Eur J Nucl Med Mol Imaging (2013) 40:693700 DOI 10.

1007/s00259-012-2331-5

ORIGINAL ARTICLE

I PET/CT in the pretherapeutic staging of differentiated thyroid carcinoma: comparison with posttherapy 131 I SPECT/CT
Cecile de Pont & Servais Halders & Jan Bucerius & Felix Mottaghy & Boudewijn Brans

124

Received: 8 August 2012 / Accepted: 18 December 2012 / Published online: 23 January 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Purpose To compare pretherapy 124I PET/CT and posttherapy 131 I SPECT/CT in the identification of pathological lesions and the staging of patients with differentiated thyroid carcinoma. Methods 124I SPECT with low-dose CT in addition to a standard whole-body scan was performed 5 days following 131 I therapy with the administration of 1,1107,728 MBq. Pretherapy 124I PET/CT was done 24 h and 96 h after oral ingestion of 2028 MBq, including a noncontrast high-dose CT scan. Scans were evaluated by two independent experienced nuclear physicians. In addition to the total number of lesions found, patient-based analyses and lesion-based analyses were performed to ascertain the discrepancies between the findings of the two scanning techniques, as well as to evaluate the clinical impact of the findings. Results A group of 20 consecutive patients were analysed. In the lesion-based analysis, a total of 62 foci were found with all modalities together. Of these, 124I PET/CT found 57 (92 %), 131I SPECT/CT 50 (81 %) and planar imaging 39 (63 %). In the patient-based analysis, in 50 % of patients complete concordance between the findings of 124I PET and 131 I SPECT was seen, in 5 % complete discordance and in the remaining 45 % partial discordance, i.e. a focus or some foci seen with both modalities but another or others seen
C. de Pont : S. Halders : J. Bucerius : F. Mottaghy : B. Brans (*) Department of Nuclear Medicine, Maastricht University Medical Center, Postbox 5800, 6202 AZ Maastricht, The Netherlands e-mail: b.brans@mumc.nl J. Bucerius : F. Mottaghy Department of Nuclear Medicine, University Hospital RWTH Aachen, Aachen, Germany J. Bucerius Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, The Netherlands

more or less with one or other modality. In 5 of the 20 patients (25 %), tumour stage was changed according to the findings of one of the modalities. In 60 % of these patients this was only with the findings of 124I PET/CT. Conclusion This study showed that 124I PET/CT is preferred over 131I imaging for staging differentiated thyroid carcinoma. Keywords Differentiated thyroid carcinoma . Radioiodine . SPECT/CT . PET/CT . Iodine-124 . Iodine-131

Introduction Hybrid tomographic scanning techniques in nuclear medicine have been proven to be of substantial incremental diagnostic value in the imaging of various diseases, including differentiated thyroid carcinoma [1]. In this regard, 131I SPECT/CT has been shown to be an effective adjunct to planar imaging. Several imaging protocols have been evaluated, i.e. pretherapy and posttherapy 131I SPECT/CT in patients scheduled for remnant ablation, in patients with metastatic disease or in mixed patient groups [26]. With the addition of posttherapy SPECT/CT to planar whole-body scans (PTWBS) following 131I remnant ablation therapy, nodal stage was changed from N0 or Nx to N1 in 14 % of patients, with a resulting change of risk stratification in 25 % of patients [2]. However, that study showed potential underestimation of the incidence of microscopic disease in cervical lymph node metastases with WBS as well as 131I SPECT/CT. In patients with metastatic disease [3, 4], the addition of posttherapy SPECT/CT to PTWBS substantially improved the specificity by reducing false-positives by better characterization, localization of thyroid tissue and differentiating it from physiological uptake. However, in the study by Oh et al. [4], the diagnostic sensitivity determined in a lesion-

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based analysis was only slightly better (63 % versus 55 % for PTWBS) but determined in a patient-based analysis was the same (both 65 %). Pretherapy (low-activity) 131I SPECT/CT in the followup of patients with suspicion of persistent locoregional and/or metastatic disease provided an incremental value in the characterization of foci (i.e. better localization, identification and differentiation) in 68 % of patients [5], and led to a change in therapeutic management (i.e. indication for 131I or other therapy, 131I activity dosing) in 3658 % of patients [5, 6]. However, again the effect on diagnostic sensitivity of the addition of SPECT/CT was not as significant as found in the study by Spanu et al. [5], which showed 131I SPECT/CT discordantly positive for metastatic disease with a negative WBS in only 7 of 117 patients (6 %). On the other hand, 124I PET/CT has emerged as a powerful diagnostic and dosimetry tool providing quantitative images with superior spatial resolution and image sensitivity [7]. Several studies have shown its superiority over pretherapy [8, 9] as well as posttherapy [10, 11] planar 131I WBS. However, until now, no studies have addressed its diagnostic value in comparison to that of 131I SPECT/CT.

