Clinical value of ^99mTc-MIBI scintigraphy combined with posttherapeutic ¹³¹I whole-body scanning in patients with differentiated thyroid cancer with sTg ≥10 ng/mL before initial radioiodine therapy: a retrospective study

Introduction

Differentiated thyroid cancer (DTC), which mainly includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most common thyroid malignancy (1). In general, DTC progresses slowly, and approximately 85% of patients with DTC receive good benefit from surgery, postoperative radioactive iodine therapy (RAIT), and thyroid-stimulating hormone (TSH) suppression therapy (2). However, 4–15% of patients with DTC develop distant metastasis (DM-DTC) at initial diagnosis or during follow-up (3,4). Distant metastasis (DM) is the primary cause of death in patients with DTC (5). The lung metastasis accounts for approximately 55–85% of DM in DTC, whereas other metastatic sites include the bones, brain, liver, and kidneys, among others (6).

Before ¹³¹I administration, stimulated thyroglobulin (sTg) is highly valuable in both disease monitoring and management decision-making, with its elevation closely related to the recurrence and metastasis of DTC (7,8). The 2015 American Thyroid Association (ATA) guidelines indicate that patients with sTg ≥10 ng/mL may need further evaluation (1). Posttherapeutic ¹³¹I whole-body scanning (pt-¹³¹I WBS) is commonly used to detect thyroid remnants and metastatic foci in patients with DTC (9). Technetium-^99m-methoxyisobutylisonitrile (^99mTc-MIBI) is a type of lipophilic cationic molecule. ^99mTc-MIBI scintigraphy has been examined in studies on myocardial perfusion and hyperparathyroidism (primary or secondary) imaging (10,11). Research indicates that ^99mTc-MIBI scintigraphy also has auxiliary qualitative diagnostic value for a variety of tumor metastases, including from head, neck, and chest malignant tumors (12,13). Furthermore, it offers a reliable and convenient means of detecting metastases in patients with DTC (14).

The objective of this study was thus to investigate the clinical value of ^99mTc-MIBI scintigraphy combined with pt-¹³¹I WBS in patients with DTC and sTg ≥10 ng/mL before initial RAIT and to determine the relationship between the response to RAIT and the two imaging modalities. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-571/rc).

Methods

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (No. QYFYWZLL29244). The requirement for informed consent was waived due to the retrospective nature of the analysis.

In this retrospective study, we included patients with DTC and sTg ≥10 ng/mL before initial RAIT who underwent both ^99mTc-MIBI scintigraphy before RAIT and pt-¹³¹I WBS at the Department of Nuclear Medicine at the Affiliated Hospital of Qingdao University from January 2022 to June 2023. A total of 195 patients (115 females and 80 males; mean age 45.2±14.0 years; range, 18–78 years) were enrolled. The median follow-up time was 16 months.

The inclusion criteria in this study were as follows: (I) diagnosis of DTC via pathology in patients who had undergone total thyroidectomy or near-total thyroidectomy with or without neck dissection; (II) sTg ≥10 ng/mL before initial RAIT, (III) ^99mTc-MIBI scintigraphy performed 1 day before RAIT and ¹³¹I-WBS performed 4 days after RAIT, and (IV) a follow-up after initial RAIT of at least 6 months. The exclusion criteria were as follows: (I) completion of partial thyroidectomy; (II) positivity for thyroglobulin antibody (TgAb) (TgAb ≥115 IU/mL); (III) presence of other malignant tumors; and (IV) loss to follow-up.

^99mTc-MIBI scintigraphy and pt-¹³¹I WBS procedures and image analysis

^99mTc-MIBI scintigraphy of the whole body for planar WBS and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging for the neck and chest were performed in routine fashion with a Symbia T2 SPECT/CT system (Siemens Healthineers, Erlangen, Germany) equipped with low-energy, high-resolution, parallel-hole collimators with an energy peak of 140 keV and a window width of 20% 1 day before the initial RAIT. One hour after the intravenous administration of 740 MBq of ^99mTc-MIBI, two planar images of the whole body (anterior and posterior) and SPECT/CT images of the neck and chest regions were obtained. An additional SPECT/CT study was carried out if there were positive findings on the whole-body images, except for the neck and thoracic regions.

