Introduction: The absence of anatomical landmarks in the whole body scan makes it challenging to precisely localize ¹³¹I uptake, which is used to treat patients with differentiated thyroid cancer (DTC). Recently, SPECT/CT studies have been utilized to increase the diagnostic sensitivity and specificity.

Aim: To evaluate the clinical role of post-treatment ¹³¹I SPECT/CT imaging in the management of DTC.

Materials and methods: The study included 564 patients (384 women and 180 men) aged 12 to 83 years with DTC referred to our hospital between 2011 and 2021. A post therapeutic ¹³¹I whole-body scintigraphy (WBS) with SPECT/CT imaging was performed.

Results: 370 (65%) cases with papillary carcinoma, 101 (18%) cases with follicular carcinoma, and 93 (17%) cases with follicular variant of papillary DTC were histologically proven. ¹³¹I WBS was positive in 423 (75%) cases. SPECT/CT showed thyroid remnant in 237 (42%) patients, tumor persistence – in 15 (2.7%), and local recurrence in the thyroid bad in 17 (3%) cases. Enlarged cervical and mediastinal lymph nodes were visualized in 141 (25%) cases. Forty-eight (8.5%) patients had pulmonary metastases, 14 had osteolytic bone lesions and 6 (1.4%) had brain metastases detected on the SPECT/CT images. Negative ¹³¹I SPECT/CT data influenced significantly the clinical management of a large cohort with recurrent and metastatic DTC, leading to rejection of radioiodine treatment as a therapeutic alternative.

Conclusion: SPECT/CT improved the ¹³¹I WBS accuracy, thus changing the management of DTC determining indications for surgery, the need to give or withhold ¹³¹I therapy, and selecting cases for radiotherapy or chemotherapy in order to personalize the treatment.

3D iodine scanning, anatomical correlation, individualized clinical management

It is difficult to precisely localize the ¹³¹I uptake used to treat patients with differentiated thyroid cancer (DTC) because whole body scans lack anatomical landmarks.^[1] The utility of ¹³¹I whole-body scintigraphy (WBS) and thyroglobulin (Tg) assessment in DTC has been describe in a lot of publications as an integral component of the “gold standard” to follow-up patients after radioiodine treatment.^[2] The first scientific paper of co-registered and superimposed SPECT and CT images without the use of external markers in patients with thyroid cancer was published by Perault et al. in 1997. The authors concluded that fused CT and SPECT images increased the diagnostic power of each separate imaging modality for detection and localization of thyroid cancer recurrence or metastases and could be of clinical utility in the management and care of the patients.^[3]

Recently SPECT/CT studies have been utilized in order to increase the diagnostic sensitivity and specificity of planar and SPECT images. This new hybrid modality provide perfect registration of functional (SPECT) and anatomical (CT) images. The CT part of the study is used for attenuation correction of SPECT images for improvement of image quality and visualization of lesions <10 mm.^[4] Depending on the histological type and tumor stage, local recurrence, regional cervical lymphadenopathy or distant metastases may be present or develop during disease monitoring.^{[2, 4]}

To evaluate the clinical role of post-treatment ¹³¹I SPECT/CT imaging in the management of DTC.

A total of 564 patients, aged 12 to 83 years (384 women and 180 men) with proven DTC, who were referred to our Department of Nuclear Medicine at Sofia Cancer Center between 2011 and 2021 were involved. A post therapeutic ¹³¹I whole-body scintigraphy (WBS) with subsequent target SPECT/CT imaging was carried out 5 days after high-dose radioiodine treatment and 4 weeks of L-thyroxin withdrawal.

WBS was performed at a speed of 8 cm/min. Additional SPECT/CT studies of the head and neck, chest, abdomen and/or pelvic regions were acquired if necessary using HEAP (High Energy All Purpose) collimator. Symbia T2, Siemens SPECT/CT gamma camera was used for topographic localization and morphological substratum of ‘hot’ abnormal foci. Dual-head SPECT acquisition included 64 projections, 25 s/file, and matrix 256×256. Low-dose CT was performed in the helical mode. Acquisition parameters included settings at 130 KV, 30 mA, and 3-5 mm slide thickness.