Materials and methods Patients A total of 20 consecutive patients were included in this retrospective analysis. These patients consisted of those who had received both posttherapy 131I SPECT/CT and pretherapy 124I PET/CT, the former performed as a standard part of posttherapy 131I scanning in our institution and the latter performed in those with larger thyroid remnants and/or suspected metastatic disease (introduced as an additional diagnostic approach in our department with the aim of improving patient care, i.e. to avoid unnecessary high doses of 131I). Secondary inclusion criteria were: (1) preparation by thyroid hormone withdrawal (THW) or by administration of recombinant human thyroidstimulating hormone (rhTSH, thyrotropin alfa), (2) a maximum of 8 weeks between 124I PET/CT and 131I SPECT/CT, and (3) availability of correlative imaging to determine the nature of positive 124I/131I PET/SPECT findings. 131I therapy was typically administered orally according to a fixed activity dosing protocol employing 2,775 MBq (75 mCi) for simple thyroid remnant ablation and 5,555 MBq (150 mCi) for regional nodal disease or distant metastasis. Image acquisitions Patients who received THW preparation, were withdrawn from tetraiodothyroxine (T4) medication for 46 weeks, or remained without medication postoperatively. In two patients,

triiodothyroxine (T3) was administered between the 124I PET/CT scan and the 131I therapy/SPECT/CT scan for logistical reasons resulting in a longer time between 124I PET/CT and 131I SPECT/CT (7 and 8 weeks, respectively). In the other patients, the time between 124I PET/CT and 131I SPECT/CT was 12 weeks. At the time of oral administration of 124I, serum TSH levels were determined to assess the level of endogenous stimulation. 124I PET/CT was performed after 24 h and 96 h (Fig. 1). In patients who received rhTSH preparation, 0.9 mg rhTSH (Thyrogen; Genzyme, Haverhill, UK) was injected intramuscularly on days 1 and 2. 124I was then administered orally on day 4, and 124I PET/CT was performed on day 5 (24 h after 124I administration) and day 8 (96 h after 124I administration) (Fig. 1). With subsequent 131I therapy, rhTSH was reinjected on days 1 and 2, and then 131I was administered on day 3, and 131I PTWBS and 131I SPECT/CT were performed on day 8 (120 h after injection). In one patient, scanning and therapy were done within 1 week. In the other patients, the time between scanning and therapy was 48 weeks. 124 I PET/CT was performed using a PET camera equipped with time-of-flight (Gemini TF PET/64-slice CT scanner; Philips, Best, The Netherlands). PET scans were acquired from the head, neck and thorax using four or five bed positions of 4 min each. In selected cases imaging was continued as far as the pelvis. The standard energy window of 439664 keV was set. Reconstruction was performed using a standard protocol with a matrix size of 288, resulting in a voxel size of 2.02.02.0 mm, with a standard kernel truncation of 14.1. A standard CT scan was performed in low-dose mode (120 keV, 30 mAs, 4-mm slice thickness, 4.0 increment) with a supplementary high-dose CT scan without administration of contrast agent (120 keV, 150 mAs, slice thickness 2 mm, increment 1.8 and matrix 512512 for the neck; 120 keV, 175 mAs, slice thickness 5 mm, increment 4.0 and matrix 512512 for the thorax). 131 I SPECT/CT was performed using a standard SPECT/CT camera (Precedence SPECT/6-slice CT scanner; Philips, Best, The Netherlands) equipped with dual 1.6-cm detectors equipped with high-energy general-purpose collimators. SPECT data were obtained using a noncircular orbit, a 12812816 matrix (voxel size 4.74.74.7 mm) and 32 angles over 180 and 45 s per stop, using a 364-keV photo peak with a 10 % window. Reconstruction space and width was 3 mm using the Philips Astonish algorithm. The WBS was acquired from head to toe using a table speed of 10 cm/min. SPECT/CT was performed immediately after planar imaging. Data analysis The 131I PTWBS SPECT/CT and 124I PET/CT scans were analysed separately and independently by two experienced nuclear medicine physicians aware of the clinical findings,

