The role of FDG-PET in localization of recurrent lesions of differentiated thyroid cancer (DTC) in patients with asymptomatic hyperthyroglobulinemia in a real clinical practice

in European Journal of Endocrinology
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  • 1 Nuclear Medicine and Endocrine Oncology Department
  • | 2 Department of Epidemiology and Silesia Cancer Registry, M.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland

Correspondence should be addressed to A Kukulska; Email: akukulska@io.gliwice.pl
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Introduction

Available methods, including serum thyroglobulin (Tg) measurement and whole-body scan (WBS) performed after radioiodine administration, allow for a precise diagnostics in differentiated thyroid cancer (DTC). However, some asymptomatic patients demonstrate negative WBS despite a high Tg serum concentration. In these subjects, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered. The primary aim of our study was to evaluate a diagnostic value of FDG-PET in asymptomatic hyperthyroglobulinemia. The secondary one was to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level.

Material

One hundred and ten FDG-PET/CT scans were retrospectively analyzed, 85 scans were done under TSH stimulation and 25 on LT4 suppressive therapy. Follow-up ranged between 4 and 9 years.

Results

The first FDG-PET/CT detected cancer foci in 49 subjects with a global sensitivity of 45%. When the sensitivity was evaluated with reference to TSH stimulation and suppression, its values were 50 and 28% respectively. In 42 patients, FDG-PET failed to diagnose the reason for elevated Tg level. During further follow-up, in 17 of them, DTC recurrence was detected by other methods (CT, MRI, US). Fourteen subjects with asymptomatic hyperthyroglobulinemia were free of DTC progression for at least 4 years.

Conclusions

FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during the 5-year follow-up.

Abstract

Introduction

Available methods, including serum thyroglobulin (Tg) measurement and whole-body scan (WBS) performed after radioiodine administration, allow for a precise diagnostics in differentiated thyroid cancer (DTC). However, some asymptomatic patients demonstrate negative WBS despite a high Tg serum concentration. In these subjects, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered. The primary aim of our study was to evaluate a diagnostic value of FDG-PET in asymptomatic hyperthyroglobulinemia. The secondary one was to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level.

Material

One hundred and ten FDG-PET/CT scans were retrospectively analyzed, 85 scans were done under TSH stimulation and 25 on LT4 suppressive therapy. Follow-up ranged between 4 and 9 years.

Results

The first FDG-PET/CT detected cancer foci in 49 subjects with a global sensitivity of 45%. When the sensitivity was evaluated with reference to TSH stimulation and suppression, its values were 50 and 28% respectively. In 42 patients, FDG-PET failed to diagnose the reason for elevated Tg level. During further follow-up, in 17 of them, DTC recurrence was detected by other methods (CT, MRI, US). Fourteen subjects with asymptomatic hyperthyroglobulinemia were free of DTC progression for at least 4 years.

Conclusions

FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during the 5-year follow-up.

Introduction

Differentiated thyroid cancer (DTC) is generally characterized by a good prognosis and long-term course of the disease. Available methods allow for a precise diagnostics and effective treatment in most DTC patients (1, 2). Serum thyroglobulin (Tg), a protein produced by both normal thyroid follicular cells and DTC cells, constitutes a very useful DTC marker. In patients who underwent total thyroidectomy and complementary radioiodine (RAI) treatment, the only source of thyroglobulin are DTC cells (3). Moreover, DTC cells show the ability of iodine uptake. This feature enables the use of RAI for DCT diagnostics and treatment (4, 5). However, in some patients, DTC cells do not demonstrate iodine uptake. In such cases, the sensitivity of whole-body scan (WBS), performed after RAI administration, is insufficient to localize cancer foci despite a high serum Tg concentration. It concerns mostly asymptomatic patients, without clinically apparent disease and no abnormalities in imaging studies, in whom a rise in serum Tg level is the only signal of DTC progression (asymptomatic hyperthyroglobulinemia). Early detection of DTC relapse in these patients significantly increases the possibility of an effective treatment, especially in a case of local recurrence or single metastases amendable for surgery. In a patient with elevated serum Tg level, negative WBS and normal results of imaging studies fluorodeoxyglucose-positron emission tomography (FDG-PET) may be considered (6, 7, 8). It is in fact an examination dedicated for the diagnostics of other types of cancer that, in contrary to DTC, show a high dynamics and rapid cell divisions. However, loss of the ability of RAI uptake by DTC cells may be a signal of a partial cancer dedifferentiation. Additionally, some DTC subtypes are characterized by a more aggressive course of the disease, observed from its onset (9, 10). In such cells, glucose metabolism is increased, which results in a higher and more intense FDG uptake in cancer foci than in normal tissues and enables cancer localization (11). Positive FDG-PET result has a negative prognostic significance, while the value of a negative FDG-PET scan in patients with isolated hyperthyroglobulinemia is unclear.