Focal uptake of the radionuclide on the WBS and fusion images was described as likely benign, malignant, and equivocal. Our results were interpreted based on all other clinical and radiological data and compared with the control ¹³¹I diagnostic images, performed 6-12 months later to evaluate the treatment response.

During the abovementioned period, we analyzed 564 patients with DTC. A summary of the patients’ characteristics including demographic, histological data and initial staging is presented in Table 1. Histologically, there were 370 (65%) cases with papillary carcinoma and 101 cases (18%) with follicular carcinoma, while 93 (17%) patients had a follicular variant of papillary DTC. The G1-G2 cell differentiation was present in most of the patients – in 96.2% of patients with papillary carcinoma, while G3, the insular type of thyroid cancer, was present in 6 (1%) patients. Non-favorable subtypes of follicular cancer such as the tall cell variants were detected in 9 (1.6%) patients. Patients were selected and staged according to the Union for International Cancer Control (UICC) 8th edition of TNM classification.

Thirty-three of the examined patients (5.8%) had elevated TgAb (anti-thyroglobulin antibodies) and low serum Tg (thyroglobulin) levels. In 4 (0.7%) patients with locally advanced DTC, cytoreductive operation was carried out in a maximum volume. All other 560 (99.3%) patients had undergone total or near-total thyroidectomy with subsequent radioiodine treatment for ablation of post-surgical residual thyroid tissue and/or therapy of local and distant metastases. In 247 patients, one course of ¹³¹I treatment was performed, in 74 patients – two courses, in 28 – three courses, and in 4 patients – 4 courses radioiodine therapy were applied, with total activity ranging from 2.2 to 14.0 GBq (60-380 mCi). Five patients with locally advanced tumors were admitted with a tracheal cannula for radioiodine therapy. Sixty-four (11.3%) patients were with known metastases at the first ¹³¹I imaging.

¹³¹I WB scan was positive for abnormal radionuclide uptake in 423 (75%) cases. SPECT/CT data showed thyroid remnants in 237 (42%) patients; tumor persistence – in 15 (2.7%), and local recurrent disease in the thyroid bed in 17 (3%) cases. Enlarged cervical and upper mediastinal lymph nodes were visualized in 141 (25%) cases, ¹³¹I positive nodules were found in 130 of them (Figs 1, 2). In 11 out of 141 cases, there was no tracer uptake, the possibility of lymphatic dissection or alternative radiotherapy was discussed in inoperable patients.

Fusion images enabled precise morphological characterization and right topography of unclear planar findings. ¹³¹I SPECT/CT imaging in the neck region enabled the differentiation of abnormal active foci as thyroid remnant or recurrence and enlarged cervical lymph nodes from physiological uptake in the esophagus or salivary glands in 24 (4.3%) patients (Figs 3, 4). This hybrid method reduced the false-positive findings scanned on the WBS, increasing the specificity of the study.

¹³¹I SPECT/CT studies should be used as a routine N-staging procedure in Nx patients with DTC at first radioablation because of the increasing trend to avoid initial ¹³¹I WBS with diagnostic activity (74 MBq) after surgery in order to prevent a stunning effect of the thyroid remnant and metastatic lesions. The analysis of the results obtained in 86 patients with Nx nodal status showed regional lymphogenic metastases in 18 of them (Fig. 2).

Forty-eight (8.5%) patients had pulmonary metastases: 29 patients were with intensive tracer uptake; 19 patients were ¹³¹I refractory, found on the CT images of SPECT/CT studies. Fourteen patients were with osteolytic bone lesions and in 6 cases brain metastases were depicted correctly on the SPECT/CT images, confirmed by clinical CT or MRT, and used to plan palliative radiotherapy (Figs 5, 6).

The adequate SPECT/CT determination of the exact localization, dimension, number and morphological structure of loco-regional lymph nodes and distant visceral and bone metastases is particularly important for N/M – staging and treatment monitoring, comparing the results of successive ¹³¹I post-therapeutic studies in repeated radioiodine treatment. Hybrid images identified false negative metastatic foci that were not depicted on the planar WB images, thus increasing the specificity of the ¹³¹I imaging.

