Introduction

In thyroid cancer, nuclear medicine is able to cover the broad spectrum from diagnosis and treatment to follow up keeping patient’s management in one institution. Thyroid cancer is a rare malignancy and incidence rates vary from 4 to 9 per 100,000 per year. In Austria, a former iodine-deficient and due to salt iodination now iodine-sufficient country, an increasing incidence rate of 8.5 per 100,000 per year is reported by “Statistik Austria” in 2009. Papillary thyroid cancer is the dominant histopathologic form and accounts for more than two thirds of differentiated thyroid cancer (DTC) [1–3], followed by follicular DTC and a mixed form that have different incidence and prognosis. These subtypes have a favourable prognosis with high cure rates, especially when diagnosed at an early stage. Medullary thyroid cancer, a completely different form originating from the C-cells of the thyroid gland and the non iodine storing forms of Hurthle cell carcinoma and anaplastic carcinoma are less frequent and have a poorer prognosis.

This article will highlight the role of nuclear medicine in diagnosis as well as treatment and follow up of patients with differentiated thyroid cancer.

Nuclear medicine and diagnosis of differentiated thyroid cancer

Ultrasound and ultrasonography-guided fine-needle aspiration biopsy

According to the AACE/AME/ETA guidelines, published in 2010, ultrasound and ultrasonography-guided fine-needle aspiration biopsy (US-FNAB) are the most adequate tools to diagnose DTC. The clinical presentation of patients with thyroid cancer varies. Thyroid nodules are quite common and the objective is to exclude malignancy in the majority of cases. Most thyroid cancer nowadays are diagnosed at an early stage, presenting as small indolent nodules incidentally diagnosed on routinely performed ultrasound of the neck. Only in rare cases, the thyroid cancer is diagnosed as large cervical mass, often growing fast, sometimes involving the recurrent laryngeal nerve followed by hoarseness of voice and often associated with a poorly differentiated histopathologic pattern and poor prognosis. Many studies have been performed to evaluate sonographic features of benign and malignant thyroid nodules in order to define those patients that require US-FNAB. Most studies [4–10] showed that nodules that present as solid, hypoechogenic, irregular and taller-than-wide shape, with micro and macrocalcifications, blurred and ill-defined margins, with intranodular dominant flow are more likely to be malignant. Furthermore, growth beyond the thyroid capsule and the detection of suspicious lymph nodes are associated with malignancy. Benign nodules are described as hyper or isoechoic, solid or cystic. Recently, a few studies have been published evaluating elastography in the setting of differential diagnosis of benign and malignant thyroid nodules using hardness of tissue as an indicator for malignancy [11, 12]. All mentioned criteria, however, are not fully reliable and different studies show different results regarding sensitivity and specificity rates when combining the different ultrasonographic features. Besides high specificity of ultrasound malignancy criteria sensitivity is quite low. In addition, the previously reported ultrasonography findings of thyroid malignancies are in conformity with most of the papillary but not with follicular carcinomas. Therefore, cytologic criteria should be carefully applied and other diagnostic tools should be implemented in the diagnostic work-up of thyroid nodules.

US-FNAB is an excellent tool to assess thyroid nodules that are suspicious with regard to ultrasonographic features. In the hands of an experienced physician it is highly effective (representative results up to 95 %) [13], easy to perform and of low complication rate. Mikosch et al. [14] reported a sensitivity of 87.84 % per specificity of 78.50 % per negative predictive value of 98.13 % per positive predictive value of 33.51 % and accuracy of 79.53 % when cytology indicated suspicion of thyroid malignancy. Other studies [15, 5] showed similar results. Especially in papillary thyroid cancer, cytology is highly predictive. In follicular DTC, cytologic analysis remains controversial and often only histological work-up after surgery can establish a definitive diagnosis of follicular adenoma or carcinoma.

In order to improve diagnostic management of thyroid nodules, nuclear medicine imaging procedures using radionuclides with affinity to malignancy have been evaluated.

