-46 SUVₘₐₓ for identifying metastatic disease. The area under the ROC curve (AUC) was calculated, and the optimal cutoff value was determined by maximizing the Youden index. Corresponding 95% confidence intervals (CIs) for the AUC were reported. A two-tailed P value < 0.05 was considered statistically significant for all tests. Results All patient characteristics are summarized in Table 1 . Table 1 Characteristics of 18 patients. No age sex pTN sTg RSTR FDG FAPI 1 37 Male pT1bN1b 45.7 3 - + 2 43 female pT1bN1a 121 3 + + 3 32 male pT2N1b 167 3 - + 4 29 female pT1aN1a 33.2 3 - - 5 31 female pT3bN1b 55.9 3 + - 6 44 female pT1aN1a 1.6 2 - - 7 34 female pT1bN- 12.7 2 - - 8 21 female pT1bN1b 23.5 2 + - 9 41 male pT4aN1a 26.7 2 + + 10 46 male pT1aN1a 59.9 3 - + 11 37 male pT1aN1b 123 3 - + 12 31 male pT1bN1b 134 3 + + 13 44 female pT1aN1b 11.7 2 - - 14 28 female pT1aN1a 2.6 2 - - 15 38 female pT2N1a 24.8 2 - - 16 61 female pT4aN- 25.2 2 - - 17 31 male pT1bN1b 34.9 2 + - 18 37 female pT1bN1a 41.4 2 - - pTN: stage of pathology; sTg: Stimulated thyroglobulin; RSTR: Risk Stratification; FDG: [ 18 F]FDG PET/CT; FAPI: [ 18 F]FAPI-46 PET/CT; RSTA: Reference Standard. Diagnostic Value of [ 18 F]FDG and [ 18 F]FAPI-46 PET/ CT in Nodal and Bone Metastases [ 18 F]FDG PET/CT and [ 18 F]FAPI-46 PET/CT totally detected 23 suspected metastatic lymph nodes in 10 patients. Six suspected metastatic lymph nodes were confirmed by postoperative pathology, and the remaining 17 metastatic lymph nodes were examined on follow-up as the reference standard. Finally, 17 lymph nodes were confirmed to be metastatic, and 6 lymph nodes were reactive hyperplasia or inflammatory (Fig. 1 ). Details are summarized in Table 2 . The sensitivity of [ 18 F]FAPI-46 PET/CT in diagnosing lymph node metastasis was 82.3%, the specificity was 66.7%, and the accuracy was 78.3%. The sensitivity of [ 18 F]FDG PET/CT in diagnosing lymph node metastasis was 29.4%, the specificity was 33.3%, and the accuracy was 30.4%. [ 18 F]FAPI-46 PET/CT was more effective than [ 18 F]FDG PET/CT( P = 0.022). The SUVmax of [ 18 F]FDG and [ 18 F]FAPI-46 was significant difference (1.6 ± 2.6 vs 4.2 ± 3.2; P = 0.015) for true positive lymph nodes. Receiver operating curve analysis showed that the threshold of [ 18 F]FAPI-46 SUVmax for diagnosing lymph node metastasis was 2.3 (AUC = 0.765, sensitivity 88.2%, specificity 66.7%, 95%CI: 0.530–0.999) (Fig. 2 ). Table 2 Details of 23 suspected metastatic lymph nodes. n = 23 [ 18 F]FDG SUVmax [ 18 F]FAPI-46 SUVmax RSTA 1 NA NA + 2 3.6 NA + 3 18.4 NA - 4 8.1 NA - 5 NA 2.4 + 6 NA 2.5 + 7 2.5 5.9 + 8 2.5 6.7 + 9 NA 2.3 + 10 NA 2.3 + 11 NA 2.3 + 12 NA 2.2 + 13 7.6 2.7 + 14 8.2 3.9 + 15 2.3 12.1 + 16 NA 7.4 + 17 NA 5.2 + 18 NA 4.0 + 19 NA 9.2 + 20 NA 3.1 - 21 6.0 NA - 22 NA 4.5 - 23 6.9 NA - Among these 18 patients, no patients had bone metastasis. [ 18 F]FAPI-46 PET/CT showed three false positive bone lesions with an SUVmax ranging from 7.7–7.9 in two patients, which were negative in [ 18 F]FDG PET/CT (Fig. 3 ). These bone lesions often show annular hyperdense shadows, suggesting fibroproliferative lesions. False-Positive Lymph Nodes in [F]FDG PET/CT [ 18 F]FDG PET/CT had 4 false-positive lymph nodes in 3 patients. These patients showed no lymph node cancer metastasis based on reference standard. The average SUVmax of the 4 false-positive lymph nodes was 10.1. Two of these lymph nodes were visualized on [ 18 F]FAPI-46 PET/CT in one patient. The average SUVmax was 4.5, which was lower than [ 18 F]FDG PET/CT. The two lymph nodes showed reactive hyperplasia of lymph nodes by puncture biopsy. The diagnostic value of serum stimulated Tg level for metastasis of thyroid cancer after operation There was a significant difference in stimulated Tg level between the metastasis group and the non-metastasis group (P = 0.044), and the former was higher than the latter (79.1 ± 51.1VS33.9 ± 36.5). Receiver operating curve analysis showed that the threshold of serum stimulated Tg for diagnosing lymph node metastasis was 25.9ng/mL (AUC = 0.862, Youden index = 0.7, 95%CI: 0.679-1.000) (Fig. 4 ). Discussions This head-to-head comparative study demonstrates the superior diagnostic performance of [¹⁸F]FAPI-46 PET/CT over [¹⁸F]FDG PET/CT for detecting lymph node metastases in postoperative PTC patients. The significantly higher sensitivity (82.3% vs. 29.4%) and accuracy (78.3% vs. 30.4%) of [¹⁸F]FAPI-46 align with the known biology of FAP expression, which is highly upregulated (> 90%) in cancer-associated fibroblasts (CAFs) within the tumor stroma of epithelial cancers, including DTC[ 15 , 16 ]. Unlike [¹⁸F]FDG, which images glucose metabolism that can be variable and low in indolent or small-volume disease, [¹⁸F]FAPI-46 specifically targets the reactive stromal microenvironment. This mechanism likely enhances its ability to detect small metastatic deposits or residual tumor nests often embedded within postoperative fibrotic tissue. Notably, our study also found that the SUVmax of [¹⁸F]FAPI-46 in true-positive lymph nodes was significantly higher than that of [¹⁸F]FDG (4.0 ± 3.4 vs. 1.4 ± 2.7, P = 0.040), and ROC analysis identified an optimal diagnostic threshold of 2.3 (AUC = 0.745). This provides a preliminary basis for the quantitative interpretation of [¹⁸F]FAPI-46, although its optimal cutoff value requires validation in larger cohorts.[¹⁸F]FAPI-46 consistently provided superior lesion-to-background contrast, facilitating more confident localization, a finding consistent with prior studies using ⁶⁸Ga-labeled FAPI tracers in head and neck cancers[ 17 , 18 ]. The analysis of false-positive findings provides crucial clinical insights. [¹⁸F]FDG PET/CT produced four false-positive lymph nodes, attributable to postoperative inflammation or reactive hyperplasia—a well-known pitfall of metabolic imaging. In contrast, [¹⁸F]FAPI-46 showed only two such false positives, suggesting a potentially lower affinity for inflammatory processes, which could be a distinct diagnostic advantage. However, [¹⁸F]FAPI-46 demonstrated three false-positive bone lesions (SUVₘₐₓ 7.7–7.9) that were negative on [¹⁸F]FDG. Their annular, sclerotic appearance on CT is highly suggestive of benign fibroproliferative changes (e.g., bone islands or healed benign fractures), where FAP uptake has been documented in reactive fibroblasts [Wei et al., 2022]. This underscores that while [¹⁸F]FAPI-46 offers high contrast, its interpretation must be rigorously correlated with CT morphology to avoid misinterpretation. The lack of a significant SUVₘₐₓ difference between true-positive and false-positive lesions in our small cohort precludes defining a reliable diagnostic threshold based on uptake value alone. Serum stimulated thyroglobulin (sTg) measured prior to