Asymptomatic hyperthyroglobulinemia in DTC patients after primary treatment, involving total thyroidectomy and complementary RAI therapy, constitutes an unquestionable indication for FDG-PET. However, the conditions under which PET/Ct should be done are yet to be established. Hormonal status is particularly important in DTC diagnostics. It is believed that TSH stimulates glucose uptake by an increase in GLUT expression in cellular membrane and glycolysis stimulation. According to some authors, TSH increase may improve the sensitivity of FDG-PET (9, 12). It is believed that endo- and exogenous TSH stimulation gives similar outcomes (13).

Though there are no doubts regarding the need of FDG-PET in patients with asymptomatic hyperthyroglobulinemia, the value of Tg cut-off level that should indicate FDG-PET is still discussed. The most often recommended Tg value is 10 ng/mL (14, 15). However, any detectable Tg level may be worrying. Recently, the role of dynamic changes in serum Tg concentration is particularly emphasized.

FDG-PET is recommended when Tg doubling time is shorter than 1 year (16). Noteworthy, the role of FDG-PET in DTC is not confined to asymptomatic Tg increase. Its prognostic value as well as the usefulness in DTC follow-up is also emphasized (17). Although previous studies have reported sufficient FDG-PET sensitivity, in real clinical practice the results are often disappointing. Thus, our report considers the sensitivity of FDG-PET in real practice.

Thus, the aim of our study was rather to evaluate the usefulness of a widely accepted method in a real clinical practice than the exact diagnostic value of FDG-PET in DTC patients with elevated serum Tg level. We also tried to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level.

Subjects and methods

The study involves 92 DTC patients, 55 women and 37 men in whom 110 FDG-PET examinations, performed between 2006 and 2011, were done to localize the source of increased Tg level. Mean age was 54 years (range 9–86) in women and 57 years (range 21–86) in men. There were 60 subjects with papillary, 17 with follicular and 6 with oxyphilic thyroid cancer, whereas in the remaining 9 patients, poorly differentiated thyroid cancer was diagnosed. According to TNM classification (version 6 from 2002), a primary tumor was postoperatively staged as pT1 in 10, pT2 in 13, pT3 in 35 and pT4 in 14 subjects. In 20 patients, T feature was not reported in the histopathological examination (Tx). Lymph node metastases (pN1) were found in postoperative histopathological examination in 43 subjects (Table 1). No patient presented distant metastases at DTC diagnosis. All subjects underwent primary treatment involving total thyroidectomy and complementary RAI therapy. Therapeutic RAI activities ranged between 60 and 100 mCi and no patient demonstrated RAI uptake outside thyroid bed in posttherapeutic WBS. The patients were subjected to DTC monitoring due to asymptomatic elevated serum Tg level. Nobody showed DTC recurrence or distant metastases on WBS or in systematically repeated different imaging studies. Duration of the further follow-up after FDG-PET examination was 4–9 years – most often 6 years (Table 2). During this period, subsequent imaging studies, including FDG-PET, were performed. Noteworthy, in 13 patients, FDG-PET was repeated several times.

Table 1

Characteristics of the study group.

CharacteristicsValues
Sex
Women55
Men37
Age (years; mean (range))
Women54 (9–86)
Men57 (21–86)
Histologic type
Papillary60
Follicular17
Oxyphilic6
Poorly differentiated9
T stage*
pT110
pT213
pT335
pT414
pTx20
Lymph node metastases§
pN143
Risk of disease recurrence after initial therapy
ATA low risk26
ATA intermediate risk40
ATA high risk18
Unknown8

As reported in the histopathological examination after thyroidectomy; §As reported in the histopathological examination after surgery.

Table 2

Follow-up period of the patients under the study (a median of 6 years). Median follow-up of patients who did not demonstrate DTC relapse was 5.5 years.

Time of follow-up (years)987654
Number of patients41718191618

Twenty-five FDG-PETs were done under TSH suppres­sion and 85 under TSH stimulation, of them 46 with the use of recombined thyrotropin α (rhTSH) (exogenous stimulation). These examinations done under TSH suppression were prompted either by consecutively increasing Tg level or by previous statement of Tg > 10 ng/mL at the TSH stimulation. Detectable serum Tg level and prolonged hyperthyroglobulinemia, especially increasing Tg concentrations, constituted the indications for FDG-PET (Table 3).

Table 3

Serum Tg concentrations that constituted an indication to perform PET-FDG examination.