SPECT/CT studies are very important in patients with clinical data for disease progression but with negative Tg due to positive TAT to continue radioiodine treatment. Enlarged regional lymph nodes with intensive ¹³¹I uptake were visualized in 7 out of 33 TAT positive patients during the disease follow-up (Fig. 7).

¹³¹I SPECT/CT is a very useful modality in non-iodine avid disease due to lack or subsequent loss of ¹³¹I uptake possibility and increased Tg level. This has been reported to occur more frequently in Hürthle cell thyroid cancer, in some papillary subtypes (tall cell) and poorly differentiated (insular) thyroid treatment.^{[2, 4] 131}I positive disease or ¹³¹I negative disease, determined by post-therapeutic SPECT/CT imaging, correlated more closely to success or failure of radioiodine treatment and to necessity to abandon additional radioiodine application (Figs 8, 9).

Negative ¹³¹I SPECT/CT data significantly impact clinical management in a significant number of patients with recurrent and metastatic DTC to reduce the prescription of inefficient ¹³¹I therapeutic doses. Proposed changes in management include:

1. Selection of patients for external beam radiotherapy in non-operable cases (Figs 10 A-J).

2. Indication and volume determination of lymph node dissection in cases with cervical lymphadenopathy.

3. Correct radiotherapy planning of the target volume in bone osteolytic lesions, mediastinal and non-operable cervical metastatic lymph nodes.

4. Indication to carry out target therapy in progressive non-iodine avid metastatic disease.

The analysis of the obtained results / true negative results – 141; true positive results – 399; false positive results – 24; false negative results – 30/ showed that the sensitivity of ¹³¹I post treatment whole-body scintigraphy was 93% (399/429); the specificity was 85% (141/165) and diagnostic accuracy respectively – 89.3% (504/564). After applying ¹³¹I SPECT/CT method to studied patients, the possibility of obtaining false negative results in iodine-refractory secondary lesions and false-positive foci is eliminated, as a result of which the sensitivity and specificity of the detection thyroid residual tissue, local relapse, lymphogenic and hematogeneous metastases reach up to 100% compared to the ¹³¹I WBS.

Figure 1.

A female patient, 12 year old with DTC, pT3N1M0 after near total thyroidectomy and ¹³¹I therapy; Tg=223 ng/ml. ¹³¹IWB post-treatment scan showed 2 ‘hot’ spots in the region of thyroid bed and the neck. There was also high tracer uptake in the mediastinum. SPECT/CT localized correctly tumor persistence in the right lobe with calcifications, 1 enlarged cervical lymph node on the left – level IB, and enlarged lymph nodes in the anterior mediastinum – level VII with intensive tracer uptake, significant for disease extension.

Figure 2.

A female patient, 64 years old, with DTC after radical thyroidectomy and ¹³¹I therapy, pT3NxMx. Tg=186 ng/ml. WB ¹³¹I scans showed abnormal focal tracer uptake in the neck and thyroid bed. SPECT/CT images localized “hot” spots in the right laterocervical – level III and bilateral above the clavicle lymph nodes – level IV, and also a thyroid remnant.

Figure 3.

A 24-year-old woman with DTC after total thyroidectomy, pT1N1aM0. ¹³¹I post-treatment WB scan with background activity in the thyroid bed and asymmetrical “hot” spot in the left cervical region. SPECT/CT localized enlarged reactive salivary submandibular gland after oral administration of therapeutic dose of ¹³¹I on the left.

Figure 4.

A 61-year-old man with DTC after radical thyroidectomy and ¹³¹I therapy. Tg=0.22 ng/ml. WB ¹³¹I scan showed focal mediastinal tracer abnormal uptake. SPECT/CT showed physiological uptake in the region of esophagus.

Figure 5.