Diagnostic nuclear medicine imaging

Planar scintigraphy with Tc99m-pertechnetate and iodine-123 is commonly used in clinical routine in order to discriminate hypofunctional nodules in the thyroid gland. Scintigraphy, however, is of limited value in small thyroid nodules. Although it has been proven by various studies that hypofunctionality of a thyroid nodule is associated with malignancy, only 3–5 % of nodules in iodine-sufficient areas (10 % in iodine-deficient areas) are malignant in definitive histology [16–18). In patients with multinodular goiter, scintigraphy may add information and guide the clinician which nodule should be further evaluated by US-FNAB (Fig. 1, 2).

Fig. 1
figure 1

Tc99m pertechnetate scintigraphy in a 40-year-old female patient with a suspicious nodule (Fig. 2) in the left thyroid lobe showing a hypofunctioning area

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Fig. 2
figure 2

Transverse and longitudinal ultrasonography show a suspicious hypoechoic, solid thyroid nodule with poorly defined margins and taller than wide shape presenting hypofunctional on scintigraphy (Fig. 1). Ultrasound-guided fine-needle aspiration biopsy indicated papillary thyroid cancer

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Other nuclear medicine imaging procedures have been investigated in the diagnostic management of thyroid nodules, especially when cytology is inconclusive.

Several studies have been performed to assess malignancy by using 201Tl chloride, Tc99m sestamibi, Tc99m tetrofosmin, but results showed low specificity [19, 20]. 18F-FDG positron emission tomography (PET) is a well-established method in the follow up of DTC patients with elevated tumour marker (Thyroglobulin (Tg)) and negative 131I scintigraphy. More recently the diagnostic role of 18F-FDG PET-CT was studied, but these data also showed that a clear differentiation between benign and malignant nodules is not possible. Adding 18F-FDG PET-CT findings especially to neck ultrasound provided no diagnostic benefit [21–23]. In anaplastic or poorly differentiated thyroid cancer, preoperative 18F-FDG PET-CT may play a role in order to assess the full extent of disease to plan a patient-tailored regimen (Fig. 3).

Fig. 3
figure 3

18F-FDG PET-CT of a 53-year-old man with a fast growing thyroid mass, US-FNAB indicated dedifferentiated thyroid cancer. 18F MIP and transaxial fused images show the extent of disease with additional multiple lymph node metastases, lung and bone metastases. The patient died 3 months after diagnosis despite systemic chemotherapy because of progressive tumour disease

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Nuclear medicine and therapy of differentiated thyroid cancer

131I therapy-remnant ablation

Differentiated thyroid cancer is known to have an excellent prognosis after initial treatment with surgery and 131I systemic therapy. After successful treatment thyroglobulin (Tg, tumour marker) should not be detectable and diagnostic imaging with 131I whole body scintigraphy (WBS) should be negative [24]. Thus, systemic radioiodine treatment is routinely performed as a standard procedure in DTC patients with the exception of unifocal papillary DTC £ 1 cm confined to the thyroid gland. TSH serum levels > 30 mU/l are required to optimise radioiodine intake into thyroid tissue. These levels are achieved either through endogenous TSH elevation with thyroid hormone withdrawal over 3–5 weeks or through exogenous TSH stimulation (recombinant TSH, Thyrogen® intramuscularly on two following days) [25, 26]. In anaplastic thyroid cancer, due to dedifferentiation and inability of iodine intake as well as in medullary thyroid cancer (originating from the parafollicular C-cells that do not store iodine), radioiodine treatment is not recommended [27–30]. The rationale for radioiodine-remnant ablation is to eliminate residual thyroid tissue in order to facilitate follow up and to destroy possible microscopic thyroid cancer cells after surgery. Furthermore, highly sensitive posttherapeutic whole body scans can be acquired in order to detect iodine positive metastases previously not diagnosed. In suitably equipped centres, the administered 131I activities vary and range between 1,100 MBq and 3,700 MBq or even higher, e.g. in case of known distant metastases. Recently, studies with lower activities of 131I under exogen TSH stimulation for initial treatment have been published. A prospective randomized study by Pilli et al. [31] showed that patients under exogenous TSH stimulation receiving an activity of 1,850 MBq (50 mCi) 131I differed not significantly with regard to successful ablation compared with those receiving higher activities of 3,700 MBq (100 mCi). They even found no difference in the presence of cervical lymph node metastases. Further studies, however, and maybe longer follow up intervals are needed towards a possible direction to lower activities in initial treatment under recombinant TSH.