Mean/median Tg concentration measured under TSH suppression (ng/mL)Range of Tg concentrations measured under TSH suppression (ng/mL)Mean/median Tg concentration measured under TSH stimulation (ng/mL)Range of Tg concentrations measured under TSH stimulation (ng/mL)
The first FDG-PET/CT examination54/100.2–738122/190.9–1067
Subsequent FDG-PET/CT examinations166/183.4–113441/4128–54

At the beginning, serum Tg concentration was measured by Trace (Timed Resolved AMplified Cryptate Emission) method (BRAHMS Aktiengeselschaft, Kryptor). Next, ECLIA (ElectroChemiluminescent Immuno Assay) method (Roche diagnostic, Cobas e411) was used. The analytic sensitivities of both methods were 0.17 and 0.1 ng/mL, whereas functional sensitivities were 0.5 and 1 ng/mL respectively.

PET combined with computed tomography (PET/CT hybrid scanner Philips GEMINI GXL) was performed 60 min after intravenous administration of 7.4 mCi of 18flourodeoxyglucose (18FDG). The scanning volume covered the area from the top of the skull to the middle of the thighs. The reconstruction was made in three basic planes after correction for attenuation based on CT examination. CT scan was performed in the spiral mode, without intravenous contrast administration, with images reconstructed every 3 mm.

Locoregional neck abnormalities have always been verified by neck US. If it was possible (when the recurrent tumor was visualized), FNAB was carried out to confirm DTC recurrence. If necessary, in a case of distant metastases with tracer uptake on FDG-PET, additional CT or MRI have been done. All patients were negative at WBS, performed before FDG-PET.

Statistical analysis was carried out using STATISTICA software, version 10 (2011; StatSoft, Inc; USA and Stata 13.1 for Windows). Comparison between the groups was performed using Yates’ chi-square test or Fisher’s exact test; P value <0.05 was considered as significant.

Results

Forty-nine FDG-PETs (45%) detected cancer foci, 3 (2%) examinations gave an equivocal result, whereas in 58 remaining FDG-PETs (53%), no pathological tracer uptake was noticed. The sensitivity of FDG-PET, carried out under TSH suppression, was 28%, whereas, when the examination was performed after TSH stimulation, it was 50% (P = 0.069; Fisher’s exact test) (Table 4). When FDG-PET was done under TSH stimulation, its sensitivity did not differ significantly regarding the way of TSH stimulation (endogenous or exogenous). These values for endogenous and exogenous TSH stimulation were 54 and 46% respectively (P = 0.592) (Table 5).

Table 4

The sensitivity of FDG-PET with reference to patient’s hormonal condition at the time of the examination.

Positive resultNegative resultEquivocal resultTotal
Whole group49 (45%)58 (53%)3 (2%)110
TSH suppression7 (28%)17 (68%)1 (%)25
TSH stimulation42 (50%)41 (48%)2 (2%)85
Table 5

The results of FDG-PET depending on the way of TSH stimulation.

Results of FDG-PETPositiveNegativeE
FDG-PET carried out on TSH stimulation42 (50%)41 (48%)2 (2%)
FDG-PET carried out on exogenous TSH stimulation (rhTSH)21 (46%)25 (54%)
FDG-PET carried out on endogenous TSH stimulation21 (54%)16 (41%)2 (5%)

The change in the cut-off value of serum Tg level, which constituted an indication for FDG-PET, influenced its sensitivity. When we used Tg cut-off value of 10 ng/mL, measured in patients under TSH suppression, the obtained FDG-PET sensitivity was 68% (Table 6). Among 31 patients in whom serum Tg level, measured under TSH suppression, was >10 ng/mL, FDG-PET performed under TSH stimulation allowed for the detection of Tg source in 19 subjects with a sensitivity of 73%.

Table 6

Results of FDG-PET with reference to Tg cut-off level used. This table presents a number of patients categorized according to Tg cut-off value, measured under TSH suppression, on which basis the decision to perform FDG-PET/CT was made. Patients with Tg > 10 ng/mL are also included in the groups with Tg > 5 and 2 ng/mL.

Tg concentration measured under TSH suppressionNumber of patientsNegative PET-FDGPositive PET-FDG
Tg ≥ 10 ng/mL3110 (32%)21 (68%)
Tg ≥ 5 ng/mL4321 (49%)22 (51%)
Tg ≥ 2 ng/mL5027 (53%)23 (47%)

The sensitivity of FDG-PET differs depending on histopathological cancer subtype (P = 0.049), especially when FDG-PET was performed after TSH stimulation (P = 0.005) (Table 7). The global sensitivity of FDG-PET, carried out in a subgroup of patients with papillary thyroid carcinoma, was 37% (27% when FDG-PET was performed under TSH suppression and 40% after TSH stimulation). Considering follicular thyroid cancer, the global sensitivity was 70%, for studies done under TSH suppression and stimulation 25 and 92% respectively. The differences were statistically significant (P = 0.025 for the whole groups and P = 0.002 when FDG-PET was done after TSH stimulation). Considering oxyphilic and poorly differentiated thyroid cancer, the sensitivity of FDG-PET was 67 and 33% respectively.