ablation showed significant predictive value. Metastatic patients had markedly higher sTg levels than non-metastatic patients (79.1 ± 51.1 ng/mL vs. 33.9 ± 36.5 ng/mL, P = 0.044). ROC analysis identified an optimal diagnostic threshold of 25.9 ng/mL (AUC = 0.862, Youden index = 0.7). Notably, all patients with positive [¹⁸F]FAPI-46 scans had sTg > 25.9 ng/mL, whereas the majority of scan-negative patients had values below this cutoff. This finding aligns with the spirit of the 2025 American Thyroid Association (ATA) guidelines, which emphasize the use of serum Tg as a stratification tool to guide imaging selection. This suggests that sTg could serve as a valuable stratification tool to identify patients most likely to benefit from [¹⁸F]FAPI-46 PET/CT, especially in the setting of negative conventional imaging but clinical suspicion of disease. For patients with elevated sTg and negative diagnostic ¹³¹I whole-body scans, [¹⁸F]FAPI-46 PET/CT proved effective in localizing occult disease. In our cohort, it identified [¹⁸F]FDG-negative metastases (e.g., Case 11) and correctly characterized intense [¹⁸F]FDG uptake as false-positive reactive nodes (e.g., Case 8). This precise localization directly impacts clinical management, guiding decisions regarding surgical re-intervention or the initiation of targeted therapies. Regarding imaging protocol, we performed scans at approximately 60 minutes post-injection, a standard time point for both tracers based on prior pharmacokinetic studies. While emerging data suggest that FAP-targeted tracers can achieve high tumor-to-background contrast as early as 20–30 minutes post-injection[ 19 , 20 ], potentially reducing patient time in the scanner. The dual-tracer (e.g., [ 68 Ga]FAPI-46 and [ 18 F]-FDG) combined scan in a single session, not only improves sensitivity but also avoids the repeated CT radiation exposure associated with separate scans[ 5 , 21 ]. These protocols were not evaluated in our study. Exploring earlier imaging time points for [¹⁸F]FAPI-46 represents a valuable direction for future research to further optimize patient convenience and departmental workflow. Limitations This pilot study has several limitations: (1) The small sample size (n = 18) and single-center design limit the statistical power and generalizability of our findings. (2) The lack of histopathological confirmation for all lesions, despite rigorous multimodal follow-up, remains an inherent constraint on diagnostic certainty. (3) We did not explore the correlation between FAPI uptake intensity (SUVₘₐₓ) and histopathological markers of tumor aggressiveness or patient outcomes. (4) Only a single, standard (60-min) imaging time point was used. Conclusion In conclusion, [¹⁸F]FAPI-46 PET/CT demonstrates superior diagnostic performance to [¹⁸F]FDG PET/CT for detecting lymph node metastases in postoperative PTC patients and shows promise in distinguishing malignant from reactive nodes. Serum sTg (> 25.9 ng/mL) may help select patients for this imaging modality. Clinicians should be aware of potential false-positive bone uptake and must integrate PET findings with diagnostic CT morphology. Future larger, multicenter studies are warranted to validate these findings, explore earlier imaging protocols, and investigate the theranostic potential of FAPI-directed therapy in thyroid cancer. Abbreviations FAPI fibroblast activation protein inhibitor CAFs cancer-associated fibroblasts DPP dipeptidyl peptidase Rx-WBS postablation whole-body 131I scan DTC differentiated thyroid cancer sTg stimulated thyroglobulin ROC receiver operator characteristic curve AUC The area under the receiver operating curve SUVmax Maximal standardized uptake value Declarations Author information Taisong Wang and Rui Zhang are joint first authors who contributed equally to this work. Ethics approval and consent to participate This study was conducted following the Declaration of Helsinki (2013 revision). The study received approval from the Clinical Research Ethics Committee of Shanghai General Hospital, Shanghai Jiaotong University School of Medicine (2021 − 113). Written informed consent was obtained from the participants of this study. Consent for publication The permission for publication of the individual’s data included in this manuscript has been obtained from the person. Competing interest The authors declare that they have no competing interests. Author details 1 Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China 2 Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China Funding The study was supported by the construction project of the Shanghai Key Laboratory of Molecular Imaging (18DZ2260400). Author contributions TSW and YX designed this research. WLQ, QQH and YX provided necessary administrative support. NS, LJS and LZZ provided study materials and initiated patient enrollment work. TSW, RZ completed data collection. TSW, RZ, QQH and YX completed data analysis and interpretation. All authors read and approved the final manuscript. Acknowledgements We would like to acknowledge the contribution of Key Laboratory of Molecular Imaging and nuclear medicine department in the management of these patients. Data availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. References Filetti S, Durante C, Hartl D, Leboulleux S, Locati LD, Newbold K, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Annals oncology: official J Eur Soc Med Oncol / ESMO. 2019;30(12):1856–83. Schlumberger MJ, Pacini F. 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Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 14 Feb, 2026 Reviewers invited by journal 05 Feb, 2026 Editor assigned by journal 30 Jan, 2026 First submitted to journal 29 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8736306","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586087356,"identity":"5de2d269-44f1-4c2f-a260-f95e2874df27","order_by":0,"name":"Taisong Wang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Taisong","middleName":"","lastName":"Wang","suffix":""},{"id":586087357,"identity":"f440eaa5-82de-4abe-aac3-417e0bdb90ed","order_by":1,"name":"Rui Zhang","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Zhang","suffix":""},{"id":586087358,"identity":"11d0a8cf-71d7-43a9-bb94-4d21f9a2c5ce","order_by":2,"name":"Na Sun","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Na","middleName":"","lastName":"Sun","suffix":""},{"id":586087359,"identity":"10aece45-ad7f-4cac-b9cc-abdb57ae8b6f","order_by":3,"name":"Lijuan Shen","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lijuan","middleName":"","lastName":"Shen","suffix":""},{"id":586087360,"identity":"a1c474dc-c7ac-427b-8279-900b44e6850b","order_by":4,"name":"Wenli