In recent time, the need of subsequent radioiodine ablation therapy in patients with minimally invasive follicular thyroid cancer (MIFTC) has been a matter of debate. With respect to an estimated low malignant potential and a very favourable prognosis, a less radical surgery approach is discussed. In case of MIFTC with capsular invasion only and maybe also in case of limited vascular invasion (£ 3, examination of at least 10 tissue blocks of the entire tumour mandatory), based on the criteria of Rosai 2005, a hemithyroidectomy without systemic lymphadenectomy with a lower postsurgical complication rate is maybe sufficient without subsequent radioiodine treatment concluded Hermann et al. [32]. The difficulty, however, is that data from literature are not homogeneous because of inconsistent histopathological classification and amount of obtained tissue blocks in case of MIFTC. Thompson et al. [33] published a study in 2001 where the histopathologic records of 130 patients with diagnosed MIFTC were re-evaluated and complete clinical follow up was mandatory for study inclusion. According to their classification with regard to capsular and vascular invasion, 95 patients were confirmed to have MIFTC and the remaining 35 patients showing tumours with large vessel invasion or other features were classified as “not low grade.” The authors could show that despite the extensive heterogenous treatment approaches in the two groups (lobectomy followed by complete thyroidectomy, lobectomy alone, subtotal thyroidectomy, subsequent or no subsequent radioiodine therapy), the prognosis was generally excellent. Taking all arguments into account, there is the need to perform prospective studies with clearly defined histopathologic criteria comparing patient outcome of hemithyroidectomy alone in case of MIFTC or total thyroidectomy with subsequent radioiodine ablation. However, there is also the need for a long follow up period, because it is known that in DTC, the recurrences or distant metastases may occur years after initial treatment.

Nuclear medicine treatment in metastatic differentiated thyroid cancer

The various national and international recommendations and guidelines from different medicine specialities with regard to metastatic thyroid cancer disease show quite similar treatment approaches. In case of local tumour recurrence, lymph node or distant metastases, the whole armamentarium of possible treatment options should be taken into account. If limited disease is diagnosed, surgery should be considered. In case of single or few small, not resectable or multiple iodine positive metastases, subsequent circles of iodine treatment with activities up to 7,400 MBq (200 mCi) should be performed as long as iodine avidity is present and disease regression is documented by decrease of iodine uptake on posttherapeutic WBS and decline in serum Tg levels. Also external radiation therapy, e.g. in symptomatic bone metastases for pain control and additional treatment options with bisphosphonates or Denosumab should be considered. Other parameters, however, considering patient age, health status, tumour burden, quality of life and disease symptoms should be also taken into account. Especially in presence of additionally FDG positive metastases, an individual patient approach is mandatory.

Posttherapeutic 131I whole body scintigraphy and SPECT/CT

After first radioiodine-remnant ablation, whole body scintigraphy is performed 5–7 days after treatment. This nuclear medicine imaging procedure offers the opportunity not only to judge effectiveness of treatment but also allows a whole body staging [34, 35]. The precise anatomical localization of pathological lesions and the diagnosis of physiological iodine uptake are sometimes difficult on conventional planar imaging. With the growing availability of integrated SPECT-CT, a precise anatomical localization of foci with increased iodine uptake is possible. SPECT-CT, a dual imaging modality combines functional information from the scintigraphic data (SPECT) and anatomic information (CT) in a single examination. In a prospective study [36], we evaluated the diagnostic impact and influence on patient management of posttherapeutic 131I SPECT-CT findings when they were inconclusive on planar images. Regarding neck lesions, the SPECT-CT provided a diagnostic impact in 28.9 %, on a patient basis SPECT-CT changed N-status in 36.4 % and led to a treatment change in 24.2 %. Regarding lesions distant from the neck, SPECT-CT had a diagnostic impact in 12.7 %. Considering all patients together, SPECT-CT led to a treatment change in 24.4 %. Also other studies showed the superiority of SPECT-CT over planar scintigraphy in case of inconclusive lesions [37, 38] and confirmed its usefulness in daily clinical routine (Fig. 4).

