Jpn J Radiol (2010) 28:629–636 DOI 10.1007/s11604-010-0488-z
REVIEW
Role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients affected by differentiated thyroid carcinoma, high thyroglobulin level, and negative 131I scan: review of the literature Francesco Bertagna · Giorgio Biasiotto Emanuela Orlando · Giovanni Bosio · Raffaele Giubbini
Received: May 24, 2010 / Accepted: July 7, 2010 © Japan Radiological Society 2010
Abstract Differentiated thyroid carcinoma (DTC) is a slow-growing tumor that represents 1% of all malignant tumors and is the most frequent endocrine cancer. 18 F-Fluorodeoxyglucose positron emission tomography/ computed tomography (18F-FDG-PET/CT) imaging is an increasingly important imaging tool in oncology and is still under investigation in numerous studies looking into its efficacy and cost-effectiveness. Despite the fact that 18F-FDG-PET/CT has been shown to be a powerful and accurate diagnostic tool in patients affected by DTC with high serum thyroglobulin (Tg) levels and negative radioiodine (131I) total body scan, its definitive role is not completely clear, in particular regarding the role of thyroid stimulating hormone (TSH) and Tg value “cutoff ” over which is better to perform the study. In this review, these issues are analyzed to clarify controversial aspects and identify established cornerstones. In particular, the literature analysis suggests that levothyroxine withdrawal is preferable in cases of relatively low Tg
F. Bertagna (*) · G. Bosio Department of Nuclear Medicine, Spedali Civili di Brescia, P. le Spedali Civili 1, Brescia 25123, Italy Tel. +39-30-3995468; Fax +39-30-3995420 e-mail:
[email protected] G. Biasiotto Dipartimento Materno Infantile e Tecnologie Biomediche, University of Brescia, Brescia, Italy E. Orlando 1st Division of Radiology, Spedali Civili Brescia, Brescia, Italy R. Giubbini Department of Nuclear Medicine, University of Brescia, Brescia, Italy
levels (<10 ng/ml) and good clinical compliance to hypothyroidism. Moreover, recombinant thyrotropin stimulating hormone (rTSH) could be a preferable alternative in patients clinically unable to tolerate therapy withdrawal. A Tg cutoff level over which to perform the study seems to be 10 ng/ml, a reasonable value maintaining high accuracy in terms of a good compromise between sensitivity and specificity. Key words PET · Thyroid carcinoma · Negative iodine scan
Introduction Differentiated thyroid carcinoma (DTC), a slow-growing tumor, represents 1% of all malignant tumors. It is the most frequent endocrine cancer, with a world standard incidence of 1.0/100 000 in men and 2.6/100 000 in women and mortality rates of 0.3% and 0.6%, respectively.1 It is generally characterized by long-term survival2,3 (survival rate >90% after 10 years),4 good prognosis, and low aggressiveness proven by the frequent discovery of DTC on necroscopic examination.5 The diagnosis is often incidental. The incidence peak is at 35–45 years for the papillary type and 45–55 years for the follicular histotype.6,7 Prognosis is related to the age at diagnosis, tumor dimension, extracapsular extension, and presence of distant metastases.8 Distant metastases are relatively rare, with the incidence ranging from 4% to 27%.9,10 The incidence of metastases at diagnosis is about 1%–4%,11 most frequently involving lymph nodes, lungs, and bone.3,6 Overall 10-year survival is 93% for papillary carcinoma, 85% for follicular carcinoma, and 76% for Hurthle cell carcinoma.12
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Diagnosis of thyroid cancer is principally based on clinical evaluation, ultrasonography (US), and fine needle aspiration biopsy (FNAB). DTC is managed initially by surgical intervention (total thyroidectomy and, potentially, lymphadenectomy) followed by thyroid ablation with radioiodine therapy (131I).3,6 The latter aims to ablate residual thyroid tissue after surgery and to treat residual, recurrent, or metastatic cancer. In many institutions, therapy remains based on empirically determined, fixed amounts of radioiodine that do not account for individual differences in the mass of tissue to be treated or in radioiodine kinetics. Over the last 25 years, techniques have been developed and refined based on pretherapy, diagnostic quantitative radiation dosimetry, and imaging with 131I that permit individualized treatment, which balances efficacy and the risk of adverse effects.7 Treatment of metastases includes surgical removal (mostly for cervical lymph nodes), external beam radiation therapy (EBRT), most frequently for single bone lesions, and radioiodine therapy. The clinical follow-up after total thyroidectomy and radioiodine treatment is usually based on whole-body scanning with 131I, measurement of plasma thyroglobulin (Tg) levels, and neck US. Neck US, which is highly sensitive and specific for evaluating the thyroid bed and locoregional lymph nodes,13–15 is considered the examination of choice for evaluating suspected locoregional and lymphatic recurrence during follow-up.14 When radioiodine uptake is significantly reduced or absent, suggesting loss of differentiation of neoplastic cells, retinoic acid therapy has been proposed16 to promote neoplastic cell redifferentiation, leading to partial recovery of the capacity to concentrate radioiodine.16–19 Complete loss of radioiodine uptake is generally considered to indicate tumor progression due to transformation of the tumor to a less differentiated state, which may require chemotherapy as a therapeutic option.18
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F-Fluorodeoxyglucose positron emission tomography/ computed tomography 18