Table 7

FDG-PET sensitivity with reference to histopathological characteristics of DTC.

Histopathological subtypeFDG-PET sensitivity in the whole group (%)FDG-PET sensitivity performed under TSH suppression (%)FDG-PET sensitivity performed under TSH stimulation (%)
Papillary thyroid cancer362740
Follicular thyroid cancer702592
Oxyphilic thyroid cancer6710060
Poorly differentiated thyroid cancer33050

A group of 42 subjects, in whom FDG-PET did not localize DTC foci, was observed during the next 4–9 years. The analysis involved all patients, regardless of Tg and TSH concentration at FDG-PET. In 17 of them (40%), DTC progression was diagnosed and new cancer foci were visualized by subsequent imaging studies. In eight patients, locoregional recurrence, found in neck ultrasound (US), was confirmed by the fine needle aspiration biopsy (FNAB). In four other patients, mediastinal lymph nodes or bone metastases were detected by another FDG-PET, performed 1–3 years later, and in two lung and bone metastases were observed in posttherapeutic WBS, done after RAI treatment due to persistent hyperthyroglobulinemia following FDG-PET. However, in the remaining three patients, mediastinal or lung metastases were diagnosed by CT scan. Eleven (26%) of these 42 subjects demonstrated small lung nodules of clinically undetermined significance and 14 (33%) were free of disease for a median period of 5.5 years. Mean serum Tg level for the whole group of 42 patients was 6.25 ± 2.8 ng/mL, when measured by TSH suppression and 15 ± 6.6 ng/mL after TSH stimulation, median values were 6.9 and 15.0 ng/mL respectively.

Discussion

FDG-PET is routinely used in oncology, especially for the evaluation of disease stage and the course of highly aggressive neoplasms. Its diagnostic value is related to its high sensitivity. DTC, characterized by an indolent nature, may not be a good ‘candidate’ for such diagnostics. Nevertheless, currently, FDG-PET has been widely accepted in DTC diagnostics, particularly in patients without clinical evidences of the disease and with a negative WBS after RAI administration, in whom the only symptom of DTC progression is asymptomatic hyperthyroglobulinemia. However, the data related to FDG-PET sensitivity vary across the studies and range between 50 and 98% (18, 19). Altenvoerde et al. reported the group of 12 DTC patients with serum Tg level >20 ng/mL. FDG-PET revealed the source of hyperthyroglobulinemia in a half of them (18). While Finkelstein et al., on the basis of the results of FDG-PET performed in 65 DTC patients, calculated its sensitivity to be 98% (19).

In 2009, Dong et al. carried out a meta-analysis that assessed the sensitivity and specificity of FDG-PET as 94 and 84% respectively (20). Similar data, reported by Caetano et al. in 2015, was obtained from a meta-analysis evaluating the sensitivity and specificity of FDG-PET/CT in the detection of DTC recurrences to be 93 and 81% respectively (21). The sensitivity of FDG-PET/CT in our study was relatively low probably because some enrolled patients showed only a slight increase in serum Tg level. We are aware that the evaluation of the diagnostic value of PET/CT is an old issue, better analyzed by previous studies and that our results in terms of FDG-PET sensitivity are not in line with the literature. However, we should emphasize that our study was not in fact aimed to evaluate the sensitivity of FDG-PET and to perform a prognostic analysis. We rather focused on the clinical usefulness of a widely accepted method in the real clinical practice. According to the published data and our own analysis, a positive FDG-PET result was achieved in DTC patients with higher serum Tg level (18, 22). When Tg cut-off level that constitutes an indication for FDG-PET is lower, the sensitivity of FDG-PET decreases as a larger tumor volume is related to the higher Tg level and simultaneously the larger tumor is easier to detect. The choice of an appropriate Tg cut-off value for FDG-PET, in DTC patients with asymptomatic hyperthyroglobulinemia, results in a better accuracy of FDG-PET. We are aware that the Tg cut-off value, proposed by the ATA guidelines, is not always confirmed in the daily practice (14). The low sensitivity observed in our study also reflects that higher Tg value may be required to achieve a better accuracy of FDG-PET.