Eur J Nucl Med Mol Imaging (2013) 40:693700 Fig. 1 Flow diagram of the diagnostic and therapeutic procedures
(0.9 mg (0.9 mg 1110rhTSH) rhTSH) 7728 MBq 131I

695

131I

WBS + SPECT/CT

D1

D2

D3

D4

D5

D6

D7

D8

(0.9 mg (0.9 mg rhTSH) rhTSH)

20-28 MBq 124I

124I PET/CT

124I PET/CT

other diagnostic imaging data and definite histopathological diagnosis. Discrepancies were resolved by consensus. The 124I PET/CT findings were compared to the 131I WBS and 131I SPECT/CT findings. All results were correlated with the highdose CT scan findings. Additionally, ultrasonography with cytology of abnormalities suspicious for malignancy, MRI and/or 18F-FDG PET/CT were done to confirm positive, discrepant, unexpected and/or unresolved findings, if necessary. Abnormal findings on 124I PET/CT, 131I SPECT/CT and planar imaging were defined as areas of focally increased uptake not attributable to physiological activity. Foci were localized as (1) paratracheal, being immediately adjacent to the tracheal space, classified as thyroid remnants; (2) thyroid bed, as identifiable on the CT scan, to be correlated with other imaging modalities; (3) centrally positioned foci above the thyroid bed, classified as thyroid remnants; (4) centrally positioned foci below the thyroid bed, to be correlated with other imaging modalities; (5) laterally localized foci, classified as lymph node metastases; and (6) distantly localized foci, classified as distant metastases. To obtain the total number of foci, all foci were separately scored except in one patient with diffuse micronodular metastases of both lungs which were arbitrarily scored as two foci. Foci were regarded positive on PET if they were visible on the scan on day 1 as well as day 4. Statistics Differences in discordance between the THW and rhTSH groups were assessed using an independent samples MannWhitney U test. P values <0.05 were considered statistically significant.

received THW preparation. The use of rhTSH preparation was restricted to three patients with (very) low-risk disease (patients 15, 16 and 19) and to three patients with metastatic disease because of poor tolerability (patients 17, 18 and 20). Patient-based analysis Table 2 shows the results of 124I PET, 131I SPECT and planar imaging. Comparing 124I PET and 131I SPECT, overall in 10 of the 20 patients (50 %) completely concordant results were seen. In one patient, the results were completely discordant. The remaining 9 patients (45 %) showed partially discordant results, with a focus or some foci seen with both modalities but another or others seen more or less with one or other modality. Of the 10 patients with partial or complete discordance, 4 (40 %) received rhTSH preparation and six (60 %) THW preparation. In other words, 4 of 6 (67 %) who received rhTSH preparation showed discordance versus 6 of 14 patients (43 %) who received THW preparation. This difference was not statistically significant (p =0.342, independent samples Mann-Whitney U test). In 5 of the 20 patients (25 %), tumour stage was changed as a result of discrepant findings between the modalities (Table 2). In 3 of these patients (patients 2, 12, 16; 3 of 20, 15 %) this was only by 124I PET/CT: nodal status upstaged to a N1a or N1b in comparison to the other modalities (patients 2 and 16) and a solitary lung metastasis upstaged to M1 (patient 12). In one patient (patient 3), 124I PET/CT and 131I SPECT/CT findings led to the same upstaging of nodal status as compared to planar imaging. In one patient (patient 14), M1 disease was only seen by planar imaging, and not by 124I PET or 131I SPECT. Lesion-based analysis A total of 62 foci were found by all modalities together. Of these, 124I PET/CT found 57 of 62 (92 %), 131I SPECT/CT found 50 (81 %) and planar imaging found 39 (63 %). Thus, 124I PET found more foci than either 131 I PTWBS or SPECT.

