Differentiated thyroid carcinoma (DTC) is the most common endocrine cancer accounting for 1 % of all cancers diagnosed each year [1]. The incidence of thyroid cancer has more than doubled since the early 1970s and, in women, it is the cancer showing the fastest-growing number of new cases. Papillary and follicular carcinomas account for the majority of DTCs and these histological variants are characterized by radioiodine (131I) uptake. After initial thyroidectomy, 131I treatment is performed in most patients to ablate thyroid remnants and to treat locoregional or distant metastases [2].

For many years, planar 131I whole-body scintigraphy (131I WBS), performed using diagnostic (131I DxWBS) or therapeutic (131I TxWBS) activities of radioiodine, was the standard method used to identify thyroid remnants or metastases [3].

Although 131I WBS boasts good sensitivity and high specificity, because of the lack of anatomical landmarks, it shows limitations in anatomical localization of the tumor and in differentiation of neoplastic from normal iodine-avid tissue. Low resolution and a paucity of anatomical information, along with a long list of physiological variants, make interpretation of 131I WBS challenging. Multiple maneuvers and strategies to aid in the differentiation of physiological from pathological foci of activity (e.g. swallowing water, separate-day imaging, oblique and lateral imaging, washing the patient’s skin, correlation with other imaging techniques, etc.) have traditionally been used to improve the diagnostic accuracy [4].

Hybrid SPECT/CT systems integrating a SPECT (single photon emission computed tomography) gamma camera with an X-ray computed tomography (CT) scanner in one gantry have been in use ever since they were first described in 2001 [5]. Thanks to a dual imaging modality, they allow combination of scintigraphic functional imaging (SPECT) data with anatomical (CT) information in a single examination. In the management of DTC patients, SPECT/CT with 131I (131I SPECT/CT) provides metabolic and anatomical information about a lesion, allows accurate alignment of anatomical and functional images, and by allowing morphological and metabolic data to be collected in an all-in-one procedure, makes for better cost-effectiveness [6].

Several studies have demonstrated that 131I SPECT/CT has incremental diagnostic value in the diagnosis, treatment, and management of DTC [6–17].

In this article, we discuss the contribution of 131I SPECT/CT to better identification and localization of radioiodine uptake sites, its emerging role in staging and patient management, its role in 131I therapy based on dosimetry data, and finally the limitations and disadvantages of this technology.

Detection and localization of 131I uptake sites

The human sodium iodide symporter (NIS) gene, which is located on chromosome 9p12–13.2 and was cloned in 1996, determines expression of NIS and consequent uptake of radioiodine both in normal thyroid tissues and in up to 80 % of thyroid carcinoma cells through an electrochemical sodium gradient generated by sodium–potassium adenosine triphosphatase [18].

NIS is normally expressed in: thyroid cells, ductal cells of salivary glands, parietal and mucus-secreting cells of the gastric mucosa, lacrimal glands, choroid plexus, ciliary bodies of the eye, thymus, placenta, and lactating mammary glands; NIS expression is also detected in most neoplastic cells of locoregional and distant metastases of DTC [18, 19].

As consequence, 131I WBS can show radioiodine uptake not only in thyroid remnants or metastases from DTC, but also in non-thyroid tissue showing physiological expression of NIS [19]. Several physiological variants and pitfalls may occasionally lead to mimicking of residual disease on 131I WBS, and these variants are usually recognized on planar imaging.

However, it is difficult to establish the precise anatomical localization of foci of 131I uptake on planar images because of the lack of anatomical landmarks and the low resolution, and 131I SPECT/CT has been demonstrated have incremental value over 131I WBS in characterizing and localizing pathological and physiological sites of radioiodine uptake [9, 10].

There are many studies showing the value of 131I SPECT/CT in cases that are difficult to resolve due to unusual biodistributions of radioiodine, such as ectopic thyroid tissue, ovarian teratoma, struma ovarii, kidney cysts, or accumulation of physiological secretions in the thorax, abdomen or genitourinary tract [4].

In a recent study, Aide et al. [14] reported that indeterminate findings on 131I WBS after ablation in 16 out of 55 patients (29 %) were reduced to 7 % after 131I SPECT/CT and that these results closely correlated with persistence or absence of disease at the end of follow-up. Blum et al. [15] highlighted the role of SPECT/CT in resolving cryptic findings in 40 out of 184 (22 %) whole-body scans performed after diagnostic or therapeutic administration of radioiodine.