Some authors recommend Tg value of 10 ng/mL, measured under TSH suppression (15), whereas others, including ATA guidelines, recommend Tg 10 ng/mL, measured under TSH stimulation. In our study, we evaluated the Tg cut-off value under TSH suppression, because most Tg evaluations are carried out during L-T4 administration in the majority of our patients.

Another important issue that should be considered with reference to FDG-PET in DTC subjects is the hormonal status when FDG-PET is performed. Wang et al., in a paper published in 1999, did not report any improvement in the detection of DTC foci after TSH stimulation (9). However, Moog et al. suggest carrying out FDG-PET under TSH stimulation, as according to them glucose uptake by DTC cells depends on serum TSH concentration (23). Similarly, Chin et al., in a small series of DTC patients, confirmed the beneficial effect of TSH stimulation on the FDG-PET results (24). Moreover, the meta-analysis of Ma et al. also demonstrated a positive impact of TSH stimulation on the sensitivity of FDG-PET. On the other hand, Leboulleux et al. found more DTC foci after rhTSH stimulation although they did not observe any increase in the number of positive FDG-PETs comparing with negative ones with reference to TSH stimulation (13). Hormonal stimulation in our study improved PET-FDG sensitivity and when the criterion of Tg cut-off value of 10 ng/mL in patients qualified for FDG-PET was used, the sensitivity was 73%.

The differences in the sensitivity of FDG-PET according to histological subtype of thyroid cancer are interesting. It points a higher sensitivity of FDG-PET in follicular thyroid carcinoma. Noteworthy, the most aggressive cancer in analyzed group – poorly differentiated thyroid carcinoma – was related to much lower FDG-PET sensitivity. However, the PDTC subgroup was very small, so further studies are required.

Even under the most optimal conditions, there are some patients in whom FDG-PET gives a negative result despite the elevated serum Tg level. Therefore, we asked the question whether negative FDG-PET in a patient with asymptomatic hyperthyroglobulinemia might be related to a good prognosis. According to Robbins et al., a negative or positive FDG-PET result allows for allocation of a particular patient to a low-risk or a high-risk group of DTC-related death (25). However, the authors also included DTC patients with clinically overt metastases into the study group, where the lack of FDG uptake in cancer foci is related to lower DTC aggressiveness and simultaneously to the slower DTC progression. Regarding our group of DTC patients without clinically apparent metastases, the lack of FDG uptake did not unequivocally exclude the presence of aggressive metastases still too small to be detected. Our data did not indicate unequivocal relationship between the negative result of FDG-PET and favourable DTC course. We did not evaluate the overall survival because all study participants were alive at the end of follow-up. We were not able to compare the event-free survival (EFS) depending on FDG-PET result either. In FDG-PET, the detection of a cancer lesion, leading to an increase in Tg level, was equal to DCT progression (EFS = 0).

The follow-up for at least 4 years of a group of 42 DTC patients with a negative FDG-PET result showed that DTC progression was diagnosed in most of them. Thus, negative FDG-PET in such patients does not guarantee a long-term asymptomatic DTC course. In our study, a long-term event-free survival, at least 4 years, was observed in 33% of FDG-negative patients only. These data may change after a longer period if we are able to evaluate the character of multiple small lung nodules noticed in nearly every third patient. DTC progression and new DTC foci were found in subsequent imaging studies in 40% of patients. Most often, local recurrences, detected by neck US and confirmed by FNAB, were observed. Noteworthy, in four patients, DTC foci were localized by subsequent FDG-PET, performed 1–3 years later. This observation not only emphasizes the important role of FDG-PET in diagnostics of asymptomatic hyperthyroglobulinemia but also underlines the significance of conditions under which FDG-PET is carried out and their impact on its sensitivity. We believe that FDG-PET done under TSH stimulation is related to its increased sensitivity. Moreover, the use of an appropriate Tg cut-off level may additionally improve it. On the other hand, our analysis indicates that FDG-PET might be carried out in patients with lower than required serum Tg level, especially when its growth is noticed during the follow-up. Based on the follow-up of a group of DTC patients in whom the first FDG-PET did not localize the source of hyperthyroglobulinemia, we demonstrated that a negative FDG-PET did not guarantee a long-term progression-free survival and did not justify any less strict DTC monitoring. A negative result of the first FDG-PET did not constitute any contraindication to repeat this examination, especially when further increase in serum Tg level was observed. The use of TSH stimulation showed a beneficial effect on the quality of FDG-PET, particularly when rhTSH may be administered, demonstrating a comparable efficacy to endogenous stimulation without an unfavorable impact on quality of life. The small number of our group, additionally divided regarding Tg serum concentration and hormonal condition, is the essential limitation of our study. However, considering the fact that DTC is a rare neoplasm, other studies involving even a smaller number of patients are commonly published (9, 22, 23, 24). On the other hand, long follow-up constitutes the most important value of our analysis, crucial in a case of DTC characterized by a long-term disease course. The authors plan the reassessment of the whole group, particularly in patients with small lung nodules. If a long-standing DTC remission is obtained, it will allow for a better evaluation of the prognostic value of a negative FDG-PET result in patients with asymptomatic hyperthyroglobulinemia.