Results Patient characteristics Table 1 shows the patient characteristics. The group consisted of 12 men and 8 women aged between 17 and 87 years (mean 53, median 58 years). Most (14 of 20) patients who

696

Table 1 Patient characteristics Pathological stage

124

Patient I 2,775 2,775 2,775 2,775 2,775

131

Gender I 8 2 2 2 2

Age (years)

Type

Prior

131

I (MBq)

Indication

Preparation

Administered activity (MBq)

Interval (weeks)

TSH (mU/l)a

1 2 3 4 5 (2,775)

M F M M M

57 42 27 27 58

pT1mN0 PT1Nx pT2Nx pT2Nx pT3N0

Follicular Papillary Papillary Papillary Papillary

No No No No No

Ablation Ablation Ablation Ablation Ablation

THW THW THW THW THW

24 25 27 23 23

111 71.7 135 140 110

(2,775) (2,775) (13,875) (14,985)

6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

M F F M M M F F M M F F M M F

82 39 26 33 87 68 82 72 72 63 17 44 67 24 72

pT3N0 pT3N1a pT3N1b pT3Nx pT3Nx pT4aN0 pT4aN0 pT4aN1a pT4aN1b pT1N0 pT1Nx pT1N1b pT2N1b pT2N0 pTxNx

Follicular Papillary Papillary Follicular Papillary Papillary Papillary Papillary Papillary Follicular Papillary Papillary Papillary Follicular Follicular

No Yes No No No No No No No Yes No Yes Yes No Yes

Ablation Residual disease Ablation Ablation Ablation Ablation Ablation Ablation Ablation Residual Ablation Recurrence Recurrence Ablation Residual disease

THW THW THW THW THW THW THW THW THW rhTSH rhTSH rhTSH rhTSH rhTSH rhTSH

22 24 26 22 24 22 28 26 24 20 22 23 20 22 22

2,775 5,550 2,775 2,775 2,775 2,775 7728 2,775 2,775 1,110 2,775 2,775 5,550 2,775 5,550

1 7 1 2 2 1 1 2 2 6 7 4 8 5 1

27.4 78.1 n.d. 58.9 n.d. 72.6 61.5 68.7 n.d. 42.8 94.5 n.d. 177 91.8 7.8

n.d. no data.
124

Eur J Nucl Med Mol Imaging (2013) 40:693700

Serum TSH levels in (mU/l) at the day of

I administration.

Eur J Nucl Med Mol Imaging (2013) 40:693700 Table 2 Findings of

124

697

I PET/CT, 131I SPECT/CT and 131I planar imaging in thyroid carcinoma

Patient Thyroglobulin (ng/ml)

Number and localization of foci Paratracheal Thyroid bed Upper central Lower central cervical cervical PET/SPECT/ PET/SPECT/ Interpretation planar scans planar scans Lateral neck Distant

PET/SPECT/ PET/SPECT/ Interpretation planar scans planar scans 1 2a 3a 4 5 6 7 <0.25 0.7 68 8.2 1.3 4,028 <0.25 2/1/1 Negative 1/1/1 3/2/1 1/1/1 Lymph node metastasis, by CT 1/1/1 Remnant, by CT 1/1/1 1/1/1 Remnant, by US/cytology Remnant, by US/cytology

PET/SPECT/ PET/SPECT/ planar scans planar scans

1/1/1 1/1/1

1/0/0 1/1/0

1/1/1 (skull)

8 9 10 11 12a 13 14a

12.2 6.6 <0.25 44 803 2.6 2/2/2 3/3/3 2/2/2 2/2/2 1/1/1

1/1/1 Remnant, by CT and US/cytology Remnant, by CT 1/0/1 2/1/0 0/1/0 Lymph node 0/2/0 metastasis, by MRI 1/0/0 (lung) 0/0/2 (lung)

Not performed 2/2/1

15 16a

0.9 <0.25

1/2/1 1/1/1

1/1/0 1/0/0

Remnant, by US/cytology Lymph node metastasis, by FDG PET

1/1/1

17 18 19

<0.25 7.8 1.2

Negative 1/0/0 3/3/2 1/1/0 Lymph node metastasis, by CT 14/11/9 21/19/15 10/9/7 5/4/5 0/1/0 4/4/0 16/12/12

20 Total
a

36,790

Patients in whom discrepant findings resulted in a change in tumour stage.