By using the one-station 131I SPECT/CT procedure, the multiple maneuvers and strategies to improve the diagnostic accuracy mentioned earlier (e.g. swallowing water, using laxatives, washing skin, removing and scanning clothing, separate-day imaging, oblique and lateral imaging, correlation with other imaging modalities) may become redundant and can possibly be avoided. Similarly, it is no longer necessary to remain vigilant for pitfalls such as dentures (Fig. 1) and other sources of contamination (Fig. 2).

Fig. 1
figure 1

Post-therapeutic 131I WBS showed a small punctiform uptake of 131I in the left submandibular region (a, arrow). 131I SPECT/CT revealed that this lesion was 131I uptake in dentures (b, arrows)

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Fig. 2
figure 2

Post-therapeutic 131I WBS demonstrated intense radioactivity in the area of left shoulder (a, arrow). To accurately locate the 131I uptake lesion, 131I SPECT/CT was performed and the 131I uptake was found to be skin contamination (b, arrows)

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The capacity of 131I SPECT/CT to better identify physiological and pathological sites of 131I uptake in the head and neck, thorax, abdomen, pelvis, and bone are examined in the following sections.

Head and neck

To minimize the risk of surgical complications (e.g., vocal cord paralysis), surgeons commonly leave small amounts of normal thyroid tissue (thyroid remnants) in the thyroid bed, near the expected location of the recurrent laryngeal nerve [4].

Thyroid remnants are depicted on 131I WBS as focal, intense central neck radioiodine uptake. However, because of the close proximity of adjacent structures in the head and neck and variations in body habitus, it is possible for uptake in the neck to be equivocal or indeterminate on planar imaging [4].

Thyroid remnants and thyroglossal duct remnants (small remains of thyroid tissue that concentrate radioiodine in the setting of elevated TSH levels) have a typical appearance on 131I SPECT/CT. Thyroid remnants commonly appear as focal (unilateral or bilateral) paratracheal activity associated with surgical clips, while a thyroglossal duct remnant will appear as an intense focal uptake in the midline of the central neck that localizes to the tip of the hyoid bone, along the expected path of descent of the embryological thyroid gland [4, 20].

131I SPECT/CT can be helpful for characterizing thyroid remnants and it may influence both the selection of patients and the choice of radioiodine activity for radioiodine treatment (Fig. 3) [9–11]. After radioiodine treatment with empirical activities of 131I, it has been found that 131I SPECT/CT has an incremental value over planar imaging, also in terms of its capacity to depict response to radioiodine treatment [9, 14].

Fig. 3
figure 3

Post-therapeutic 131I WBS revealed two rounded foci of 131I uptake in the neck. It was difficult to distinguish whether these corresponded to residual thyroid or cervical lymph node tissue (a, arrows). The subsequent 131I SPECT/CT fusion images showed the two lesions to be residual thyroid tissue (b, arrows)

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To classify a paratracheal central neck activity as benign thyroid remnant or residual tumoral tissue, 131I SPECT/CT studies must be always evaluated together with the surgical pathology report, which provides information on tumor invasion into local structures and the completeness of the surgical resection [20]. Focal paratracheal central neck activities associated with a total thyroidectomy specimen demonstrating no evidence of extra thyroid tumor extension and negative surgical excision margins on pathology review may be usually characterized as thyroid remnants [21–23].

In addition to its use in the evaluation of thyroid remnants, 131I SPECT/CT can also be used to characterize other sites of benign radioiodine uptake in the head and neck region, e.g. in the nasal mucosa or nasolacrimal duct. Such uptake may be due to secretions or inflammation, pooling of salivary secretions, dental abscesses or recent dental or periodontal procedures, and secretions in a tracheostomy tube [24–27]. 131I SPECT/CT can also be useful for evaluating asymmetry of salivary gland uptake (related to radiation-induced salivary duct narrowing or sialadenitis due to prior radioiodine treatment), which can be another potentially misleading pattern [28].