Qiao","email":"","orcid":"","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Wenli","middleName":"","lastName":"Qiao","suffix":""},{"id":586087361,"identity":"f7640a38-89f8-4dc4-a738-080fb6cbe5e4","order_by":5,"name":"Qingqing Huang","email":"","orcid":"","institution":"Shanghai Key Laboratory of Molecular Imaging","correspondingAuthor":false,"prefix":"","firstName":"Qingqing","middleName":"","lastName":"Huang","suffix":""},{"id":586087362,"identity":"b7e59265-ee31-4942-9149-fbed0000baaf","order_by":6,"name":"Yan Xing","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAm0lEQVRIiWNgGAWjYJCCAx8MbOxI0sF4cEZBWjJJWpgP83w4xNhAtHqDGwkMh20MDjAzsB8+uoEoLZIzgFpyDO7wMfCkpd0gSgu/BFjLM2YGCR4z4rSwgbRYGBxmbCBaC9gWBpK0SPY8bDjYY5CWzEa0XwyOJx/+8OOPjR0/++FjxGlhEEhsANNsxCkHAf4DxKsdBaNgFIyCEQoAX7guYANvAS4AAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0003-0700-3626","institution":"Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Yan","middleName":"","lastName":"Xing","suffix":""}],"badges":[],"createdAt":"2026-01-30 02:43:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8736306/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8736306/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102297016,"identity":"f037ba56-7736-42f8-9493-b7a04cb3de45","added_by":"auto","created_at":"2026-02-10 10:24:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":3313023,"visible":true,"origin":"","legend":"\u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT of a 46-year-old male patient who presented with papillary thyroid carcinoma one month after surgery. An enlarged lymph node was revealed adjacent to the left carotid sheath with increased uptake of [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46, the SUVmax was 12.1, which with little accumulation of [\u003csup\u003e18\u003c/sup\u003eF]-FDG, the SUVmax was 2.3. Subsequent lymph node needle biopsy confirmed papillary thyroid carcinoma metastasis.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8736306/v1/4f61150630ae7a2a72b42896.png"},{"id":102397106,"identity":"9e1f9c5b-0ace-4fd5-ad7f-14ba959cd4a1","added_by":"auto","created_at":"2026-02-11 09:58:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":80534,"visible":true,"origin":"","legend":"\u003cp\u003eROC analysis of SUVmax of [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8736306/v1/f5fb9bc89ac91d6e1bbfb867.png"},{"id":102297158,"identity":"c2e9dd64-cfaf-4e30-9745-89404bc8145a","added_by":"auto","created_at":"2026-02-10 10:26:10","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":2066564,"visible":true,"origin":"","legend":"\u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT of a 44-year-old female who presented 1 month after total thyroidectomy. The [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT showed a hypodense nodules with a sclerotic border in left ilium, the SUVmax was 6.6, which with no uptake of [\u003csup\u003e18\u003c/sup\u003eF]FDG.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8736306/v1/41df3e54ecb382f668f39c26.png"},{"id":102297463,"identity":"609535c6-c2cf-462f-b3eb-1627bea40d22","added_by":"auto","created_at":"2026-02-10 10:27:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":63523,"visible":true,"origin":"","legend":"\u003cp\u003eROC analysis of stimulated Tg level.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-8736306/v1/ecad1ada0fcce406cc55d6a3.png"},{"id":102745390,"identity":"825c772f-4757-48aa-a293-250c7207b68f","added_by":"auto","created_at":"2026-02-16 08:47:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5813104,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8736306/v1/a12dc1d7-a80d-48c0-bdf9-9f465d194292.pdf"}],"financialInterests":"","formattedTitle":"AL[18F]-NOTA-FAPI-46 and [18F]FDG PET/CT in Detecting Postoperative Recurrence and Metastasis of Papillary Thyroid Cancer: A Head-to-Head Comparative study","fulltext":[{"header":"Background","content":"\u003cp\u003ePapillary thyroid cancer (PTC) is the most common endocrine malignancy, and its incidence has been steadily increasing worldwide. While most patients have an excellent prognosis after total thyroidectomy followed by radioiodine therapy, postoperative monitoring for recurrence or metastasis is critical, particularly in intermediate to high-risk cases. Biochemical recurrence, characterized by elevated serum thyroglobulin (Tg) or anti-Tg antibody levels, poses a diagnostic challenge, as conventional imaging modalities, including neck ultrasound, computed tomography (CT)and diagnostic radioiodine whole-body scan (Rx-WBS), may fail to localize the disease[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to current guidelines from the American Thyroid Association (ATA), 2-[\u0026sup1;⁸F]fluoro-2-deoxy-D-glucose ([\u0026sup1;⁸F]FDG) positron emission tomography/computed tomography (PET/CT) is recommended in patients with suspected recurrence or metastasis when radioiodine imaging is negative[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, the sensitivity of [\u0026sup1;⁸F]FDG PET/CT is suboptimal in certain scenarios, such as in the presence of low Tg levels, small metastatic deposits, or well-differentiated tumors with low metabolic activity. Reported false-negative rates range from 8% to 21.1%[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], underscoring the need for more accurate imaging techniques.\u003c/p\u003e \u003cp\u003eIn recent years, fibroblast activation protein (FAP), a type II transmembrane serine protease highly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma, has emerged as a promising target for oncologic imaging. FAP-specific inhibitors (FAPIs), particularly those labeled with gallium-68 (e.g., [⁶⁸Ga]FAPI-46), have demonstrated superior tumor-to-background ratios compared to [\u0026sup1;⁸F]FDG in various cancers, including thyroid cancer[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Studies have shown that [⁶⁸Ga]FAPI PET/CT outperforms [\u0026sup1;⁸F]FDG in detecting lymph node, pleural, and bone metastases in radioiodine-refractory differentiated thyroid cancer [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough most clinical studies have used ⁶⁸Ga-labeled FAPI tracers, the use of fluorine-18 offers practical advantages, including a longer half-life (110 minutes) that facilitates centralized production and distribution, as well as potentially higher image resolution due to lower positron energy[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. [\u0026sup1;⁸F]FAPI-04 PET/CT has been used in detection of recurrent lesions in differentiated thyroid cancer[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, head-to-head comparisons between [\u0026sup1;⁸F]FAPI-46 and [\u0026sup1;⁸F]FDG PET/CT in postoperative PTC patients are lacking.