A 48-year-old woman with DTC after radical thyroidectomy and ¹³¹I therapy. Tg=1036 ng/ml. WB ¹³¹I scan showed multiple secondary lesions with intensive ¹³¹I uptake in the head, thyroid bed and lungs. SPECT/CT showed correct topography of these ‘hot’ spots in the skull, lung parenchyma, 5th rib on the right and Th-1.

Figure 6.

A female patient, 73 years old with thyroid insular carcinoma after partial thyroidectomy and ¹³¹I therapy; pT4apN1aM0, G2, Tg=123.2 ng/ml; TAT (−). Post-treatment ¹³¹I WB scan showed intensive uptake in the thyroid bed and left parietal region of the brain. SPECT/CT localized enlarged positive supraclavicular lymph node on the right and tumor persistence in the right lobe with bilateral enlarged laterocervical lymph nodes without ¹³¹I uptake. There was scanned a solitary positive metastatic lesion in the brain.

Figure 7.

(A, B, C) A 34-year-old woman with DTC after radical thyroidectomy and ¹³¹I therapy; pT2pN1M0. Tg=0.13 ng/ml; TAT(+). ¹³¹I WB scan showed intensive uptake in the left laterocervical lymph nodes. SPECT/CT localized 1 enlarged cervical lymph node measuring 17.7 mm on the left significant for metastatic involvement. (D, E) The same patient after treatment: a control ¹³¹I WB scan and SPECT/CT showed normal tracer distribution in the neck area.

Figure 8.

62-year-old woman with thyroid insular carcinoma after partial thyroidectomy and ¹³¹I therapy; pT4apN1aM0, G2, Tg=123.2 ng/ml; TAT (−). Post-treatment ¹³¹I WB scan showed intensive uptake in the thyroid bed. SPECT/CT localized 1 enlarged laterocervical lymph node on the right – level V and persistence of the tumor tissue in the right lobe with infiltration of the surrounding tissues both of them without ¹³¹I uptake. There are “hot” spots in the paratracheal area probably because of the normal thyroid tissue.

Figure 9.

A female patient, 54 years old, with thyroid insular carcinoma after partial thyroidectomy and ¹³¹I therapy; pT4pN1aM1, G2, Tg >5000 ng/ml. Post-treatment ¹³¹I WB scan showed intensive uptake in the left thyroid lobe. SPECT-CT localized advanced tumor mass in the right lobe with infiltration of the surround tissues, multiple hilar, lung and hepatic metastases both of them without ¹³¹I uptake. Target therapy with sorafenib was prescribed.

Figure 10.

(A, B, C, D) A 83-year-old woman with locally advanced thyroid carcinoma (108.4 mm) after partial resection and biopsy; Tg=352 ng/ml. ¹³¹I WB scan and SPECT/CT showed partial uptake only in the right thyroid lobe (A, B). SPECT/CT localized tumor mass in the upper anterior mediastinum and enlarged laterocervical lymph nodes on the left without ¹³¹I uptake (C, D). (E, F, G, H) The same patient after 20 Gy EBRT (CTV included target soft tissue – GTV and radiation dose distribution). Control ¹³¹I WB scan and SPECT/CT showed partial response to therapy with reduced size of the primary tumor till 96.5 mm and cervical lymph nodes on the left. (I, J). The same patient. Histological confirmation of differentiated multifocal thyroid cancer H&E, 4× (I) and lymph node mets H&E, 4× (J).