Fig. 4
figure 4

Additional information and exact lesion localisation in case of multiple foci of iodine uptake in the neck. SPECT-CT demonstrates 131I-positive lymphnode metastases. Because of the size and patient’s age, surgery was performed with precise anatomical information provided to the surgeons preoperatively

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Nuclear medicine and follow up of differentiated thyroid cancer

Thyroglobulin and ultrasound

Thyroglobulin and ultrasound are highly effective tools in the follow up of patients with DTC. Because it is not the main topic of the article, only a short overview is given.

Thyroglobulin(Tg) is the tumour marker of DTC after total thyroidectomy and radioiodine ablation. Thyroglobulin measured with sensitive and ultrasensitive immuno-radiometric assays offering also recovery rates of Tg and in the absence of antibodies should be undetectable in case of complete remission [39–42]. Elevated or rising Tg levels in the follow up most likely indicate DTC local recurrence, lymphnode or distant metastases. Besides ultrasonography of the neck imaging procedures with iodine or other tracers, favourable 18F-FDG PET-CT are recommended in those cases. Thyroglobulin measurement, however, is most reliable under TSH elevation > 30 mU/l (either through thyroid hormone withdrawal over 4–5 weeks or with the use of recombinant TSH). Under thyroid hormone medication, thyroglobulin has been found falsely negative in up to 20 %, thus a negative stimulated Tg is highly predictive for absence of disease [35, 42]. Only in rare cases, e.g. in dedifferentiated or anaplastic thyroid cancer, Tg may remain in lower ranges under huge tumour burden due to dedifferentiation of cells.

Ultrasound of the neck is a highly accurate imaging technique for the detection of thyroid local recurrence and lymph node metastases and is therefore mandatory at any visit in follow up [34]. Especially papillary thyroid cancer has a high propensity to spread to lymph nodes in the neck, less common in follicular thyroid cancer. A round shape, loss of the nodal hilum, peripheral hypervascularity, necrosis, cystic appearance, calcifications, sometimes also increased echogenecity are signs of thyroid lymphnode metastases [43, 44]. There are, however, rare false negative stimulated serum Tg levels in presence of especially small lymph node metastases [45, 46]. US-FNAB is recommended in suspicious lymphnodes to improve accuracy of ultrasound [34].

Diagnostic 131I whole body scintigraphy (WBS) and SPECT/CT

Iodine-131 WBS is still performed in many institutions as part of the posttherapeutic assessment to state a patient free of disease. In a European consensus paper by Pacini et al. [34], a successful ablation is defined as an undetectable serum Tg level following endogenous or exogenous TSH stimulation and a normal ultrasound of the neck. The authors argue that diagnostic WBS according to low sensitivity ranging from 45 to 75 % adds no additional information. Lubin et al. [47] showed that in 261 patients, there were no instances of diagnostic whole body scans and negative stimulated TSH. The role of routine diagnostic radioiodine whole body scintigraphy has been recently evaluated by de Meer et al. [48] in patients with high-risk differentiated thyroid cancer. The authors concluded in case of undetectable stimulated Tg levels diagnostic WBS added no additional information. On the other hand, it is well known that a negative diagnostic scan in case of elevated serum Tg does not necessarily indicate a negative posttherapeutic scan in presence of iodine positive metastases due to the higher activities administered [49, 50]. With the increasing availability of SPECT-CT devices, the value of diagnostic WBS has been re-evaluated by several studies. Barwick et al. [51] showed in a study that SPECT-CT significantly improved the diagnostic information over conventional 123I WBS and SPECT alone. Spanu et al. [52] found in 108 patients who underwent diagnostic imaging for DTC, a clear superiority compared to planar imaging with regard to precise localisation and additional lesions diagnosed.