Regarding paratracheal foci, 124I PET/CT found the highest number of foci, but in only one patient (patient 18) was thyroid remnant demonstrated by PET but not by the other modalities. Regarding foci in the thyroid bed, 124I PET and 131I SPECT were highly concordant; only in one patient (patient 16) a focus was seen only on 124I PET/CT, and this focus was confirmed by 18F-FDG PET/CT. Regarding foci in the upper central cervical region, the findings were quite similar; only in one patient (patient 11) was a focus seen only on 124I PET/CT (and planar imaging). In the lower central cervical region, only one focus was found by 131I SPECT/CT but not by 124I PET/CT, and this focus was confirmed as lymph node metastasis by MRI (patient 14). In four patients (patients 2, 3, 12 and 14) lateral lymph nodes were found and confirmed as metastases; the findings were often discrepant between modalities, but the

overall detection rate was highest for 124I PET/CT, as shown in Fig. 2. Finally, 124I PET/CT was clearly most sensitive in terms of the number of detected distant metastases (patients 12 and 20), with the exception of one patient (patient 14) with micronodular lung metastases that were only seen on planar imaging. Day 1 and day 4 124I PET/CT images were generally similar. Positive lesions were usually clearly visible on both days. However, the target-to-background ratio improved over this time, making lesion detection easier.

Discussion This study showed superior results with pretherapy 124I PET/CT than with posttherapy 131I planar imaging and

698 Fig. 2 Comparison between pretherapy 124I PET/CT and posttherapy 131I SPECT/CT images. On the 124I PET/CT MIP image (top left) and on the fused PET/CT image (top right), a lateral neck focus is clearly seen (arrows). On the CT image (centre), this focus corresponds to a small lymph node (arrow). On the corresponding 131I SPECT/CT images (bottom), no abnormality is seen in this area

Eur J Nucl Med Mol Imaging (2013) 40:693700

SPECT/CT, resulting in a clinically relevant upstaging in 15 % of the included, consecutive and clinically representative patient group. We believe this difference was related to falsenegative findings with SPECT/CT as a result of the inferior spatial resolution and camera sensitivity, despite much higher administered activities, and not to false-positive findings with PET/CT, as positive findings were verified by correlative imaging and/or cytology. The most important advantage of pre- rather than posttherapy staging is that it provides optimal risk stratification before therapy, disclosure of unexpected sites influencing specific therapy (surgery, radioiodine, local therapy), prognostic information, and the opportunity for lesion dosimetry [6]. Although high-activity radioiodine administration as empirical therapy, together with posttherapy diagnostic scintigraphy and 131I SPECT/CT (because of the low sensitivity of planar 131I imaging and the risk of stunning), is still a widely accepted practice, the long-term side effects of this practice have increasingly been emphasized [12, 13]. Presently, there are no studies in the literature that have compared pre- and posttherapy 131I SPECT/CT scanning. Theoretically, the sensitivity of radioiodine imaging depends on the administered radioactivity, implying that low-activity pretherapy planar 131I scanning would have a lower detection rate than a high-activity posttherapy scan [14]. Therefore, although our study population was small,

extrapolation of this would imply a higher detection rate with 124 I PET/CT than with posttherapy as well as pretherapy 131I SPECT/CT. Several authors have indicated the usefulness of pretherapy 123I imaging [15, 16]. Indeed, high-quality images can be obtained and SPECT/CT performed. Unfortunately, up to now no studies have compared pretherapy 124I PET/CT with pretherapy 123I SPECT/CT. However, the big downside of 123I is its short half-life of 12.3 h (as compared to 4.2 days for 124I) which is insufficient to accurately model the washout phase of radioiodine from the target lesion beyond 24 h, during which most of the radiation dose is delivered. Because the resulting effective half-life of radioiodine varies between patients and even between lesions, accurate dose estimates can only be derived from individual calculations of this washout phase [17]. An important question in this study is whether confounding factors other than those related to differences in performance of the imaging techniques could have influenced the observed differences. For logistic reasons, there were slight differences between the imaging schedules. Patients received 124I 1 day later than 131I following rhTSH administration on 2 days. However, as can be seen from Table 1, TSH values at the time of 124I administration generally indicated a maximum stimulatory effect. Second, scanning was done on day 5 for 131I as compared to day 4 for 124I, and