\u003c/p\u003e \u003cp\u003eThis study aims to directly compare the diagnostic performance of [\u0026sup1;⁸F]FAPI-46 and [\u0026sup1;⁸F]FDG PET/CT in detecting postoperative recurrence and metastasis in PTC patients, using a composite reference standard including histopathology, imaging follow-up, and clinical outcome. The findings may help refine imaging strategies for metastasis and recurrence and pave the way for future theranostic applications of FAPI-targeted radionuclide therapy[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e The study received approval from the Clinical Research Ethics Committee of Shanghai General Hospital, Shanghai Jiaotong University School of Medicine (2021\u0026thinsp;\u0026minus;\u0026thinsp;113) and was conducted in accordance with the 1964 Helsinki Declaration for ethical standards. Informed written consent was obtained from all of these enrolled patients. A prospective evaluation was carried out on 18 consecutive patients diagnosed with PTC referred to our clinic between September 2022 and June 2023 for postoperative \u003csup\u003e131\u003c/sup\u003eI therapy, guided by histopathological risk factors suggesting a potential increase in tumor aggressiveness. The inclusion criteria for patients were as follows: (1) posttotal thyroidectomy duration exceeding one month; (2) two-week low-iodine diet preparation, and discontinuation of levothyroxine tablets for three weeks resulting in a serum TSH level\u0026thinsp;\u0026ge;\u0026thinsp;30 mIU/L; (3) Patients underwent [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT and [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT within one week before treatment. The exclusion criteria for patients included inability or reluctance to provide informed consent, the presence of a secondary cancer or chronic inflammation, and pregnancy or lactation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePET/CT imaging protocols\u003c/h3\u003e\n\u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 tracers were synthesized in the Department of Nuclear Medicine Shanghai General Hospital, Shanghai Jiaotong University School of Medicine. The synthesis process is as follows: A quantity of 2\u0026ndash;10 GBq of [18F] fluoride, generated by a MINITRACE Cyclotron (GE, USA) in 2.5 mL of water was subsequently trapped on a preconditioned anion exchange cartridge (Waters Plus QMA Light cartridge, preconditioned with 5 mL of saline and 10 mL of water). The [18F] fluoride was then eluted with 0.3 mL of saline. For the labeling reaction, the eluate was mixed with AlCl3 (24 \u0026micro;L, 2 mM), Potassium hydrogen phthalate (65\u0026micro;L, 2 mM), NOTA-FAPI-46 (26 \u0026micro;L, 4 mM) and anhydrous MeCN (300 \u0026micro;L). The mixture was incubated at 95\u0026deg;C for 15 minutes. Upon cooling to ambient temperature, the reaction mixture was diluted with 5 mL of water and passed through a preconditioned C18 cartridge (Waters Oasis HLB Plus Light cartridge, preconditioned with 5 mL of ethanol and 10 mL of water) to remove unreacted [18F] fluoride. This cartridge was subsequently washed with 10 mL of water and dried with nitrogen gas. The radiolabeled product was then eluted using 1 mL of ethanol, followed by a 10 mL wash with 0.9% NaCl solution. The final eluate was filtered through a 0.22 \u0026micro;m sterile Millipore filter into a sterile vial. The final drug product solution was evaluated through a quality control.\u003c/p\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG tracers were ordered from Shanghai Atomsun Pharmaceutical Co., Ltd. The PET scans, using two radio-labelled tracers, were applied with at least a 24-hour interval for each patient in our cohort. All patients underwent PET/CT imaging via a PET/CT system (uMI780, United Imaging Medical). For [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT, patients were asked to fast for 6 hours. Their blood glucose levels were measured to ensure that they were within the reference range (3.9\u0026ndash;6.1 mmol/L). No special preparation is required for the [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT examination. IV doses of [\u003csup\u003e18\u003c/sup\u003eF]FDG and [\u0026sup1;⁸F]FAPI-46 were 3.7 MBq/kg (0.1 mCi/kg). PET/CT scans were performed approximately 60 minutes after IV administration. The CT scan was performed and acquired according to the following parameters: tube voltage, 120 kV; current, 120 mA; layer thickness, 3.00 mm, layer spacing, 5 mm; pitch, 0.813. The PET scan was then performed in 3D acquisition mode on the same bed as the CT.\u003c/p\u003e\n\u003ch3\u003ePET/CT image analysis\u003c/h3\u003e\n\u003cp\u003eTwo experienced nuclear medicine physicians (SN and SLJ, with over 5 and 10 years of experience, respectively) performed blinded evaluations and delineations of [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 and [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT imaging. The evaluation included PET, CT, and fused whole-body images presented in the axial, coronal, and sagittal planes for detailed assessment. A semiquantitative analysis of tracer activity was performed to determine the maximal standardized uptake value (SUVmax) of both [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT and [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT via software provided by the United Imaging Medical. If the SUVmax value is lower than that of the mediastinal blood pool, it is recorded as not applicable(NA).\u003c/p\u003e \u003cp\u003e \u003cb\u003eReference Standard\u003c/b\u003e \u003c/p\u003e \u003cp\u003eGiven the clinical context of this study, obtaining histopathological confirmation for all suspected lesions was not feasible due to a combination of technical and ethical considerations. Technical challenges included the small size or deep location of some lesions (e.g., subcentimeter lymph nodes or bone changes), which made percutaneous biopsy high-risk or non-diagnostic. Ethically, subjecting patients to invasive procedures for lesions with low pre-test probability or those located in high-risk anatomical areas was not justified, especially when alternative, non-invasive monitoring could provide sufficient diagnostic certainty. Therefore, we employed a composite reference standard, integrating all available clinical, imaging, and follow-up data to adjudicate the final status of each suspected lesion. The reference standard was constructed from the following elements, listed in order of priority:\u003c/p\u003e \u003cp\u003e(1) Histopathological confirmation from surgery or biopsy (when available and clinically indicated).