Incremental diagnostic value of [18F]tetrafluoroborate PET-CT compared to [131I]iodine scintigraphy in recurrent differentiated thyroid cancer

Introduction Efficient therapy of recurrent differentiated thyroid cancer (DTC) is dependent on precise molecular imaging techniques targeting the human sodium iodide symporter (hNIS), which is a marker both of thyroid and DTC cells. Various iodine isotopes have been utilized for detecting DTC; however, these come with unfavorable radiation exposure and image quality ([131I]iodine) or limited availability ([124I]iodine). In contrast, [18F]tetrafluoroborate (TFB) is a novel radiolabeled PET substrate of hNIS, results in PET images with high-quality and low radiation doses, and should therefore be suited for imaging of DTC. The aim of the present study was to compare the diagnostic performance of [18F]TFB-PET to the clinical reference standard [131I]iodine scintigraphy in patients with recurrent DTC. Methods Twenty-five patients with recurrent DTC were included in this retrospective analysis. All patients underwent [18F]TFB-PET combined with either CT or MRI due to newly discovered elevated TG levels, antiTG levels, sonographically suspicious cervical lymph nodes, or combinations of these findings. Correlative [131I]iodine whole-body scintigraphy (dxWBS) including SPECT-CT was present for all patients; correlative [18F]FDG-PET-CT was present for 21 patients. Histological verification of [18F]TFB positive findings was available in 4 patients. Results [18F]TFB-PET detected local recurrence or metastases of DTC in significantly more patients than conventional [131I]iodine dxWBS and SPECT-CT (13/25 = 52% vs. 3/25 = 12%, p = 0.002). The diagnosis of 6 patients with cervical lymph node metastases that showed mildly increased FDG metabolism but negative [131I]iodine scintigraphy was changed: [18F]TFB-PET revealed hNIS expression in the metastases, which were therefore reclassified as only partly de-differentiated (histological confirmation present in two patients). Highest sensitivity for detecting recurrent DTC had the combination of [18F]TFB-PET-CT/MRI with [18F]FDG-PET-CT (64%). Conclusion In the present cohort, [18F]TFB-PET shows higher sensitivity and accuracy than [131I]iodine WBS and SPECT-CT in detecting recurrent DTC. The combination of [18F]TFB-PET with [18F]FDG-PET-CT seems a reasonable strategy to characterize DTC tumor manifestations with respect to their differentiation and thereby also individually plan and monitor treatment. Future prospective studies evaluating the potential of [18F]TFB-PET in recurrent DTC are warranted.


Introduction
The diagnostic workup of patients with recurrent differentiated thyroid cancer (DTC) requires molecular imaging strategies targeting the human sodium iodide symporter (hNIS), which is a key molecular marker of thyroid and DTC cells [1]. The radiopharmaceuticals [ 124 I]iodide, [ 123 I]iodide, and [ 131 I]iodide are substrates of hNIS and thus are predominately used for molecular imaging of recurrent DTC [2]. However, positron emitting [ 124 I]iodine is of subordinate diagnostic significance, as it is only available at few sites and delivers image acquisitions with a low signal to noise ratio [2]. Therefore, diagnostic [ 131 I]iodine or [ 123 I]iodine whole-body scintigraphy (dxWBS) and single photon emission tomography (SPECT-CT) are the current clinical reference standards for the diagnostic workup of DTC patients. Yet both iodine dxWBS and SPECT-CT achieve only unsatisfactory image quality, especially when compared to positron emission tomography (PET) imaging approaches [3][4][5][6]. Moreover, [ 131 I]iodine causes significant radiation exposure, and the administration might require an in-patient stay due to radiation protection legislation [7].
The detection of local recurrence or metastases of DTC by iodine imaging is of great relevance for the planning of localized therapies, like surgery or radiation therapy [2]. Moreover, negative iodine imaging despite elevated tumor marker levels is a prerequisite for diagnosing the "Thyroglobulin Elevated and Negative Iodine Scintigraphy" (TENIS) syndrome, which requires fundamentally different diagnostic and therapy concepts [8][9][10]. Therefore, a failure in detecting hNISexpressing local recurrences or metastases of DTCs might result both in a missed opportunity for localized therapy and an erroneously assumed TENIS syndrome.

Results
A total number of 25 patients underwent [ 18 F]TFB-PET, combined with either CT (n = 24) or MRI (n = 1; due to logistic reasons). In the following, PET-CT is used as phrase to refer to both PET-CT and PET-MRI acquisitions. Detailed patient characteristics are given by Tables 1 and 2. Patients were referred to imaging due to elevated TG levels (n = 19), elevated antiTG levels (n = 7), sonographically suspicious cervical lymph nodes (n = 10), or combinations of these findings. Therefore, all enrolled patients were regarded as suffering from recurrent DTC. [18F]TFB detection rate and reference standards The detection rate of [ 18 F]TFB-PET-CT was 52.0% (n = 13). Details are given in Fig. 1   nuclear medicine [2]. Moreover, PET imaging with [ 124 I]iodine requires a tracer administration days before image acquisition, which causes patient management issues. Finally, the image quality of [ 124 I]iodine-PET is not preferable due to low signal-to-noise ratios. In contrast, [ 18 F]TFB-PET-CT can easily be produced by a cyclotron equipped radiochemistry department and delivers excellent image to noise ratios and the image acquisition can be initiated minutes after tracer administration. Interestingly, patients 1 and 10 showed similar blood parameters (TG 0.55 ng/ml, antiTG < 15); however, only patient 10 showed suspicious [ 18 F]TFB accumulation, which was histologically confirmed to be a metastasis. Therefore, [ 18 F]TFB-PET-CT might be advisable in patients with minimally elevated tumor marker levels.
[ 18    Recurrence of DTC was histologically validated. Respectively, contrast enhanced foci were retrospectively detected in prior CT acquisitions (c, e) [9]. This constellation is known as TENIS or flip-flop phenomena [3,8,9] The present retrospective study faces some limitations. First, the enrollment of patients was done retrospectively and is therefore prone to selection biases. For instance, many enrolled patients had only minimally elevated TG levels or had undergone [ 131 I]iodine dxWBS/SPECT-CT imaging several times with inconclusive findings. Therefore, the pretest probability of positive imaging findings might be low. This could affect the transferability of the results to the clinical routine and underestimate the diagnostic performance of [ 18 F]TFB-PET-CT. Moreover, only a relatively small patient collective was included due to the limited application of [ 18 F]TFB-PET-CT in the clinical routine.
Finally, [ 18 F]TFB shows increased retention in the blood, which caused difficulties in the reading of head and neck acquisitions, especially when combined with low dose CT (note the blood pool in Fig. 3). Therefore, future studies should optimize the interval between injection of [ 18

Compliance with ethical standards
Conflict of interest KR is a clinical consultant for ABX and has received consultant fees from Bayer and lectureship fees from Janssen Cilag, Amgen, AAA, and SIRTEX. The University of Muenster received consulting fees from ABX Advanced Biochemical Compounds, Radeberg, Germany, for KR. The authors declare that they have no conflict of interest regarding this study.
Research involving human participants and/or animals All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research Informed consent Imaging was performed in the clinical routine with informed consent. This retrospective analysis was approved by the local ethics committee (Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Westfälischen Wilhelms-Universität Münster, 2019-615-f-S).
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