PET and PET/CT imaging in thyroid and adrenal diseases: an update

Address for correspondence:
Giorgio Treglia, MD, Department of Nuclear Medicine and PET/CT Center, Oncology Institute of Southern Switzerland, via Ospedale 12, 6500, Bellinzona, Switzerland, Tel.: +41 918118919, Fax: +41 918118250, e-mail: giorgiomednuc@libero.it

Received 06-09-2012, Accepted 10-01-2013

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INTRODUCTION

Positron emission tomography (PET) and PET/computed tomography (PET/CT) are established diagnostic tools in the management of many solid tumors. PET/CT is a hybrid technique which combines morphological information obtained by the CT component with functional data provided by PET imaging.¹ There is increasing evidence in the literature about the usefulness of PET and PET/CT imaging with different tracers in various endocrine disorders. Fluorine-18-Fluorodeoxyglucose (¹⁸F-FDG) is the most frequently used PET tracer in oncology.¹ This glucose analogue is trapped by cells via the glucose transporters (GLUTs). GLUTs overexpression is particularly prevalent in aggressive endocrine tumors; in addition, overexpression of hexokinase-1 promotes ¹⁸F-FDG uptake in cancer cells.² Several PET tracers other than ¹⁸F-FDG have also been used in endocrinology to evaluate different metabolic pathways (Tables 1, 2). For example, Iodine-124 (¹²⁴I) has been used to study the iodine metabolism in thyroid tumors.³ Fluorine-18-Dihydroxyphenylalanine (¹⁸F-DOPA), which assesses the amino acid uptake, decarboxylation and storage,⁴ and Gallium-68-somatostatin analogues (⁶⁸Ga-SMS), which evaluate the somatostatin receptor status,⁵ are PET tracers particularly useful in medullary thyroid carcinoma, paraganglioma/pheochromocytoma and other neuroendocrine tumors (NETs). Fluorine-18-Dopamine (¹⁸F-Dopamine) and Carbon-11-Hydroxyephedrine (¹¹C-HED) assess the catecholamine uptake and storage and are useful in NETs and in tumors of the adrenal medulla. Lastly, Carbon-11-Metomidate (¹¹C-Metomidate) and analogues are PET tracers used in the evaluation of lesions of the adrenal cortex.⁶

The aim of this article is to provide an overview about the role of PET and PET/CT with different tracers in thyroid and adrenal diseases

PET AND PET/CT IN THYROID DISEASES

During the last two decades PET and PET/CT with different tracers have been used increasingly in patients with thyroid diseases, including differentiated thyroid carcinoma (DTC), poorly differentiated and anaplastic thyroid carcinoma (PDTC and ATC), and medullary thyroid carcinoma (MTC). The usefulness of these techniques in assessing indeterminate thyroid nodules at fine needle aspiration biopsy (FNAB) and the clinical relevance of thyroid incidental ¹⁸F-FDG uptake at PET imaging have been also evaluated.

– PET and PET/CT in differentiated thyroid carcinoma

DTC cells expressing the sodium-iodine symporter take up radioiodine. In a small percentage of DTC the cells are de-differentiated and the radioiodine uptake capacity is lost. These cells multiply more rapidly and are metabolically more active, while their glucose metabolism is increased.⁷

Low-risk patients with DTC are very unlikely to require ¹⁸F-FDG-PET or PET/CT as part of initial staging or follow-up. Moreover, to date, ¹⁸F-FDG-PET and PET/CT are not recommended for preoperative assessment of DTC.⁸ Currently, the most valuable role of ¹⁸F-FDG-PET and PET/CT in the work-up of DTC is to be seen in those patients who present with increasing serum thyroglobulin (Tg) levels and a negative diagnostic radioiodine whole-body scan post-thyroidectomy, according to the American Thyroid Association (ATA) guidelines.⁸ If no disease sites are identified on conventional imaging or radioiodine whole-body scan or Tg levels are elevated out of proportion to minor disease found on conventional imaging, ¹⁸F-FDG-PET or PET/CT should be performed to detect recurrent or metastatic disease.^7,8 A meta-analysis to determine the diagnostic accuracy of ¹⁸F-FDG-PET and PET/CT in DTC patients who presented with elevated serum Tg levels post-thyroidectomy and negative radioiodine whole-body scan reported a good diagnostic accuracy of these methods with pooled sensitivity and specificity of 88.5% and 84.7%, respectively. The pooled values of sensitivity increased when only ¹⁸F-FDG-PET/CT studies were considered in the analysis (93.5%), demonstrating a superior diagnostic accuracy of PET/CT compared to PET alone.⁹