PET/CT in the follow up of differentiated thyroid cancer

The performance of18 F-FDG PET-CT in patients with suspected iodine negative metastases in case of elevated serum Tg and iodine negative posttherapeutic WBS is quite established. Due to dedifferentiation of tumour cells and because of high proliferation index, the tumour glucose metabolism is significantly increased, indicating a poorer prognosis of DTC. The superiority of PET-CT combining functional (PET) and morphological (CT) information in a single device has been evaluated in multiple studies [53]. Other tracers such as 201Tl, Tc99m-tetrofosmin and Tc99m-sestamibi have been replaced in case of availability of PET or better PET-CT. As discussed earlier, 18F-FDG PET-CT in a preoperative setting of suspicious nodules is still a matter of debate, in case of elevated Tg levels and negative posttherapeutic 131I scans it is classified as I A indication. It is also known that in DTC patients, iodine positive and negative metastases may be present in one patient. In case of markedly elevated Tg levels and only minor pathology on iodine WBS, FDG positive metastases have to be suspected (Fig. 5).

Fig. 5
figure 5

131I posttherapeutic WBS 5 days after administration of 3,700 MBq 131I showing a thyroid remnant in the neck and multiple iodine positive lung metastases. 18F FDG PET-CT shows intense FDG uptake in the thyroid bed and faint uptake in lung metastases—indicating both iodine positive and negative lesions in one patient

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Several studies evaluated sensitivity, specificity and accuracy of 18F-FDG PET-CT with respect to serum thyroglobulin levels in patients with negative 131I scans. Bannas et al. [54] investigated 30 patients with elevated serum Tg and negative I131 WBS for diagnostic accuracy of 18F-FDG PET-CT for two subgroups below and above 10 ng/ml, respectively. They reported overall sensitivity, specificity and accuracy of 68.0, 60.0 and 66.7 %, respectively. In the group with Tg levels above 10 ng/ml (n = 21), the sensitivity, specificity and accuracy reached 70.0, 100.0 and 71.4 %, respectively. Shammas et al. [55] evaluated 61 patients in a similar setting using cut off serum Tg levels less than 5, 5–10 and more than 10 ng/ml. They found an overall sensitivity, specificity and accuracy of 18F-FDG PET-CT of 68.4, 82.4 and 73.8 %, respectively. Regarding sensitivities of Tg less than 5.0, 5–10 and above 10 ng/ml they reported 60, 63 and 72 %, respectively, showing similar results for the > 10 ng/ml group as Bannas et al. [54]. A study by Giovanella et al. [56], however, reported higher sensitivity, specificity and accuracy for serum Tg levels ³ 4.6 ng/ml of 93, 84 and 90 %, respectively. Other studies reported an increased sensitivity of 18F-FDG PET-CT when performed under TSH stimulation, especially in presence of low serum Tg levels [57, 58].

The positron emitter isotope 124 I with a long half life of 5 days is also used for diagnostic and dosimetry purposes in patients with thyroid cancer. The performance of 124I PET-CT therefore allows not only a precise visualisation of iodine positive lesions from DTC—because of the higher sensitivity and spatial resolution of PET compared to gamma scintigraphy—it can also be used for patient specific radioiodine therapy dosimetry for a tailored patient treatment protocol [59, 60].

There are only few studies published using 6 8 Ga-somatostatin receptor (SRS) PET-CT in dedifferentiated thyroid cancer. Middendorp et al. [61] reported about 17 patients who underwent both 18F-FDG PET-CT and 6 8Ga-DOTATOC PET-CT. They concluded that 18F-FDG PET-CT was superior to 6 8Ga-SRS PET-CT in the detection of iodine negative lesions. Gabriel et al. [62] showed results in patients with radioiodine negative metastases where 6 8Ga-SRS PET/CT guided towards somatostatin receptor (SRS) mediated radionuclide therapy.