Pt-¹³¹I WBS and SPECT/CT of the neck and chest were acquired 4 days after RAIT via the Symbia T2 system. Whole-body images were acquired from the head to the tips of the toes (anterior and posterior views; magnification: 1.0; matrix: 256×256).

Positive images from ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS were identified as follows: abnormal foci on planar images of the whole body except the thyroid bed. Two experienced nuclear medicine physicians independently reviewed all ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS images and provided diagnoses separately. Differences were resolved through discussions or consultations with other nuclear medicine physicians on final image-based diagnoses. All nuclear medicine physicians were unaware of the reference standard outcome. The gold standard of results was confirmed by pathologic diagnosis, cytologic examination, or clinical follow-up.

According to the images obtained via ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS, we divided the patients into four groups as follows: group 1, ^99mTc-MIBI(+) and ¹³¹I-WBS(+); group 2, ^99mTc-MIBI(−) and ¹³¹I-WBS(+); group 3, ^99mTc-MIBI(+) and ¹³¹I-WBS(−); and group 4, ^99mTc-MIBI(−) and ¹³¹I-WBS(−).

RAIT procedures and follow-up

Following the withdrawal of thyroid hormone treatment and a 3 to 4-week low-iodine diet, the patients reached the target TSH level of ≥30 mU/L. The RAIT dose was determined by each patient’s extent of disease according to the 2015 ATA guidelines (1). The administration of levothyroxine was continued after RAIT. The follow-up data, including serum Tg, TgAb, diagnostic WBS (Dx-WBS), and neck ultrasound data, were documented every 6 to 12 months. Furthermore, the outcomes of chest CT scans, ¹⁸F-fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scans, and fine needle aspiration (FNA) biopsies were documented as required.

Responses to therapy assessment

The response to RAIT was divided into the following four categories according to the 2015 ATA guidelines (1): (I) excellent response (ER; negative imaging and nonstimulated Tg <0.2 ng/mL or sTg <1 ng/mL), (II) indeterminate response (IDR; nonspecific findings on imaging studies and faint uptake in the thyroid bed on RAIT scanning, with nonstimulated Tg <1 ng/mL or sTg <10 ng/mL, (III) biochemically incomplete response (BIR) (negative imaging and nonstimulated Tg ≥1 ng/mL or sTg ≥10 ng/mL), and (IV) structural incomplete response (SIR; structural or functional evidence of disease with any Tg level).

Statistical analysis

Statistical analysis was performed via SPSS 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables are presented as medians with interquartile ranges or as means with standard deviations. Categorical variables are represented as counts and percentages, and differences between groups were assessed with the chi-squared test. The Mann-Whitney test was used to detect continuous variables with a nonnormal distribution. Chi-squared tests (or Fisher exact tests) were used to test the associations between two categorical variables. The Kruskal-Wallis test was employed to examine the differences in response to therapy between the four groups. Differences between groups were considered significant when the P value was less than 0.05.

Results

The flowchart in Figure 1 shows the management of the enrolled patients. In our cohort, there were 188 patients with PTC and 7 patients with FTC. There were 175 classic PTCs, 7 tall cell variants, 3 follicular variants, 1 diffuse sclerosing variant, 1 eosinophilic cell variant, and 1 columnar variant among the PTC cases. The median follow-up time was 16 months. Table 1 shows the clinical and pathological characteristics of the enrolled patients.

Figure 1 Management of the enrolled patients. ^99mTc-MIBI, Technetium-^99m-methoxyisobutylisonitrile; BIR, biochemical incomplete response; ER, excellent response; IDR, indeterminate response; nUS, neck ultrasound; pt-¹³¹I WBS, posttherapeutic ¹³¹I-whole-body scan; RAIT, radioactive iodine therapy; SIR, structural incomplete response; sTg, stimulated thyroglobulin; THW, thyroid hormone withdrawal; TSH, thyroid-stimulating hormone.