The current ATA guidelines suggest that FDG-PET or PET/CT should be performed when Tg levels are >10 ng/mL.⁸ In any case, no clear cut-off value of Tg can be established in clinical practice.¹⁰

Clinical evidence is emerging that the performance of ¹⁸F-FDG-PET and PET/CT for the detection of Tg-positive and radioiodine-negative metastases of DTC is also improved after thyrotropin stimulation (either by hormone withdrawal or recombinant human thyrotropin administration); however, the clinical significance of this improved diagnostic performance remains uncertain.¹¹

¹⁸F-FDG-PET or PET/CT in DTC are also useful prognostic factors for identifying which patients with known distant metastases are at highest risk for disease-specific mortality.¹² These methods represent valuable selection tools for identifying those patients who are unlikely to respond to additional radioiodine therapy and may allow the measurement of post-treatment response following external beam irradiation, surgical resection, embolization or systemic therapy.^7,8

There are increasing literature data about the usefulness of ¹²⁴I-PET and PET/CT in DTC.¹³ Two aspects deserve special mention with regard to the applications of these functional imaging methods: the staging of recurrent/residual disease in DTC and the dosimetry before treatment with Iodine-131 (¹³¹I). ¹²⁴I-PET and PET/CT provide images of higher spatial resolution and lesion contrast than either planar imaging or tomographic imaging with ¹³¹I, although the impact of this improved lesion detection compared to ¹³¹I imaging in patients with known or suspected metastatic DTC remains to be proven.⁷ The combination of ¹⁸F-FDG and ¹²⁴I-PET/CT allows detection of non-iodine-avid lesions and discrimination from simultaneously occurring iodine-positive lesions, thus improving restaging in recurrent DTC.¹⁴ The pre-treatment dosimetry by using ¹²⁴I-PET may result in a significant alteration in the therapeutic procedure compared to standard therapy with fixed activities of ¹³¹I.¹³

– PET and PET/CT in poorly differentiated and anaplastic thyroid carcinoma

PDTC and ATC show aggressive clinical behavior with high glucose metabolism and intense ¹⁸F-FDG uptake. In patients with PDTC and ATC, ¹⁸F-FDG-PET or PET/CT may be indicated for staging and for prognostic purposes and, in selected cases, for evaluating the efficacy of therapy.^14,15

– PET and PET/CT in medullary thyroid carcinoma

PET imaging with different tracers is not recommended for routine initial screening of patients with a FNAB and/or serum calcitonin levels suggestive for MTC, but it may have a role in detecting suspected MTC recurrences, based on increased serum calcitonin levels post-thyroidectomy. In fact, MTC recurrences are often difficult to detect using conventional imaging and traditional scintigraphic methods.^16-18 There is increasing evidence in the literature of the beneficial role of ¹⁸F-FDG-PET and PET/CT in recurrent MTC; these methods could be very helpful in detecting MTC recurrences in those patients in whom a more aggressive disease is suspected.^17,19 To date, ¹⁸F-DOPA seems to be the most useful PET tracer in detecting recurrent MTC based on rising levels of calcitonin.²⁰ Nevertheless, the literature focusing on the use of ¹⁸F-DOPA-PET or PET/CT in the detection of recurrent MTC still remains limited.²¹ Other PET tracers, such as ⁶⁸Ga-SMS, were also evaluated for this indication in a limited number of studies.¹⁷ At any rate, the different PET tracers reflect different metabolic pathways and seem to show a complementary role in detecting recurrent MTC.^17,20