Conclusions

FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool, particularly when it is performed under optimal conditions. However, widely accepted Tg cut-off values do not always find a confirmation in a daily practice. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression for a median 5-year period. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during 5-year follow-up.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

The project was supported by the Polish National Center of Research and Development MILESTONE project – Molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant no. STRATEGMED 2/267398/4/NCBR/2015.

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  • 16

    Giovanella L, Trimboli P, Verburg FA, Treglia G, Piccardo A, Foppiani L & Ceriani L. Thyroglobulin levels and thyroglobulin doubling time independently predict a positive 18F-FDG PET/CT scan in patients with biochemical recurrence of differentiated thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging 2013 40 874880. (doi:10.1007/s00259-013-2370-6)

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  • 17

    Wang W, Larson SM, Fazzari M, Tickoo SK, Kolbert K, Sgouros G, Yeung H, Macapinlac H, Rosai J & Robbins RJ. Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2000 85 11071113. (doi:10.1210/jcem.85.3.6458)

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  • 18

    Altenvoerde G, Lerch H, Kuwert T, Matheja P, Schäfers M, Schober O. Positron emission tomography with F-18-deoxyglucose in patients with differentiated thyroid carcinoma, elevated thyroglobulin levels, and negative iodine scans. Langenbeck’s Archives of Surgery/Deutsche Gesellschaft für Chirurgie 1998 383 160163. (available at: http://www.ncbi.nlm.nih.gov/pubmed/9641890). Accessed on 25 March 2016.

    • Search Google Scholar
    • Export Citation
  • 19

    Finkelstein SE, Grigsby PW, Siegel BA, Dehdashti F, Moley JF & Hall BL. Combined [18F]fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for detection of recurrent, 131I-negative thyroid cancer. Annals of Surgical Oncology 2008 15 286292. (doi:10.1245/s10434-007-9611-5)

    • Search Google Scholar
    • Export Citation
  • 20

    Dong M-J, Liu Z-F, Zhao K, Ruan L-X, Wang G-L, Yang S-Y, Sun F & Luo X-G. Value of 18F-FDG-PET/PET-CT in differentiated thyroid carcinoma with radioiodine-negative whole-body scan: a meta-analysis. Nuclear Medicine Communications 2009 30 639650. (doi:10.1097/MNM.0b013e32832dcfa7)

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    • Export Citation
  • 21

    Caetano R, Bastos CRG, de Oliveira IAG, da Silva RM, Fortes CPDD, Pepe VLE, Reis LG & Braga JU. Accuracy of positron emission tomography and positron emission tomography-CT in the detection of differentiated thyroid cancer recurrence with negative (131) I whole-body scan results: a meta-analysis. Head and Neck 2016 38 316327. (doi:10.1002/hed.23881)

    • Search Google Scholar
    • Export Citation
  • 22

    Leboulleux S, El Bez I, Borget I, Elleuch M, Déandreis D, Al Ghuzlan A, Chougnet C, Bidault F, Mirghani H & Lumbroso J et al. Postradioiodine treatment whole-body scan in the era of 18-fluorodeoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels. Thyroid 2012 22 832838. (doi:10.1089/thy.2012.0081)

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    • Export Citation
  • 23

    Moog F, Linke R, Manthey N, Tiling R, Knesewitsch P, Tatsch K, Hahn K. Influence of thyroid-stimulating hormone levels on uptake of FDG in recurrent and metastatic differentiated thyroid carcinoma. Journal of Nuclear Medicine 2000 41 19891995. (available at: http://www.ncbi.nlm.nih.gov/pubmed/11138683). Accessed on 25 March 2016.