\u003c/p\u003e \u003cp\u003e(2) Imaging follow-up over a period of at least 6 months. Lesions were monitored using a combination of high-resolution neck ultrasound, diagnostic or post-therapeutic \u0026sup1;\u0026sup3;\u0026sup1;I whole-body scan (Rx-WBS), and cross-sectional imaging (CT or MRI) as clinically appropriate. Lesions were classified as tumor-related (positive) if they demonstrated significant progression in size or number on serial imaging, or unequivocal regression in response to systemic therapy (including radioactive iodine therapy, radiotherapy, targeted therapy, or immunotherapy). Lesions were classified as benign (negative) if they remained stable or regressed spontaneously over the follow-up period without specific anti-tumor therapy, or if their imaging features were conclusively characteristic of a benign process (e.g., reactive lymphadenopathy, benign bone island).\u003c/p\u003e \u003cp\u003e(3) Clinical course: and serial serum thyroglobulin (Tg) levels were also considered to support the imaging-based classification.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were performed using SPSS software (version 25.0; IBM, Armonk, NY, USA). Continuous variables are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) if they followed a normal distribution, as assessed by the Shapiro-Wilk test; otherwise, they are presented as median with interquartile range (IQR). Categorical variables are summarized as frequencies and percentages.\u003c/p\u003e \u003cp\u003eFor comparisons between the metastasis and non-metastasis groups, independent-sample t-tests were used for normally distributed continuous variables. The diagnostic performance (sensitivity, specificity, accuracy) of [\u0026sup1;⁸F]FAPI-46 and [\u0026sup1;⁸F]FDG PET/CT for lymph node metastasis was evaluated against the composite reference standard. The McNemar test was employed to compare the diagnostic accuracy of the two imaging modalities. The maximal standardized uptake value (SUVₘₐₓ) of true-positive lymph nodes between tracers was compared using the paired t-test.\u003c/p\u003e \u003cp\u003eReceiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic efficacy of sTg level and [\u0026sup1;⁸F]FAPI-46 SUVₘₐₓ for identifying metastatic disease. The area under the ROC curve (AUC) was calculated, and the optimal cutoff value was determined by maximizing the Youden index. Corresponding 95% confidence intervals (CIs) for the AUC were reported.\u003c/p\u003e \u003cp\u003eA two-tailed P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant for all tests.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAll patient characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of 18 patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003esex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003epTN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003esTg\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRSTR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFDG\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eFAPI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e45.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e 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\u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT3bN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e23.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT4aN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e26.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e59.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1aN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT2N1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT4aN-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN1b\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e34.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003epT1bN1a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e41.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003epTN: stage of pathology; sTg: Stimulated thyroglobulin; RSTR: Risk Stratification; FDG: [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT; FAPI: [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT; RSTA: Reference Standard.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Value of [\u003csup\u003e18\u003c/sup\u003eF]FDG and [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/ CT in Nodal and Bone Metastases\u003c/h2\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT and [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT totally detected 23 suspected metastatic lymph nodes in 10 patients. Six suspected metastatic lymph nodes were confirmed by postoperative pathology, and the remaining 17 metastatic lymph nodes were examined on follow-up as the reference standard. Finally, 17 lymph nodes were confirmed to be metastatic, and 6 lymph nodes were reactive hyperplasia or inflammatory (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Details are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The sensitivity of [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT in diagnosing lymph node metastasis was 82.3%, the specificity was 66.7%, and the accuracy was 78.3%. The sensitivity of [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT in diagnosing lymph node metastasis was 29.4%, the specificity was 33.3%, and the accuracy was 30.4%. [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT was more effective than [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT(\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022). The SUVmax of [\u003csup\u003e18\u003c/sup\u003eF]FDG and [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 was significant difference (1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6 vs 4.2\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) for true positive lymph nodes. Receiver operating curve analysis showed that the threshold of [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 SUVmax for diagnosing lymph node metastasis was 2.3 (AUC\u0026thinsp;=\u0026thinsp;0.765, sensitivity 88.2%, specificity 66.7%, 95%CI: 0.530\u0026ndash;0.999) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetails of 23 suspected metastatic lymph nodes.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG SUVmax\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 SUVmax\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRSTA\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong these 18 patients, no patients had bone metastasis. [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT showed three false positive bone lesions with an SUVmax ranging from 7.7\u0026ndash;7.9 in two patients, which were negative in [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These bone lesions often show annular hyperdense shadows, suggesting fibroproliferative lesions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eFalse-Positive Lymph Nodes in [F]FDG PET/CT\u003c/h3\u003e\n\u003cp\u003e[\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT had 4 false-positive lymph nodes in 3 patients. These patients showed no lymph node cancer metastasis based on reference standard. The average SUVmax of the 4 false-positive lymph nodes was 10.1. Two of these lymph nodes were visualized on [\u003csup\u003e18\u003c/sup\u003eF]FAPI-46 PET/CT in one patient. The average SUVmax was 4.5, which was lower than [\u003csup\u003e18\u003c/sup\u003eF]FDG PET/CT. The two lymph nodes showed reactive hyperplasia of lymph nodes by puncture biopsy.