F-Fluorodeoxyglucose positron emission tomography/ computed tomography (18F-FDG-PET/CT) imaging has gained widespread acceptance as a diagnostic tool in oncology and is an increasingly important imaging test. However, its clinical usefulness in specific clinical settings is still under investigation as is its efficacy and cost-effectiveness. A reliable and accurate diagnostic imaging in patients with negative radioiodine scintigraphy and high (>10 ng/ml) or dosable (detectable as >1 ng/ml but as low as ≤10 ng/ml) serum Tg levels is very
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important for investigating possible disease sites and for accurate restaging. A widely accepted clinical indication for 18F-FDG-PET/CT is the presence of DTC with negative total-body radioiodine scintigraphy and high serum Tg levels.20 The definitive role of 18F-FDG-PET/CT in patients with DTC, high Tg serum levels, and negative radioiodine scan is still controversial despite several studies documenting its undoubted utility in selected patients, its accuracy,21,22 and its simplicity.23 No consensus has been reached about Tg levels that assures high diagnostic accuracy and cost-effectiveness of 18F-FDG-PET/CT, thereby justifying the need for a PET study on a clinical basis. Moreover, there is not sufficient consensus on the possible incremental value of the off-therapy state or on the use of recombinant thyrotropin stimulating hormone (rTSH) to improve the sensitivity of PET/CT imaging.23 The possible utility of rTSH stimulation may have an impact on patients’ follow-up costs. From the basic molecular mechanism point of view, although glucose metabolism and its relation to the mechanisms of signal transduction involved in radioiodine-negative/glucose-avid metastases of differentiated thyroid carcinomas are not completely understood, it is well established that 18F-FDG uptake by differentiated thyroid cancer is associated with more aggressive biological behavior of the tumor and a worse prognosis.24 Mian et al.25 recently reported that the loss of 131I uptake in recurrences depends not only on a decrease in energy-dependent transport mediated by the Na+/I–symporter (NIS) gene but possibly on a reduction in the molecules regulating its intracellular metabolism. Moreover, high glucose transporter type 1 (GLUT-1) gene expression supports the use of PET with specific tracers in the clinical management of such cancers, and BRAF-V600E point mutations may lead to less differentiated phenotypes, suggesting a worse prognosis. However, discordant findings between PET and traditional nuclear medicine radioiodine imaging (the “flipflop phenomenon”: uptake of 131I with no FDG uptake, and vice versa) is frequently observed.26–29 The diagnostic accuracy of 18F-FDG-PET in patients with negative radioiodine (131I) scans and high Tg levels is generally high but different accuracy levels are reported in the literature (Table 1). In the study of Grunwald et al.,30 the sensitivity was 85% and the specificity 90%, whereas in the study of Shiga et al.31 the sensitivity was 64.3%. Zuijdwijk et al.32 reported, in a subgroup of 31 patients with high Tg levels, a sensitivity of 84% and a specificity of 100%. 18F-FDG-PET sensitivity is generally high, reaching 85%–90% in many recent studies33–35 and 100% in the studies by Plotkin et al.36 and Wu et al.37 In other studies and in the study by Cabrera Martin
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et al.,38 sensitivity was suboptimal at 71%, although specificity was satisfactory at 96%. In any case, the accuracy appears to be superior to traditional nuclear medicine imaging.31,39–43 The current PET imaging standard is hybrid imaging provided by PET/CT equipment.44–48 Palmedo et al.49 reported a diagnostic accuracy for 18F-FDG-PET/CT of 93% in comparison to 78% for PET with no simultaneous CT acquisition. Similar results were shown in the studies by Ong et al.45 and Saab et al.,44 with an improvement in sensitivity of 60.0% versus 88.2%, without or with CT, respectively. In a recent study of 59 patients, Shammas et
Table 1. Accuracy of PET or PET/CT in patients studied with high serum thyroglobulin levels and negative whole-body radioiodine scintigraphy Study
No. of patients
PET or PET/CT
Sensitivity (%)
Specificity (%)
Grunwald30 Shammas50 Palmedo49 Zuijdwijk32 Saab44 Plotkin36 Wu37
166 53 40 31 15 13 13
PET PET/CT PET/CT PET/CT PET/CT PET PET
85 68.4 95 84 88.2 100 100
90 82.4 91 100 60 / /
al. reported overall sensitivity, specificity, and accuracy of 68.4%, 82.4%, and 73.8%, respectively.50 The exact localization of 18F-FDG tumor foci is mandatory for patient management, and integrated PET/CT fusion imaging systems might have advantages over PET alone or separate PET and morphological imaging (Figs. 1, 2). The added value of PET/CT over PET alone was strengthened by the findings of Zoller et al., who emphasized that PET/CT can determine a modification of treatment plans, revealing unexpected pathological findings.51 Some studies showed that FDG-PET fails to assess miliary lung metastases <6 mm correctly; it is unclear whether this drop in sensitivity may be due to pulmonary motion artifacts or to lower metabolic activity of lung metastases.52 The use of respiratory gating may improve diagnostic accuracy by reducing motion artifacts, blurring, and the “smearing effect,” thereby allowing more precise standardized uptake value (SUV) calculation,53,54 even though no dedicated studies have been published on this specific topic.