    • Search Google Scholar
    • Export Citation
  • 24

    Chin BB, Patel P, Cohade C, Ewertz M, Wahl R & Ladenson P. Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2004 89 9195. (doi:10.1210/jc.2003-031027)

    • Search Google Scholar
    • Export Citation
  • 25

    Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M, Strauss HW, Tuttle RM, Drucker W & Larson SM. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. Journal of Clinical Endocrinology and Metabolism 2006 91 498505. (doi:10.1210/jc.2005-1534)

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  • 1

    Tubiana M, Schlumberger M, Rougier P, Laplanche A, Benhamou E, Gardet P, Caillou B, Travagli JP & Parmentier C. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 1985 55 794804. (available at: http://www.ncbi.nlm.nih.gov/pubmed/3967174). Accessed on 28 February 2016. (doi:10.1002/1097-0142(19850215)55:4&lt;794::AID-CNCR2820550418&gt;3.0.CO;2-Z)

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  • 2

    DeGroot LJ, Kaplan EL, McCormick M & Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 1990 71 414424. (doi:10.1210/jcem-71-2-414)

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  • 3

    Van Herle A & Uller RP. Elevated serum thyroglobulin a marker of metastases in differentated thyroid carcinoma. Journal of Clinical Investigation 1975 56 272277. (doi:10.1172/JCI108090)

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  • 4

    Schwartz MA. Caveat in the use of serum thyroglobulin determinations for monitoring differentiated thyroid carcinoma. Clinical Chemistry 1980 26 794. (available at: http://www.ncbi.nlm.nih.gov/pubmed/7371174). Accessed on 28 February 2016.

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  • 5

    Lubin E, Mechlis-Frish S, Zatz S, Shimoni A, Segal K, Avraham A, Levy R & Feinmesser R. Serum thyroglobulin and iodine-131 whole-body scan in the diagnosis and assessment of treatment for metastatic differentiated thyroid carcinoma. Journal of Nuclear Medicine 1994 35 257262. (available at: http://www.ncbi.nlm.nih.gov/pubmed/8294995). Accessed on 28 February 2016.

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  • 6

    Muros MA, Llamas-Elvira JM, Ramírez-Navarro A, Gómez MJ, Rodríguez-Fernández A, Muros T, López de la Torre M, Becerra A & Carreras JL. Utility of fluorine-18-fluorodeoxyglucose positron emission tomography in differentiated thyroid carcinoma with negative radioiodine scans and elevated serum thyroglobulin levels. American Journal of Surgery 2000 179 457461. (available at: http://www.ncbi.nlm.nih.gov/pubmed/11004330). Accessed on 28 February 2016. (doi:10.1016/S0002-9610(00)00381-0)

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  • 7

    Abraham T & Schöder H. Thyroid cancer – indications and opportunities for positron emission tomography/computed tomography imaging. Seminars in Nuclear Medicine 2011 41 121138. (doi:10.1053/j.semnuclmed.2010.10.006)

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  • 8

    Shammas A, Degirmenci B, Mountz JM, McCook BM, Branstetter B, Bencherif B, Bencherif BB, Joyce JM, Carty SE & Kuffner HA et al. 18F-FDG PET/CT in patients with suspected recurrent or metastatic well-differentiated thyroid cancer. Journal of Nuclear Medicine 2007 48 221226. (available at: http://www.ncbi.nlm.nih.gov/pubmed/17268018). Accessed on 25 March 2016.

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  • 9

    Wang W, Macapinlac H, Larson SM, Yeh SD, Akhurst T, Finn RD, Rosai J & Robbins RJ. [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic (131)I whole body scans and elevated serum thyroglobulin levels. Journal of Clinical Endocrinology and Metabolism 1999 84 22912302. (doi:10.1210/jcem.84.7.5827)

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  • 10

    Treglia G, Annunziata S, Muoio B, Salvatori M, Ceriani L & Giovanella L. The role of fluorine-18-fluorodeoxyglucose positron emission tomography in aggressive histological subtypes of thyroid cancer: an overview. International Journal of Endocrinology 2013 2013 856189. (doi:10.1155/2013/856189)

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  • 11

    Wadsak W & Mitterhauser M. Basics and principles of radiopharmaceuticals for PET/CT. European Journal of Radiology 2010 73 461469. (doi:10.1016/j.ejrad.2009.12.022)

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  • 12

    Ma C, Xie J, Lou Y, Gao Y, Zuo S & Wang X. The role of TSH for 18F-FDG-PET in the diagnosis of recurrence and metastases of differentiated thyroid carcinoma with elevated thyroglobulin and negative scan: a meta-analysis. European Journal of Endocrinology/European Federation of Endocrine Societies 2010 163 177183. (doi:10.1530/EJE-10-0256)

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  • 13

    Leboulleux S, Schroeder PR, Busaidy NL, Auperin A, Corone C, Jacene HA, Ewertz ME, Bournaud C, Wahl RL & Sherman SI et al. Assessment of the incremental value of recombinant thyrotropin stimulation before 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging to localize residual differentiated thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2009 94 13101316. (doi:10.1210/jc.2008-1747)

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  • 14

    Haugen BR, Alexander EK, Bible KC, Doherty G, Mandel SJ, Nikiforov YE, Pacini F, Randolph G, Sawka A & Schlumberger M et al. American Thyroid Association Management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2015 26 1133. (doi:10.1089/thy.2015.0020)

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  • 15

    Salvatori M, Biondi B & Rufini V. Imaging in endocrinology: 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in differentiated thyroid carcinoma: clinical indications and controversies in diagnosis and follow-up. European Journal of Endocrinology/European Federation of Endocrine Societies 2015 173 R115R130.