\u003c/p\u003e\n\u003ch3\u003eThe diagnostic value of serum stimulated Tg level for metastasis of thyroid cancer after operation\u003c/h3\u003e\n\u003cp\u003eThere was a significant difference in stimulated Tg level between the metastasis group and the non-metastasis group (P\u0026thinsp;=\u0026thinsp;0.044), and the former was higher than the latter (79.1\u0026thinsp;\u0026plusmn;\u0026thinsp;51.1VS33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.5). Receiver operating curve analysis showed that the threshold of serum stimulated Tg for diagnosing lymph node metastasis was 25.9ng/mL (AUC\u0026thinsp;=\u0026thinsp;0.862, Youden index\u0026thinsp;=\u0026thinsp;0.7, 95%CI: 0.679-1.000) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussions","content":"\u003cp\u003eThis head-to-head comparative study demonstrates the superior diagnostic performance of [\u0026sup1;⁸F]FAPI-46 PET/CT over [\u0026sup1;⁸F]FDG PET/CT for detecting lymph node metastases in postoperative PTC patients. The significantly higher sensitivity (82.3% vs. 29.4%) and accuracy (78.3% vs. 30.4%) of [\u0026sup1;⁸F]FAPI-46 align with the known biology of FAP expression, which is highly upregulated (\u0026gt;\u0026thinsp;90%) in cancer-associated fibroblasts (CAFs) within the tumor stroma of epithelial cancers, including DTC[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Unlike [\u0026sup1;⁸F]FDG, which images glucose metabolism that can be variable and low in indolent or small-volume disease, [\u0026sup1;⁸F]FAPI-46 specifically targets the reactive stromal microenvironment. This mechanism likely enhances its ability to detect small metastatic deposits or residual tumor nests often embedded within postoperative fibrotic tissue. Notably, our study also found that the SUVmax of [\u0026sup1;⁸F]FAPI-46 in true-positive lymph nodes was significantly higher than that of [\u0026sup1;⁸F]FDG (4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4 vs. 1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7, P\u0026thinsp;=\u0026thinsp;0.040), and ROC analysis identified an optimal diagnostic threshold of 2.3 (AUC\u0026thinsp;=\u0026thinsp;0.745). This provides a preliminary basis for the quantitative interpretation of [\u0026sup1;⁸F]FAPI-46, although its optimal cutoff value requires validation in larger cohorts.[\u0026sup1;⁸F]FAPI-46 consistently provided superior lesion-to-background contrast, facilitating more confident localization, a finding consistent with prior studies using ⁶⁸Ga-labeled FAPI tracers in head and neck cancers[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe analysis of false-positive findings provides crucial clinical insights. [\u0026sup1;⁸F]FDG PET/CT produced four false-positive lymph nodes, attributable to postoperative inflammation or reactive hyperplasia\u0026mdash;a well-known pitfall of metabolic imaging. In contrast, [\u0026sup1;⁸F]FAPI-46 showed only two such false positives, suggesting a potentially lower affinity for inflammatory processes, which could be a distinct diagnostic advantage. However, [\u0026sup1;⁸F]FAPI-46 demonstrated three false-positive bone lesions (SUVₘₐₓ 7.7\u0026ndash;7.9) that were negative on [\u0026sup1;⁸F]FDG. Their annular, sclerotic appearance on CT is highly suggestive of benign fibroproliferative changes (e.g., bone islands or healed benign fractures), where FAP uptake has been documented in reactive fibroblasts [Wei et al., 2022]. This underscores that while [\u0026sup1;⁸F]FAPI-46 offers high contrast, its interpretation must be rigorously correlated with CT morphology to avoid misinterpretation. The lack of a significant SUVₘₐₓ difference between true-positive and false-positive lesions in our small cohort precludes defining a reliable diagnostic threshold based on uptake value alone.\u003c/p\u003e \u003cp\u003eSerum stimulated thyroglobulin (sTg) measured prior to ablation showed significant predictive value. Metastatic patients had markedly higher sTg levels than non-metastatic patients (79.1\u0026thinsp;\u0026plusmn;\u0026thinsp;51.1 ng/mL vs. 33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.5 ng/mL, P\u0026thinsp;=\u0026thinsp;0.044). ROC analysis identified an optimal diagnostic threshold of 25.9 ng/mL (AUC\u0026thinsp;=\u0026thinsp;0.862, Youden index\u0026thinsp;=\u0026thinsp;0.7). Notably, all patients with positive [\u0026sup1;⁸F]FAPI-46 scans had sTg\u0026thinsp;\u0026gt;\u0026thinsp;25.9 ng/mL, whereas the majority of scan-negative patients had values below this cutoff. This finding aligns with the spirit of the 2025 American Thyroid Association (ATA) guidelines, which emphasize the use of serum Tg as a stratification tool to guide imaging selection. This suggests that sTg could serve as a valuable stratification tool to identify patients most likely to benefit from [\u0026sup1;⁸F]FAPI-46 PET/CT, especially in the setting of negative conventional imaging but clinical suspicion of disease.\u003c/p\u003e \u003cp\u003eFor patients with elevated sTg and negative diagnostic \u0026sup1;\u0026sup3;\u0026sup1;I whole-body scans, [\u0026sup1;⁸F]FAPI-46 PET/CT proved effective in localizing occult disease. In our cohort, it identified [\u0026sup1;⁸F]FDG-negative metastases (e.g., Case 11) and correctly characterized intense [\u0026sup1;⁸F]FDG uptake as false-positive reactive nodes (e.g., Case 8). This precise localization directly impacts clinical management, guiding decisions regarding surgical re-intervention or the initiation of targeted therapies.\u003c/p\u003e \u003cp\u003eRegarding imaging protocol, we performed scans at approximately 60 minutes post-injection, a standard time point for both tracers based on prior pharmacokinetic studies. While emerging data suggest that FAP-targeted tracers can achieve high tumor-to-background contrast as early as 20\u0026ndash;30 minutes post-injection[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], potentially reducing patient time in the scanner. The dual-tracer (e.g., [\u003csup\u003e68\u003c/sup\u003eGa]FAPI-46 and [\u003csup\u003e18\u003c/sup\u003eF]-FDG) combined scan in a single session, not only improves sensitivity but also avoids the repeated CT radiation exposure associated with separate scans[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. These protocols were not evaluated in our study. Exploring earlier imaging time points for [\u0026sup1;⁸F]FAPI-46 represents a valuable direction for future research to further optimize patient convenience and departmental workflow.