Chest, lungs, and mediastinum

Radioiodine uptake in the chest can be due to several benign conditions or to residual thyroid tumor, such as skeletal (in the sternum, thoracic spine or ribs), lung and mediastinal lymph node metastases [20].

131I SPECT/CT may be used to differentiate benign causes and sites of radioiodine uptake in the chest that may cause diagnostic difficulties. These include esophageal secretions, Zenker’s diverticulum, thymus, hiatal hernia, intrathoracic stomach created after esophagectomy or gastric pull-through surgery, lactating or non-lactating breast tissue, pleural and pericardial effusions, pulmonary infections, and skin contamination [4, 29].

In lactating women, focally increased uptake in the chest can be due to accumulation of radioiodine in breast tissue resulting from excretion of radioiodine into breast milk [30, 31]. Although rare, active transport by NIS can also cause symmetric or asymmetric radioiodine uptake in breast tissue in young, non-lactating women [32].

131I SPECT/CT can also be of diagnostic assistance in the assessment of mediastinal physiological radioiodine accumulation due to retention in the gastrointestinal system, as in the case of secretion in the esophagus [20] or accumulation in gastric pull-up [33], for example. 131I SPECT/CT can be used in pediatric patients to evaluate physiological thymic activity mimicking lymph node metastases [34] and in cases in which radioiodine may, by passive diffusion, concentrate in pleural and pericardial effusions, a finding that may be more common in some patients because of the hypothyroidism used before the administration of radioiodine [35].

Lung metastases on 131I WBS appear as either focal (macronodular disease) or diffuse (micronodular disease) radioiodine uptake. In patients with lung metastases 131I SPECT/CT may offer several advantages, including the possibility of avoiding a diagnostic thoracic CT, the possibility of using the study as baseline for assessment of therapy response, and the possibility of demonstrating mediastinal adenopathy not easily characterized on planar imaging (Fig. 4) [4].

Fig. 4
figure 4

Post-therapeutic 131I WBS showed a single uptake of 131I in the right upper chest (a, arrow). It was not clear whether this was bone or lymph node uptake. 131I SPECT/CT identified and localized the 131I uptake lesion in the upper mediastinal lymph node (b, arrows)

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Abdomen and pelvis

The stomach, bowel, kidneys, and bladder are the most common sites of normal radioiodine uptake in the abdomen and pelvis on 131I WBS. In addition to these physiological sites, non-neoplastic accumulation of 131I should also be anticipated and recognized in other unusual locations, such as hiatal hernias, inguinal and abdominal hernias, pelvic or transplanted kidneys, and bladder diverticula, as well as in diverticulitis and in patients previously submitted to bowel surgery [4, 36]. In the liver, hepatic metabolism of radioiodinated thyroid hormones released by remnant thyroid tissues can be responsible for diffuse uptake on 131I TxWBS. This pattern should be distinguished from the focal uptake caused by benign tumors or liver metastases [37].

Radioiodine uptake in the above-mentioned sites of may simulate skeletal metastases in the lumbar spine or pelvic bones, and 131I SPECT/CT improves reader confidence in interpretation by setting the focal activity seen on planar images in a clear anatomical context and accurately characterizing the uptake [4].

131I SPECT/CT may also distinguish Meckel’s diverticulum (which may manifest as focal radioiodine uptake in the abdomen because of active transport by ectopic gastric mucosa) [38], inguinal hernia that contains a loop of small bowel and serous cavities, and simple epithelial cysts of renal and ovarian origin accumulating radioiodine as a result of passive diffusion [4].

Bone metastases

After the lungs, the skeleton is the second most common site of distant metastases in patients with DTC and 131I SPECT/CT can play an important role in the accurate diagnosis and characterization of bone metastases. Focal radioiodine activity in bone can occur at any site and needs to be distinguished from skin contamination or adjacent skin and soft-tissue involvement. Although techniques such as additional views, delayed imaging, and washing the skin may be helpful, 131I SPECT/CT can rapidly localize activity to bone to confirm the diagnosis. Recently, Qiu et al. [39] demonstrated that 131I SPECT/CT and 18F-FDG PET/CT were superior to 99mTc-MDP bone scintigraphy for the detection of DTC bone metastases in patient-based and lesion-based analyses. 131I SPECT/CT seemed to show similar diagnostic accuracy to 18F-FDG PET/CT in the patient-based analysis but a superior performance in lesion-based analysis [39].