– PET and PET/CT in thyroid nodules with indeterminate FNAB and thyroid incidental ¹⁸F-FDG uptake

There is great interest in the role of ¹⁸F-FDG-PET and PET/CT in addressing histologically non-diagnostic or inconclusive thyroid nodules at FNAB.^22,23 A recent meta-analysis reported a pooled sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 95%, 48%, 39%, 96%, and 60%, respectively. False-negative ratio of ¹⁸F-FDG-PET or PET/CT in this setting is low; therefore, these methods may help to identify patients who would benefit from surgery. Conversely, a positive ¹⁸F-FDG-PET result does not identify cancer because approximately 50% of these patients had benign nodules.²³ In addition, a recent prospective study demonstrated that adding ¹⁸F-FDG-PET/CT findings to neck ultrasonography provides no diagnostic benefit because the sensitivity (77%) and specificity (62%) of ¹⁸F-FDG-PET/CT in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend its use routinely.²⁴ Therefore, incorporation of ¹⁸F-FDG-PET or PET/CT into the initial work-up of patients with non-diagnostic or inconclusive cytology before surgery deserves further investigation.

Sometimes ¹⁸F-FDG-PET and PET/CT reveal thyroid incidental uptake (TIU) of the tracer which may have a focal or a diffuse pattern. Diffuse TIU at ¹⁸F-FDG-PET or PET/CT can be considered at low risk of malignancy, being more likely associated with thyroiditis or diffuse thyroid autonomy. Conversely, focal TIU at ¹⁸F-FDG-PET or PET/CT can represent both benign and malignant lesions with a risk of malignancy of about 35%.^25,26 Therefore, a complete work-up including laboratory examinations, ultrasonography and FNAB should usually be obtained to exclude malignant lesions in focal TIU detected by ¹⁸F-FDG-PET or PET/CT.

PET AND PET/CT IN ADRENAL DISEASES

Nuclear medicine procedures provide unique functional information in patients with adrenal diseases, which can be particularly useful both in the presence of a hyperfunctioning clinical syndrome for localizing the site of hormonal hyperproduction (i.e. enabling the differential diagnosis between unilateral and bilateral forms), and in the presence of anatomic alteration seen on morphological imaging for characterizing the adrenal lesion (i.e. distinguishing benign from malignant ones). Currently, great interest is being focused on a variety of PET tracers that target specific characteristics of adrenal gland function, allowing an accurate characterization and staging of adrenal tumors.

– Adrenal cortex

Although ¹⁸F-FDG is not specific for the adrenal gland, PET and PET/CT using this tracer are able to differentiate benign masses which usually show faint ¹⁸F-FDG uptake, from malignant ones which show significantly higher ¹⁸F-FDG uptake, with a diagnostic accuracy of 75-100%.²⁷ A recent systematic review and meta-analysis revealed that most adrenal masses can be characterized as benign or malignant by using ¹⁸F-FDG-PET or PET/CT with high sensitivity (97%) and specificity (91%); false positive results can occur in some benign adrenal masses, particularly adenomas.²⁷¹⁸F-FDG-PET and PET/CT compare favorably with a CT washout test for the characterization of adrenal masses, so that further imaging tests are generally unnecessary.²⁷ Furthermore, ¹⁸F-FDG-PET and PET/CT may identify extra-adrenal metastatic lesions in malignant adrenal diseases and may also be useful to evaluate tumor response to treatment.²⁸

¹¹C-Metomidate is an inhibitor of ¹¹C-hydroxylase, a key enzyme in corticosteroids synthesis. PET with ¹¹C-Metomidate (or its analogues) allows identification of lesions of adrenocortical origin. Therefore, by using this tracer, adrenal metastases and pheochromocytomas are differentiated from adrenocortical tumors.²⁹ However, ¹¹C-Metomidate-PET and PET/CT do not allow differentiation between benign and malignant adrenocortical lesions. Furthermore, the short half-life of ¹¹C (20 minutes) limits the use of ¹¹C-Metomidate to centers with on-site cyclotron.²⁹