Correlation with thyroglobulin level
PET, positron emission tomography; CT, computed tomography
The high diagnostic value of the Tg level during DTC follow-up is universally accepted, but the correlation
Fig. 1. Anterior (1-C1) and posterior (1-C2) negative whole-body iodine scans and positron emission tomography maximum intensity projection (PET-MIP) scans (1-D) of a patient affected by differentiated thyroid cancer (DTC) with a serum thyroglobulin (Tg) level of
57 ng/ml and multiple metastases. Also shown are computed tomography (CT) (1-B1), PET (1-B3), and fused (1-B2) images of left thigh bone metastases (arrows) and CT (1-A1), PET (1-A3), and fused (1-A2) images of mediastinal lymph node metastases (arrows)
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Fig. 2. Anterior (2-C1) and posterior (2-C2) negative whole-body iodine scans and a PET-MIP (2-D) scan of a patient affected by DTC with a serum Tg level of 216 ng/ml and multiple thoracic
metastases. Also shown are axial CT (2-A2, 2-B2), PET (2-A3, 2-B3), and fused (2-A1; 2-B1) images of mediastinal and hilar lymph node metastases and lung metastases (arrows)
between 18F-FDG uptake and Tg levels is still debated.12 The purpose of several studies was to assess Tg level ranges that could enhance the diagnostic value of PET/ CT.31,55,56 Zoller et al.51 considered 20 ng/ml as the Tg level “cutoff”; they reached 87% sensitivity when PET was performed at levels >20 ng/ml and 22% when Tg was <20 ng/ml. Bertagna et al.,57 in 52 patients, identified a serum Tg level of 21 ng/ml as cutoff level over which 18 F-FDG-PET/CT reaches best accuracy in terms of the compromise between sensitivity (76.5%) and specificity (83.3%). A loss in sensitivity was observed for patients with Tg <10 ng/dl (35%). Schluter et al.55 described sensitivities of 11%, 50%, and 93% in the presence of Tg values of <10, 10–20, and >100 μg/l, respectively. Shammas et al.50 reported sensitivities of 60%, 63%, and 72% in patients with Tg levels of <5, 5–10, and >10 ng/ ml, respectively. Despite these considerations, the correlation between progressively higher Tg levels and a positive PET/CT study is widely accepted. As Tg is the post-therapy tumor marker to monitor for disease recurrence with both basal values and following TSH stimulation, its dosage should be reliable. False negatives or positives are a problem and antithyroglobulin antibody (TgAb) assays have been used to screen patients for potential interfering antibodies in Tg
assays.58 Despite the lack of clarification regarding what role the TgAb assay plays in the interpretation of Tg values, in the presence of a high TgAb level the Tg assay’s reliability is lower and is possibly not useful. In such cases, the patient should be monitored by clinical evaluation and other available diagnostic tools.