Rare sites of metastases

In patients with DTC, metastases to the brain, breast, liver, kidney, muscle, and skin are rare or relatively rare. Nevertheless, distinguishing rare metastases from DTC has a significant impact on clinical decision-making and on the prognosis of patients. Thanks to the use of 131I-SPECT/CT imaging fusion techniques, metastasis in rare sites in DTC is increasingly becoming an incidental finding [40]. For example, the recent literature contains reports of parapharyngeal metastasis [41], erector spinae metastasis [42], ovarian metastasis [43], adrenal metastasis [44], and orbital metastasis [45]. With the popularity of 131I treatment and the emergence of 131I SPECT/CT fusion imaging techniques, rare metastases in DTC seem to be increasingly common and may not, therefore, be as rare as once thought (Fig. 5).

Fig. 5
figure 5

Post-therapeutic 131I WBS detected a focus of 131I uptake in the right facial region (a, arrow) in addition to the cervical uptake. 131I SPECT/CT showed that this focus of 131I uptake was localized in the right parapharyngeal space (b, arrows)

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Impact on staging and patient management

Risk stratification and staging, based on clinical findings, histopathological criteria, and morphological and functional imaging, are used to predict the probability of DTC recurrence, treatment failure, and tumor-specific mortality [11–13, 46, 47].

The risk of recurrence increases when uptake of radioiodine outside the thyroid bed is present on the first radioiodine treatment after surgery and 131I SPECT/CT has been shown to be more accurate than 131I WBS for the completion of DTC staging and, moreover, for evaluating lymph node involvement during radioiodine ablation [48, 49].

131I Tx SPECT/CT was found to allow a gain in information on nodal staging in 35–36.4 % of patients and resulted in new risk stratification in 6.4–25 % [48].

Avram et al. [47] reported that 131I SPECT/CT changed the staging in 4 % of younger and 25 % of older patients before radioiodine treatment. The authors restaged 320 patients post-total thyroidectomy with 131I SPECT/CT and changed the staging (from N0 to N+) in 38 % of patients aged under 45 years and in 24 % of patients aged over 45 years. They also demonstrated that pre-ablation radioiodine imaging with SPECT/CT detected regional metastases and distant metastases in 35 % and 8 % of patients, respectively [47].

Avram [46], in a recent review, concluded that risk stratification and staging of patients should not be based solely on clinical and histopathological criteria, but should also include 131I SPECT/CT imaging to evaluate the presence of regional and distant metastases.

Grewal et al. [21] reported that SPECT/CT changed the risk classification in 7 out of 109 patients (6.5 %), modifying the intensity of their management during the subsequent follow-up. This is not a low percentage, if one considers that radioiodine scan is only one of factors determining the risk classification and that the newest guidelines do not recommend radioiodine treatment in low-risk patients.

Beyond the impact on staging, the utility of 131I SPECT/CT is defined by its impact on clinical management, which may be changed in 23.5–25 % of patients, as reported by Xue et al. [48] in their recent systematic review on the incremental value of 131I SPECT/CT.

Depending on the location of the iodine uptake sites, the results of the 131I SPECT/CT may change a patient’s planned treatment, the frequency of surveillance, and the need for additional imaging, laboratory tests or biopsy. 131I SPECT/CT can also avoid unnecessary 131I therapy in patients in whom residual and/or metastatic disease has been excluded [46].

Identification of regional and distant metastases prior to 131I therapy has significant potential to alter patient management, either by adjusting empirical 131I activities or by administering activities after dosimetric calculations [46, 48]. In addition, in patients with localized disease the size of the metastasis can be measured by SPECT/CT and this information can be useful in deciding on 131I therapy (small metastases) vs surgical resection (bulky disease).

Grewall et al. [21] reported that patient management was changed in 20 % of subjects in whom SPECT/CT results reduced the need for additional imaging studies, while Chen et al. [9] conducted 37 SPECT/CT studies in 23 patients with inconclusive foci on WBS and reported a change in management in 34.7 % (8/23) of these cases.