The diagnostic efficacy value results of ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS are shown in Table 2. The results indicated that the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ^99mTc-MIBI scintigraphy were all lower than those of ¹³¹I-WBS in detecting distant and local metastases overall. We further evaluated the diagnostic efficacy value of ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS in detecting bone metastasis, lung metastasis, and lymph node metastasis, respectively. For bone metastasis, ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS yielded similar diagnostic efficacy values (all P values >0.05). For lung metastasis, the sensitivity (χ²=28.933; P<0.001) and NPV (χ²=11.423; P<0.001) of pt-¹³¹I WBS were much greater than those of ^99mTc-MIBI scintigraphy, but the specificity and PPV were similar. For lymph node metastasis, the sensitivity (χ²=49.538; P<0.001), specificity (no F value; P=0.060), PPV (no F value; P=0.001), and NPV (χ²=22.125; P<0.001) of ¹³¹I-WBS were all greater than those of ^99mTc-MIBI scintigraphy. The details are shown in Figure 2. Notably, ^99mTc-MIBI scintigraphy may change the clinical TNM stage of some patients with asymptomatic bone metastasis before RAIT. Figure 3 provides an example of a 45-year-old male with PTC after total thyroidectomy with sTg =189 ng/mL. He underwent ^99mTc-MIBI scintigraphy and SPECT/CT of the chest before RAIT. The results showed that the sixth thoracic vertebra (T6) had high uptake of ^99mTc-MIBI, which indicated bone metastasis of the T6. Thus, we changed our clinical management of this patient before RAIT to 220 mCi of ¹³¹I for the bone metastasis.

Figure 2 Comparison of diagnostic efficacy between ^99mTc-MIBI scintigraphy and pt-¹³¹I WBS in bone metastasis, lung metastasis, and lymph node metastasis. ^99mTc-MIBI, Technetium-^99m-methoxyisobutylisonitrile; NPV, negative predictive value; PPV, positive predictive value; pt-¹³¹I WBS, posttherapeutic ¹³¹I-whole-body scan.

Figure 3 A 45-year-old male with papillary thyroid cancer after total thyroidectomy. (A-E) Findings from ^99mTc-MIBI scintigraphy and SPECT/CT of the chest before RAIT. (F-J) Findings from pt-¹³¹I WBS and SPECT/CT of the chest after RAIT. Both of the imaging modalities showed that the sixth thoracic vertebra 6 (T6) had high uptake of both ^99mTc-MIBI and ¹³¹I, indicating metastasis of the T6 (red arrows). Thus, we changed our clinical management of this patient before RAIT to 220 mCi of ¹³¹I for the bone metastasis. ^99mTc-MIBI, Technetium-^99m-methoxyisobutylisonitrile; pt^-131I WBS, posttherapeutic ¹³¹I-whole-body scan; RAIT, radioactive iodine therapy; SPECT/CT, single-photon emission computed tomography/computed tomography.

The number of ER, IDR, BIR, and SIR cases were 23, 43, 67, and 62, respectively, with 20, 54, 9, and 112 cases in group 1, group 2, group 3, and group 4, respectively. The RAIT scores of the different groups were significantly different (H=30.094; P<0.001). The details are shown in Table 3.

Further pairwise comparison showed statistically significant differences between group 4 to group 2 and between group 4 to group 1. The results of pairwise comparisons in different groups are shown in Table 4. We further examined the SIR rate of group 1, group 4, and group 2 (Figure 4) and found that the SIR rate was much higher in group 1 (25%) than in group 4 (13%) (χ²=36.674; P<0.001). Meanwhile, the SIR rate was higher in group 2 (39%) than in group 4 (13%) (χ²=40.361; P<0.001).