– Adrenal medulla

Recently, a wide range of PET radiopharmaceuticals, both specific and non-specific for chromaffin tumors, have emerged as an alternative method to radioiodinated metaiodobenzylguanidine (MIBG) scintigraphy, which is still the most widely used functional imaging technique for localizing pheochromocytoma.^30,31 Specific PET radiopharmaceuticals include ¹¹C-HED, ¹⁸F-DOPA and ¹⁸F-Dopamine, which are used for imaging purposes, and ¹²⁴I-MIBG, which is used especially for dosimetric estimates prior to ¹³¹I-MIBG therapy; non-specific PET tracers include ¹⁸F-FDG and ⁶⁸Ga-SMS.³⁰

The catecholamine analogue ¹¹C-HED was the first positron emitter tracer specific for chromaffin tumors to be used in humans. PET with ¹¹C-HED has been applied in patients with pheochromocytoma, allowing the visualization of both primary and metastatic lesions (90% sensitivity); however, its widespread clinical use is limited by the short physical half-life of ¹¹C, requiring onsite production, and high costs.³²

Furthermore, ¹⁸F-Dopamine, a catecholamine precursor, and ¹⁸F-DOPA, an amino acid that is converted by aromatic amino acid decarboxylase to dopamine, provide excellent imaging of pheochromocytomas, with higher diagnostic sensitivity than ¹⁸F-FDG and ^123/131I-MIBG, and high specificity.^32,33 Additional advantages of ¹⁸F-DOPA and ¹⁸F-Dopamine over ^123/131I-MIBG are: short time of imaging, less radiation exposure, no need of thyroid blockade and of withdrawing medication (with ¹⁸F-DOPA).^32,34

¹⁸F-FDG is not recommended for initial diagnosis of pheochromocytoma since it is not specific; due to its ability in identifying hypermetabolic lesions, it also depicts adrenocortical cancer and metastatic lesions. Moreover, ¹⁸F-FDG has a limited sensitivity, about 70% for solitary benign or malignant pheochromocytoma; nevertheless, it may have a role as an alternative modality in MIBG-negative malignant pheochromocytomas, mainly those with SDHB mutation.^30,32,35

In addition, ⁶⁸Ga-SMS are under evaluation for PET imaging in tumors originating from the adrenal medulla; the preliminary data available suggest that ⁶⁸Ga-SMS-PET and PET/CT may be useful in patients with pheochromocytoma/paraganglioma.³⁶

Recent studies with different PET radiopharmaceuticals have shown different results in the various clinical syndromes of pheochromocytoma (sporadic versus familial forms or benign versus malignant forms), supporting the need for an individualized approach guided by the clinical and genetic phenotype. According to recent published EANM guidelines for radionuclide imaging of pheochromocytomas and paragangliomas, there is no clear advantage of PET radiopharmaceuticals over MIBG in patients with non-metastatic sporadic pheochromocytoma, due to the good sensitivity of MIBG scintigraphy in these patients.³⁷A real advantage of PET radiopharmaceuticals seems to be for patients with metastatic disease, whose extent may be underestimated by MIBG scintigraphy. In these patients, different behaviors of PET radiopharmaceuticals have been reported in different clinical syndromes on the basis of specific gene mutations. In the absence of SDHB mutation or when genetic status is unknown, ¹⁸F-DOPA seems to be the tracer of choice, whereas in patients with SDHB associated pheochromocytoma/paraganglioma—in whom both MIBG and ¹⁸F-DOPA show disappointing results—¹⁸F-FDG is the preferred agent for localizing metastatic lesions.^35,37,38

CONCLUSION

There is increasing evidence in the literature about the usefulness of PET/CT imaging with different tracers in thyroid and adrenal diseases. Since PET/CT is an expensive diagnostic tool which necessitates ionizing radiation exposure, cost-effectiveness studies are needed in order to define the appropriate use of this diagnostic method in various endocrine disorders.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.

DISCLOSURES

None.

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