Eur J Nucl Med Mol Imaging (2013) 40:693700

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with much higher, posttherapeutic activities. 131I SPECT could also have been more sensitive because of more intense stimulation by TSH, either endogenous in the THW group because of a slightly longer T4 withdrawal time before 131I SPECT as compared 124I PET, or exogenous in the rhTSH group after a second pair of rhTSH injections as compared to a single pair before 124I. In the rhTSH group, there was a higher, although not statistically significantly higher, number of patients with discordance between the PET/CT and SPECT/CT findings, than in the THW group. Concern has been expressed that rhTSH preparation may not be equal to THW preparation [18]. Our patient sample was too small to allow a comparison between THW and rhTSH preparation The higher discordance between the PET/CT and SPECT/CT findings in patients who received rhTSH preparation could be explained by the fact that it is more challenging to achieve the same degree of TSH stimulation in a rhTSH diagnostic/therapeutic protocol than with THW because of double versus single rhTSH stimulation, and/or a variable degree of TSH suppression by the administration of T4/T3 in the time between diagnostic scanning and therapy. Further studies in larger groups will allow differences between THW and rhTSH to be evaluated, and this is also an important factor to consider in dosimetry oriented trials. In one patient, diffuse micronodular lung metastases were visible on planar imaging, but were false-negative on 124I PET/CT as well as on 131I SPECT/CT. This has previously been reported by others [7]. In our patient, a subtle increase in lung activity on planar imaging caused by a very moderate uptake of 131I by the metastases apparently faded away in the background activity after PET as well as after SPECT reconstruction. In such patients, a quantitative index has been suggested for use as an aid in 124I PET/CT [7]. Careful inspection of the CT portion is absolutely necessary to pick up apparently low or absent uptake in lung metastases in order to avoid this problem. The clinical heterogeneity in our population in terms of tumour stages IIV and indications for 131I (ablation, or residual or recurrent disease) may be viewed as a limitation of this study whose aim was to include a clinically representative patient population. Although a total of 62 evaluated lesions is a reasonable number, results in this relatively small patient sample should be confirmed by others. We did not study the clinical relevance of a pretherapy PET/CT or pre- or posttherapy SPECT/CT staging procedure as such, but merely the performance of these modalities. Although it is generally accepted that pretherapy staging using nuclear medicine techniques is useful in patients with high-risk disease, this may not be the case for patients with low-risk disease. In our institution, patients eligible for 124I PET/CT represent a higher percentage of patients with high-risk disease as compared to other patient populations with differentiated thyroid cancer, and thus a higher pretest probability of abnormal findings was

expected in this population. We did not use histological confirmation of lesions as the gold standard, as this is not feasible in an average patient group in whom neck surgery has been performed and in whom sampling of distant sites carries a substantial risk of complications. We relied on correlative imaging using ultrasonography, CT, MRI, 18 F-FDG PET/CT and cytological sampling, as indicated, to verify positive and discrepant findings, for example for the distinction between local remnants and local lymph node metastases, or differentiation between distant metastases and physiological activity. The purpose of our study was to compare 124I PET/CT with 131 I SPECT/CT, not to compare with these other modalities. In this series, high-dose diagnostic CT without administration of contrast agent was used to aid the identification of the anatomical substrate at sites of small thyroid remnants and/or lymph node metastases in the neck, as well as the diagnosis of (micronodular) pulmonary metastases. Recently, combined 124 I-PET/MRI has provided a further advance in the field, enhancing diagnostic sensitivity for lesions <10 mm. and improving pretherapeutic lesion dosimetry [19]. Conclusion This study showed that 124I PET/CT is preferred over 131I imaging for staging differentiated thyroid carcinoma. Further studies should be done to confirm these results, to investigate possible differences between withdrawal or rhTSH preparation and to study the impact of pretherapy 124I imaging on outcome variables such as patient survival and quality of life and its cost effectiveness. The unique capabilities of 124I PET/CT and in the future PET/MRI may allow optimal dosimetry in small and large lesions, allowing individual radiotherapy planning.
Acknowledgments The technical and logistic support of Florence de Vreede-Lacroix and Renee Franssen is highly appreciated. Conflicts of interest None.

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