Figure 4 The SIR rates of group 1, group 4, and group 2 were 75%, 13%, and 61%, respectively. Significant differences were found between group 1 and group 4 (χ²=36.674; P<0.001) and between group 2 and group 4 (χ²=40.361; P<0.001). Group 1, ^99mTc-MIBI(+) and pt-¹³¹I WBS(+); group 2, ^99mTc-MIBI(−) and pt-¹³¹I WBS(+); group 4, ^99mTc-MIBI(−) and pt-¹³¹I WBS(−). ^99mTc-MIBI, Technetium-^99m-methoxyisobutylisonitrile; pt^-131I WBS, posttherapeutic ¹³¹I-whole-body scan; NSIR, non-SIR; SIR, structural incomplete response.

There were 10 patients with DM, 3 patients with local metastasis (LM), and 2 patients with both DM and LM in group 1. For group 4, there were 5, 10, and 0 cases of DM, LM, and both DM and LM, respectively; meanwhile, for group 2, there were and 15, 15, and 3 cases, respectively. This represented a significant difference between group 1 and group 4 (F=6.925; P=0.015) but not between group 2 and group 4 (F=2.101; P=0.379) (Table 5).

Discussion

As a cost-effective nonspecific tumor imaging modality, ^99mTc-MIBI scintigraphy has been widely used in the diagnosis of parathyroid adenoma, breast cancer, and thymoma in recent years (15-20). It has also been discovered that ^99mTc-MIBI scintigraphy has a high sensitivity for identifying metastases in patients with DTC (12,14). ¹³¹I WBS is the most specific imaging examination used to detect recurrence and lymph node and DMs of DTC (21). The reported specificity of pt-¹³¹I WBS ranges between 96% and 100% (22), which is consistent with our study (99.05%). In recent years, the use of ¹⁸F-FDG PET/CT in diagnosing recurring or metastatic DTC has increased, especially in patients with increased Tg levels and negative ¹³¹I WBS findings (23,24). In contrast, the clinical use of ^99mTc-MIBI scintigraphy has been decreasing.

However, in our study, we found that ^99mTc-MIBI scintigraphy before RAIT and pt-¹³¹I WBS showed similar diagnostic efficacy in detecting bone metastasis. Since routine preoperative ¹⁸FDG-PET/CT scans are not recommended (1), bone metastasis is difficult to detect before RAIT, especially when patients are asymptomatic, which may reduce the clinical stage of these patients. Therefore, ^99mTc-MIBI scintigraphy plays an important role in guiding clinical management. In this study, bone lesions were identified in 6 patients with bone metastasis (6/8), and the clinical stage was changed due to ^99mTc-MIBI scintigraphy being performed before RAIT. However, for the overall diagnostic efficacy in detecting metastatic lesions, pt-¹³¹I WBS was substantially more effective than was ^99mTc-MIBI scintigraphy, which is consistent with previous work (25).

We found that the responses to the initial RAIT differed between group 1, group 2, group 3, and group 4. Further pairwise comparisons revealed statistically significant differences between group 4 and group 2 and between group 4 and group 1, including in SIR rates. There was no significant difference between group 4 and group 2 in terms of DM rate. However, compared to group 4, group 1 had a significantly higher DM rate, which indicated that patients with positive uptake on both ^99mTc-MIBI scintigraphy before RAIT and pt-¹³¹I WBS may have a worse prognosis.

Certain limitations to this study should be noted. First, the retrospective design might have introduced selection bias. Second, the number of enrolled patients was small, which might have led to bias in the statistical analysis. Finally, since the median follow-up time was short (16 months), the RAIT-DTC rate and the long-term efficacy between different groups were not included in the initial study design.

Conclusions

Our findings suggest that ^99mTc-MIBI scintigraphy before RAIT combined with pt-¹³¹I WBS may be a useful diagnostic tool for the early identification of DM and poorer response to RAIT in patients with DTC. Moreover, ^99mTc-MIBI scintigraphy before RAIT plays an equally vital role to that of pt-¹³¹I WBS in patients with DTC and bone metastasis. It may lead to the early detection of bone metastasis before RAIT and guide clinical management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-571/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-571/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-571/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Affiliated Hospital of Qingdao University (No. QYFYWZLL29244) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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