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations\u003c/b\u003eThis pilot study has several limitations: (1) The small sample size (n\u0026thinsp;=\u0026thinsp;18) and single-center design limit the statistical power and generalizability of our findings. (2) The lack of histopathological confirmation for all lesions, despite rigorous multimodal follow-up, remains an inherent constraint on diagnostic certainty. (3) We did not explore the correlation between FAPI uptake intensity (SUVₘₐₓ) and histopathological markers of tumor aggressiveness or patient outcomes. (4) Only a single, standard (60-min) imaging time point was used.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, [\u0026sup1;⁸F]FAPI-46 PET/CT demonstrates superior diagnostic performance to [\u0026sup1;⁸F]FDG PET/CT for detecting lymph node metastases in postoperative PTC patients and shows promise in distinguishing malignant from reactive nodes. Serum sTg (\u0026gt;\u0026thinsp;25.9 ng/mL) may help select patients for this imaging modality. Clinicians should be aware of potential false-positive bone uptake and must integrate PET findings with diagnostic CT morphology. Future larger, multicenter studies are warranted to validate these findings, explore earlier imaging protocols, and investigate the theranostic potential of FAPI-directed therapy in thyroid cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFAPI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efibroblast activation protein inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCAFs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecancer-associated fibroblasts\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDPP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edipeptidyl peptidase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRx-WBS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epostablation whole-body 131I scan\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edifferentiated thyroid cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003esTg\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estimulated thyroglobulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereceiver operator characteristic curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThe area under the receiver operating curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSUVmax\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMaximal standardized uptake value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eAuthor information\u003c/h2\u003e \u003cp\u003eTaisong Wang and Rui Zhang are joint first authors who contributed equally to this work.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eThis study was conducted following the Declaration of Helsinki (2013 revision). The study received approval from the Clinical Research Ethics Committee of Shanghai General Hospital, Shanghai Jiaotong University School of Medicine (2021\u0026thinsp;\u0026minus;\u0026thinsp;113). Written informed consent was obtained from the participants of this study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003e The permission for publication of the individual\u0026rsquo;s data included in this manuscript has been obtained from the person.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interest\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eAuthor details\u003c/h2\u003e \u003cp\u003e \u003csup\u003e1\u003c/sup\u003e Department of Nuclear Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China\u003c/p\u003e \u003cp\u003e \u003csup\u003e2\u003c/sup\u003e Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe study was supported by the construction project of the Shanghai Key Laboratory of Molecular Imaging (18DZ2260400).\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eTSW and YX designed this research. WLQ, QQH and YX provided necessary administrative support. NS, LJS and LZZ provided study materials and initiated patient enrollment work. TSW, RZ completed data collection. TSW, RZ, QQH and YX completed data analysis and interpretation. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe would like to acknowledge the contribution of Key Laboratory of Molecular Imaging and nuclear medicine department in the management of these patients.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFiletti S, Durante C, Hartl D, Leboulleux S, Locati LD, Newbold K, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-updagger. Annals oncology: official J Eur Soc Med Oncol / ESMO. 2019;30(12):1856\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchlumberger MJ, Pacini F. The low utility of pretherapy scans in thyroid cancer patients. Thyroid: official J Am Thyroid Association. 2009;19(8):815\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRingel MD, Sosa JA, Baloch Z, Bischoff L, Bloom G, Brent GA, et al. 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid: official J Am Thyroid Association. 2025;35(8):841\u0026ndash;985.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaidar M, Kassas M, Chehade F, Chahinian R, Abi-Ghosn J, Haddad MM. The role of 18 F-FDG-PET/CT in the management of differentiated thyroid cancer. Nucl Med Commun. 2023;44(11):1046\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoth KS, Voltin CA, van Heek L, Wegen S, Schomacker K, Fischer T, et al. Dual-Tracer PET/CT Protocol with [(18)F]-FDG and [(68)Ga]Ga-FAPI-46 for Cancer Imaging: A Proof of Concept. Journal of nuclear medicine: official publication. Soc Nuclear Med. 2022;63(11):1683\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePabst KM, Weber MM, Laschinsky C, Sandach P, Bartel T, Kuper AT, et al. [(68)Ga]Ga-FAPI-46 PET accuracy for cancer imaging with histopathology validation: a single-centre, single-arm, interventional, phase 2 trial. Lancet Oncol. 2025;26(9):1204\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuan D, Sun J, Han C, Cai J, Yu L, Zhao L, et al. (68)Ga-FAPI-46 PET/CT in the evaluation of gliomas: comparison with (18)F-FDG PET/CT and contrast-enhanced MRI. Theranostics. 2024;14(18):6935\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen Y, Zang J, Wu Z, Miao W. 68 Ga-FAPI-RGD PET/CT Detected Skull Metastasis Better Than 18 F-FDG in a Patient With Radioiodine-Refractory Differentiated Thyroid Cancer. Clin Nucl Med. 2024;49(10):964\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu H, Fu J, Huang J, Pang Y, Chen H. 68Ga-FAPI PET/CT Versus 18F-FDG PET/CT for Detecting Metastatic Lesions in a Case of Radioiodine-Refractory Differentiated Thyroid Cancer. Clin Nucl Med. 2021;46(11):940\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWei Y, Zheng J, Ma L, Liu X, Xu S, Wang S, et al. [(18)F]AlF-NOTA-FAPI-04: FAP-targeting specificity, biodistribution, and PET/CT imaging of various cancers. Eur J Nucl Med Mol Imaging. 