Role of thyroid-stimulating hormone The influence of thyroid-stimulating hormone (TSH) levels on radioiodine scans and Tg levels is well known, and therapy withdrawal (or rTSH use) is necessary for radioiodine scanning. The impact of the off-therapy state or rTSH use on 18F-FDG-PET/CT results is still an open issue, and there is no agreement in the literature about its real role in improving accuracy. According to many authors, the off-therapy state seems to improve sensitivity, especially in the presence of detectable but low Tg levels (>1 and ≤10 ng/ml), and small metastases with low metabolic activity under a levothyroxine regimen.27,31,59–63 According to Deichen et al.’s43 study performed on human thyroid cells in vitro, TSH significantly increases the uptake of 18F-FDG in thyroid cells, and a serum glucose level of 100 mg/dl
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reduces intracellular uptake of the radiotracer at 70% compared to the value measured in glucose-free medium. Filetti et al.61 experimentally evaluated the TSH effect on GLUT-1 expression and increased glucose transport in cultured rat thyroid cells, showing that TSH stimulates the glucose transport system by enhancing the number of functional glucose transporters in the thyroid plasma membrane. Chin et al.64 and Petrich et al.62 evaluated the influence of rTSH on 18F-FDG uptake by DTC, providing evidence of an effective stimulating TSH effect on uptake. In fact, Chin et al. revealed that the mean and maximum lesion/background uptake ratios were significantly higher with rTSH stimulation than with TSH suppression (P = 0.02 for both), showing that rTSH stimulation improves the detectability of occult thyroid metastases with FDG-PET compared with scans performed on TSH suppression. Blaser et al.65 studied the effects of TSH, an analogue of cyclic adenosine-monophosphate [dibutyryl cyclic AMP (Bu)2cAMP], inhibitors of the phosphatidylinositol 3-kinase (PI3-kinase), and inhibitors of the protein kinase A (PKA) on 18F-FDG and radioiodine uptake in the thyroid cell line. These substances are classic intracellular messengers potentially involved in signal transduction of the interaction of a first messenger with the extracellular binding domain of a membrane receptor, FRTL-5. The authors concluded that the effect of TSH and cAMP on 18F-FDG uptake by FRTL-5 cells is mediated by PI3-kinase and not by PKA, thus differing from the mechanism of radioiodine accumulation of this cell line. This observation is a possible explanation for the persistence of TSH-dependent 18 F-FDG uptake in radioiodine-negative metastases of DTC. This issue is still a matter of debate and analysis,40 and many studies do not show increased accuracy in terms of higher sensitivity in the presence of high TSH levels suggesting a loss of TSH dependence in the dedifferentiation process. Wang et al. did not find a clinically relevant difference in FDG uptake in patients who had PET scans in euthyroid or hypothyroid states,66 and FDG-PET results independent of TSH level were described by Schluter et al.55 Grunwald et al. did not find an increase in the uptake of 18F-FDG with an elevated TSH level,30,67 observing lower sensitivity (67%) of 18 F-FDG-PET in the presence of high TSH levels and 91% in the group of patients in whom 18F-FDG-PET was performed under thyroid hormone therapy. Moreover, in a study by Bertagna et al., no statistical significant difference was noted between positive or negative PET study results in the presence of high or low TSH levels, suggesting no significant differences in our study population.57
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Limitations of the study It is difficult to extrapolate a reliable and safe cornerstone from these studies with regard to the Tg “cutoff” level over which the study reaches the best accuracy in terms of the compromise between sensitivity and specificity and maintaining an acceptable cost-effective ratio. This is true mostly because of the relatively small number of studies performed and number of patients enrolled, even if we have to consider the particular and specific clinical scenario. In all nuclear medicine divisions, the number of patients with negative radioiodine scans and dosable or high Tg levels is not large; furthermore, most studies are retrospective, mostly without systematic enrolment of patients and no randomized trials have been performed to evaluate the effect of TSH on neoplastic tissue uptake. Moreover, the accuracy of PET in this field was never established based on histological examination of supposed secondary lesions but often only on Tg data, PET results, and CT findings. All these limitations must be considered but are difficult to eliminate because of ethical and clinical concerns in clinical practice. Conclusions 18
F-FDG-PET/CT is a powerful, accurate diagnostic tool for patients affected by DTC with negative radioiodine (131I) total-body scans and high Tg levels. Hybrid imaging PET/CT should be considered the current standard because of its well-established high accuracy and incremental diagnostic value. No complete consensus has been reached about the usefulness of high levels of TSH (by therapy withdrawal or rTSH use). Despite the fact that the issue is still a matter of debate and no consensus has been reached, levothyroxine withdrawal is preferable in cases of relatively low Tg levels (<10 ng/ ml) and good clinical compliance to hypothyroidism, trying to improve sensitivity; rTSH could be a preferable alternative in patients clinically unable to tolerate therapy withdrawal. A Tg cutoff level over which to perform the study has been identified; it seems that 10 ng/ml is a reasonable value, maintaining high accuracy in terms of a good compromise between sensitivity and specificity. References 1. Parkin DM, Pisani P, Ferlay J. Global cancer statistics. CA Cancer J Clin 1999;49:33–64. 2. DeGroot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment, and course of papillary thyroid carcinoma. J Clin Endocrinol Metab 1990;71:414–24.
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