Wong et al. [10] showed that the use of diagnostic 131I SPECT/CT may lead to both increases and decreases in prescribed doses for initial postoperative 131I therapy. Prescribing medium or high 131I activities in high-risk patients can improve patient outcome; conversely, in a younger patient, in whom the risks of radiation may be greater and may extend over a longer time, it can be particularly important to administer a low 131I activity [2].

131I SPECT/CT for dosimetry

Treatment with 131I should be aimed at destroying as much of the thyroid carcinoma as possible, with the absorbed dose of radiation in the carcinoma being the best predictor of success of the treatment. However, dosimetric calculations based on planar imaging are hampered by an inability to measure accurately the volumes of the tumor targets, while measurements of absorbed radiation show inherent inaccuracies [50].

The most complete information that can be used to perform accurate quantification in macroscopic tumoral lesions is that derived from SPECT/CT imaging, which allows optimal attenuation correction based on the CT data, scatter correction, and distance-dependent detector response function correction [51]. Fully 3D SPECT/CT imaging yields activity estimates at the voxel level and it is the recommended approach when dosimetry at this level is required.

Flux et al. [52], studying 23 patients receiving 3 GBq 131I following thyroidectomy, determined the absorbed dose in the voxel with the highest uptake on Tx 131I SPECT/CT, reporting values ranging from 7 to 570 Gy. The authors found a significant difference in absorbed doses delivered to thyroid remnants between patients who had a successful ablation versus those with a failed ablation.

In patients with distant functioning metastases, dosimetry with SPECT/CT can predict absorbed doses of radiation to the tumor and to the adjacent organs and thus provide a basis for data-based decisions on 131I therapies. Sisson et al. [53] reported a case of an enlarging metastasis of DTC to the skull that was impinging on the brain and in which dosimetry, enabled by 131I SPECT/CT, was performed before 131I treatments. The authors reported that dosimetry indicated delivery, in two treatments, of 1,970 and 2,870 cGy to the tumor and 35 and 42 cGy to the brain, which induced recession of tumor volume, and that the patient was still alive more than 11 years after the diagnosis.

Limitations of 131I SPECT/CT

Despite the benefits of 131I SPECT/CT, this technology has several limitations and disadvantages [10, 21, 46, 47].

First, the low activity administered for 131I Dx SPECT/CT (111–185 MBq) may lead to poor statistical counting, especially when an iterative reconstruction technique is used. This problem can be corrected with a longer acquisition time, at the expense of greater discomfort for the patient, and with the use of filtered back-projection reconstruction [10].

Second, patient motion during acquisition can cause misregistration of fusion images, also in integrated SPECT/CT cameras; immobilizers could be called for if acquisition time cannot be reduced [10].

Third, the presence of streak artifacts, common with high activity of radioiodine, and attenuation of the neck by the patient’ shoulders could give rise to doubts and problems in image interpretation. In these cases the use of a pin-hole collimator and comparison with planar images could be very useful.

Fourth, additional radiation exposure from the CT component of the study (1–4 mSv with each acquisition) should be assessed on a patient-by-patient basis, particularly in the pediatric population [46]. In addition, the spatial resolution of SPECT is limited by the partial-volume effect in small lesions and the method lacks sensitivity for the detection of micrometastatic lesions [46].

The other potential limitation is that although information obtained with diagnostic 131I SPECT/CT led to changes in staging and management, this may not directly translate into a more favorable outcome [21, 47]. In a slowly growing malignancy such as DTC, assessing the outcome of therapeutic interventions requires prolonged follow-up [21].

Finally, non-iodine-avid disease, which occurs in approximately 30 % of DTC, may remain undetected on SPECT/CT and lead to false negative interpretations [46].

Conclusion

SPECT/CT is a powerful diagnostic tool that allows accurate anatomical localization and characterization of radioiodine foci and has substantially improved the interpretation of 131I whole-body scintigraphy.

SPECT/CT may provide an important contribution to the identification of benign or malignant functional thyroid tissue, improving post-operative staging and patient risk stratification, as well as clinical management, in a significant number of patients with DTC.

This improvement in diagnostic performance has been achieved largely thanks to superior anatomical localization of radioactivity and CT-based attenuation correction of functional tomographic images. Moreover, 131I SPECT/CT can be used to measure volumes of residual tumor and metastases and thus opens the way for highly accurate dosimetry-based 131I treatments.