2022;49(8):2761\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZheng K, Zhou W, Yang J, Zhang Y, Jiang C, Xie A, et al. [(18)F]AlF-NOTA-FAPI-04 PET/CT improves detection of subcentimeter recurrent lesions in differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2025;53(1):398\u0026ndash;407.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaddio MF, Doshi S, Masri M, Jeanjean P, Hikmat F, Gerlach A, et al. Evaluating [(225)Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice. Eur J Nucl Med Mol Imaging. 2024;51(13):4026\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu H, Huang J, Sun L, Wu H, Chen H. FAP-Targeted Radionuclide Therapy of Advanced Radioiodine-Refractory Differentiated Thyroid Cancer With Multiple Cycles of 177 Lu-FAPI-46. Clin Nucl Med. 2022;47(10):906\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCivan C, Isik EG, Karadogan S, Sanli Y, Kuyumcu S. 68 Ga-FAPI-04 PET/CT and 18 F-FDG PET/CT in Metastatic Papillary Renal Cell Cancer. Clin Nucl Med. 2023;48(5):e223\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHirmas N, Hamacher R, Sraieb M, Ingenwerth M, Kessler L, Pabst KM, et al. Fibroblast-Activation Protein PET and Histopathology in a Single-Center Database of 324 Patients and 21 Tumor Entities. Journal of nuclear medicine: official publication. Soc Nuclear Med. 2023;64(5):711\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoshanravan V, Sadeghi R, Zakavi SR, Norouzbeigi N, Aghaee A. Unilateral Chronic Parotitis With 68 Ga-DOTA-FAPI-04 PET/CT and 18 F-FDG PET/CT Imaging in a Case of a Patient With Papillary Thyroid Carcinoma. Clin Nucl Med. 2023;48(12):e577\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang Y, Wen B, Li C, Tian Y, Xiao Z, Xu K, et al. The performance of (68)Ga-FAPI-04 PET/CT in head and neck squamous cell carcinoma: a prospective comparison with (18)F-FDG PET/CT. Eur J Nucl Med Mol Imaging. 2023;50(7):2114\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGu B, Xu X, Zhang J, Ou X, Xia Z, Guan Q, et al. The Added Value of (68)Ga-FAPI PET/CT in Patients with Head and Neck Cancer of Unknown Primary with (18)F-FDG-Negative Findings. Journal of nuclear medicine: official publication. Soc Nuclear Med. 2022;63(6):875\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHu K, Wang L, Wu H, Huang S, Tian Y, Wang Q, et al. [(18)F]FAPI-42 PET imaging in cancer patients: optimal acquisition time, biodistribution, and comparison with [(68)Ga]Ga-FAPI-04. Eur J Nucl Med Mol Imaging. 2022;49(8):2833\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGlatting FM, Hoppner J, Liew DP, van Genabith A, Spektor AM, Steinbach L, et al. Repetitive Early (68)Ga-FAPI PET Acquisition Comparing (68)Ga-FAPI-02, (68)Ga-FAPI-46, and (68)Ga-FAPI-74: Methodologic and Diagnostic Implications for Malignant, Inflammatory/Reactive, and Degenerative Lesions. Journal of nuclear medicine: official publication. Soc Nuclear Med. 2022;63(12):1844\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu G, Mao W, Yu H, Hu Y, Gu J, Shi H. One-stop [(18)F]FDG and [(68)Ga]Ga-DOTA-FAPI-04 total-body PET/CT examination with dual-low activity: a feasibility study. Eur J Nucl Med Mol Imaging. 2023;50(8):2271\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"[¹⁸F]FAPI-46, [¹⁸F]FDG, PET/CT, Papillary thyroid cancer, Recurrence, Metastasis","lastPublishedDoi":"10.21203/rs.3.rs-8736306/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8736306/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePostoperative monitoring of papillary thyroid cancer (PTC), especially in cases of biochemical recurrence or radioiodine-refractory disease, remains challenging. Although 2-[\u0026sup1;⁸F]fluoro-2-deoxy-D-glucose ([\u0026sup1;⁸F]FDG) positron emission tomography/computed tomography (PET/CT) is widely used, its sensitivity is suboptimal, particularly for lesions with low metabolic activity or small metastases. Fibroblast activation protein (FAP), expressed in the tumor stroma, has emerged as a promising target. This study aimed to compare the diagnostic efficacy of Al [\u0026sup1;⁸F]-NOTA-FAPI-46([\u0026sup1;⁸F]FAPI-46) and [\u0026sup1;⁸F]FDG PET/CT in detecting recurrence and metastasis in postoperative PTC patients.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e[\u0026sup1;⁸F]FAPI-46 PET/CT demonstrated significantly higher sensitivity (82.3% vs. 29.4%, P\u0026thinsp;=\u0026thinsp;0.022) and accuracy (78.3% vs. 30.4%) than [\u0026sup1;⁸F]FDG PET/CT for detecting lymph node metastases, with fewer false-positive cases (2 vs. 4). However, [\u0026sup1;⁸F]FAPI-46 showed three false-positive bone lesions (SUVₘₐₓ: 7.7\u0026ndash;7.9), likely due to benign fibroproliferative changes. In patients with metastasis, serum stimulated thyroglobulin (sTg) levels were significantly elevated (79.1\u0026thinsp;\u0026plusmn;\u0026thinsp;51.1 ng/mL vs. 33.9\u0026thinsp;\u0026plusmn;\u0026thinsp;36.5 ng/mL, P\u0026thinsp;=\u0026thinsp;0.044), with an optimal diagnostic threshold of 25.9 ng/mL (AUC\u0026thinsp;=\u0026thinsp;0.862). [\u0026sup1;⁸F]FAPI-46 PET/CT identified occult metastases in cases with elevated sTg and clarified false-positive [\u0026sup1;⁸F]FDG findings.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003e[\u0026sup1;⁸F]FAPI-46 PET/CT shows superior performance over [\u0026sup1;⁸F]FDG PET/CT in diagnosing lymph node metastases in postoperative PTC patients and effectively distinguishes metastatic from reactive lymph nodes. Caution is warranted for false-positive bone lesions, emphasizing the need for correlation with CT morphology.\u003c/p\u003e","manuscriptTitle":"AL[18F]-NOTA-FAPI-46 and [18F]FDG PET/CT in Detecting Postoperative Recurrence and Metastasis of Papillary Thyroid Cancer: A Head-to-Head Comparative study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 13:14:13","doi":"10.21203/rs.3.rs-8736306/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-02-14T16:19:25+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-05T05:07:53+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-30T05:38:10+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Research","date":"2026-01-29T21:41:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"33812e77-a70a-45a6-83ed-80684c814db3","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T13:14:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-09 13:14:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8736306","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8736306","identity":"rs-8736306","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}