Confirmation of ¹³¹I uptake with post therapeutic ¹³¹I whole-body scintigraphy and subsequent target SPECT/CT imaging can indicate the potential for successful radioiodine therapy in thyroid cancer on the basis of theragnostic approach for personalized therapy.^{[5, 6]} Theragnostic is a rapidly expanding field of nuclear medicine that combines diagnostic and therapeutic tools.^{[5, 6]} The most prominent and oldest application is radioiodine (switch of the radionuclide from diagnosis to radionuclide therapy of thyroid cancer). It is a form of personalized medicine, introduced for the first time in the clinical practice by Dr. Saul Hertz for treatment of thyroid diseases in 1941.^{[7] 131}I is still a gold standard in the therapy and diagnosis of DTC.^{[1, 2]} In January 2018, a scientific meeting was held in Martinique between representatives of the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association at which they discussed some of the “Controversies, Consensus, and Collaboration in the Use of ¹³¹I Therapy in Differentiated Thyroid Cancer”.‌^[8] After much consideration, debate, and collegial exchange of concepts, the conference participants agreed on a set of nine principles that summarize the major points of discussion during the meeting. In some of these postulates, the crucial role of SPECT/CT studies in obtaining high-quality ^123/131I images was also discussed, which is essential for determining an individual approach in each patient treated for thyroid cancer.^[8] According to literature data, SPECT/CT leads to modification of therapeutic behavior in 35%–47% of patients and prevention of ineffective treatment for about 20% of patients; the risk stratification was modified by the findings of SPECT/CT in 25% of patients.^[1,9,10]

An indication to carry out ¹⁸F-FDG PET/CT is mainly in high-risk DTC patients with elevated Tg levels and negative radioiodine ¹³¹I WBS.^[11] Its sensitivity and specificity for detection of recurrent disease was reported to be 93% and 85%, respectively.^[12] These patients, due to the low tumor differentiation and subsequent activation of cellular glucose metabolism, showed high ¹⁸F-FDG uptake and absence of radioiodine uptake, so-called “flip-flop“ phenomenon. However, it is known that both ¹³¹I-avid and ¹⁸F-FDG-avid lesions can exist in the same time in aggressive DTC.^{[13–15] 18}F-FDG PET/CT is not suggested for routine preoperative imaging. However, it is recommended for initial staging in aggressive tumors including poorly differentiated thyroid cancers and invasive Hürthle cell carcinomas.^[16] The role of ¹⁸F-FDG PET/CT as a prognostic biomarker in metastatic DTC is also reported. ¹⁸F-FDG uptake in thyroid cancer is related to the differentiation level of malignant cells. The higher the FDG uptake is, the lower the degree of tumor differentiation. Consequently, tumors with high ¹⁸F-FDG and low ¹³¹I uptake are more aggressive, have poor prognosis with shorten overall survival and are indicated for target therapy. Following that recent developments in precision medicine, there are already some promising results for tyrosine kinase inhibitors (TKI) in the treatment of advanced and metastatic ¹³¹I refractory DTC. Based on updated therapeutic guidelines, TKIs like sorafenib and lenvatinib (category 1 recommendation), vandetanib, cabozantinib are a new approach to standard systemic therapy in first-line setting for these patients. Larotrectinib or entrectinib are a reasonable option for patients with NTRK gene fusion‐positive advanced solid tumors, for DTC as well.^{[17, 18]}

It can be summarized that ¹³¹I SPECT/CT studies improved accuracy of ¹³¹I WB scan and changed management of DTC determining indications for surgical intervention, the need to give or withhold ¹³¹I therapy, to select cases for radio/chemotherapy in order to personalize the treatment.

QUESTION: Does ¹³¹I whole-body scintigraphy (WBS) with subsequent targeted SPECT/CT imaging influence the clinical management of patients with DTC?

PERTINENT FINDINGS: In a retrospective study, 564 patients with DTC were examined between 2011 and 2021. The ¹³¹I SPECT-CT imaging added significant clinical information, which was used for the modification of therapeutic management.

IMPLICATIONS FOR PATIENT CARE: SPECT/CT studies improved accuracy of ¹³¹I WB scan and changed management of DTC determining indications for surgery intervention, the need to give or withhold ¹³¹I therapy or to select cases for radiotherapy or chemotherapy in order to personalize the treatment in the routine clinical practice.

The authors have no support to report.

The authors have no funding to report.

The authors have declared that no competing interests exist.

All co-authors listed here with brief description of their contribution have agreed to have the manuscript submitted for publication:

Sonya Sergieva: report writing, data analysis and interpretation, completion of manuscript; Teodor Sofiyanski: report writing and date collection; Bozhil Robev: corresponding author, patient follow-up; Milena Dimcheva: data management and statistical analysis; Albena Fakirova: date collection and carrying out histological studies.