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  • 16

    Giovanella L, Trimboli P, Verburg FA, Treglia G, Piccardo A, Foppiani L & Ceriani L. Thyroglobulin levels and thyroglobulin doubling time independently predict a positive 18F-FDG PET/CT scan in patients with biochemical recurrence of differentiated thyroid carcinoma. European Journal of Nuclear Medicine and Molecular Imaging 2013 40 874880. (doi:10.1007/s00259-013-2370-6)

    • Search Google Scholar
    • Export Citation
  • 17

    Wang W, Larson SM, Fazzari M, Tickoo SK, Kolbert K, Sgouros G, Yeung H, Macapinlac H, Rosai J & Robbins RJ. Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. Journal of Clinical Endocrinology and Metabolism 2000 85 11071113. (doi:10.1210/jcem.85.3.6458)

    • Search Google Scholar
    • Export Citation
  • 18

    Altenvoerde G, Lerch H, Kuwert T, Matheja P, Schäfers M, Schober O. Positron emission tomography with F-18-deoxyglucose in patients with differentiated thyroid carcinoma, elevated thyroglobulin levels, and negative iodine scans. Langenbeck’s Archives of Surgery/Deutsche Gesellschaft für Chirurgie 1998 383 160163. (available at: http://www.ncbi.nlm.nih.gov/pubmed/9641890). Accessed on 25 March 2016.

    • Search Google Scholar
    • Export Citation
  • 19

    Finkelstein SE, Grigsby PW, Siegel BA, Dehdashti F, Moley JF & Hall BL. Combined [18F]fluorodeoxyglucose positron emission tomography and computed tomography (FDG-PET/CT) for detection of recurrent, 131I-negative thyroid cancer. Annals of Surgical Oncology 2008 15 286292. (doi:10.1245/s10434-007-9611-5)

    • Search Google Scholar
    • Export Citation
  • 20

    Dong M-J, Liu Z-F, Zhao K, Ruan L-X, Wang G-L, Yang S-Y, Sun F & Luo X-G. Value of 18F-FDG-PET/PET-CT in differentiated thyroid carcinoma with radioiodine-negative whole-body scan: a meta-analysis. Nuclear Medicine Communications 2009 30 639650. (doi:10.1097/MNM.0b013e32832dcfa7)

    • Search Google Scholar
    • Export Citation
  • 21

    Caetano R, Bastos CRG, de Oliveira IAG, da Silva RM, Fortes CPDD, Pepe VLE, Reis LG & Braga JU. Accuracy of positron emission tomography and positron emission tomography-CT in the detection of differentiated thyroid cancer recurrence with negative (131) I whole-body scan results: a meta-analysis. Head and Neck 2016 38 316327. (doi:10.1002/hed.23881)

    • Search Google Scholar
    • Export Citation
  • 22

    Leboulleux S, El Bez I, Borget I, Elleuch M, Déandreis D, Al Ghuzlan A, Chougnet C, Bidault F, Mirghani H & Lumbroso J et al. Postradioiodine treatment whole-body scan in the era of 18-fluorodeoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels. Thyroid 2012 22 832838. (doi:10.1089/thy.2012.0081)

    • Search Google Scholar
    • Export Citation
  • 23

    Moog F, Linke R, Manthey N, Tiling R, Knesewitsch P, Tatsch K, Hahn K. Influence of thyroid-stimulating hormone levels on uptake of FDG in recurrent and metastatic differentiated thyroid carcinoma. Journal of Nuclear Medicine 2000 41 19891995. (available at: http://www.ncbi.nlm.nih.gov/pubmed/11138683). Accessed on 25 March 2016.

    • Search Google Scholar
    • Export Citation
  • 24

    Chin BB, Patel P, Cohade C, Ewertz M, Wahl R & Ladenson P. Recombinant human thyrotropin stimulation of fluoro-D-glucose positron emission tomography uptake in well-differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 2004 89 9195. (doi:10.1210/jc.2003-031027)

    • Search Google Scholar
    • Export Citation
  • 25

    Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M, Strauss HW, Tuttle RM, Drucker W & Larson SM. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. Journal of Clinical Endocrinology and Metabolism 2006 91 498505. (doi:10.1210/jc.2005-1534)

    • Search Google Scholar
    • Export Citation