A comparison of three-dimensional-ring CZT and NaI(Tl) single-photon emission computed tomography systems using ^99mTc-methoxyisobutylisonitrile in patients with hyperparathyroidism, with concurrent phantom studies

Introduction

^99mTc-methoxyisobutylisonitrile (^99mTc-MIBI) parathyroid imaging is crucial in identifying and localizing hyperfunctioning parathyroid glands (1). However, the anatomical locations of hyperfunctioning glands exhibit a remarkable degree of diversity. Clinically, the most common locations include the superior parathyroid glands, the inferior parathyroid glands, and the upper mediastinal region (2-4). ^99mTc-MIBI single-photon emission computed tomography/computed tomography (SPECT/CT) may have difficulty distinguishing tiny lesions or those in special locations, such as intrathyroidal parathyroid adenomas (5), from the mild uptake of surrounding tissues, usually thyroid tissue. In some cases, it is necessary to combine ultrasound, contrast-enhanced neck computed tomography (CT), or even ¹⁸F-Choline positron emission tomography (PET) to aid in diagnosis, which increases the burden placed on patients (6,7).

In recent years, new SPECT/CT systems fitted with cadmium-zinc-telluride (CZT) semiconductors have gradually been introduced into clinical practice. Previous studies have shown that, compared with thallium-activated sodium iodide [NaI(Tl)] SPECT systems, CZT-based SPECT systems provide higher energy and spatial resolution (7-9). The Starguide (GE HealthCare, Starguide, Haifa, Israel), a full-ring CZT SPECT system, is equipped with 12 detectors arranged in a ring. Each detector consists of seven pixelated CZT chips, each with 16×16 individual pixels. The detectors can be automatically positioned for each bed location through rapid patient contouring at the start of the scan, which effectively reduces the scan time. The detectors can also move independently in the axial plane and be set close to the patient, which can enhance spatial resolution (10,11). This may facilitate clinicians’ identification of parathyroid lesions, especially when the lesions are adjacent to or located in the thyroid gland.

The Starguide full-ring CZT SPECT system can reconstruct images using a block sequential regularized expectation maximization (BSREM) algorithm (Q.Clear by GE HealthCare) in addition to the conventional ordered subset expectation maximization (OSEM) algorithm. BSREM replaces the standard maximum likelihood with a penalized likelihood objective function that includes a regularization term in the form of a relative difference prior (RDP) (12). This reconstruction method has been widely applied in PET. Compared with the OSEM reconstruction method, BSREM with the RDP function can maintain an acceptable noise level while increasing the number of iterations, ensuring that more iterations can be carried out to help detect tiny lesions (11,13). Previous studies have demonstrated its favorable applications in bone scanning, lung ventilation-perfusion imaging, myocardial perfusion imaging, and ¹⁷⁷Lu whole-body imaging (10,14-17). However, research needs to be conducted to determine whether it can improve the identification of small parathyroid lesions.

Standardized uptake value (SUV) measurements have various applications in PET examinations, including assisting in diagnosis and prognostic assessment. Previous studies have explored the significance of SUV in SPECT/CT for various diseases; however, its application in ^99mTc-MIBI parathyroid imaging has been very limited. Studies have shown that the maximum standardized uptake value (SUVmax) in the delayed phase may help differentiate parathyroid hyperplasia from adenoma, although further research is needed to expand its clinical applications (18).

Previous studies have shown the ability of full-ring CZT SPECT/CT systems to improve image quality in various examinations, including bone tomographic imaging, myocardial perfusion imaging, renal dynamic imaging, and ¹⁷⁷Lu wholebody imaging (19-23). This article reports the first experience of applying full-ring CZT SPECT/CT in delayed-phase ^99mTc-MIBI parathyroid imaging, and compares its diagnostic efficacy and image quality with that of NaI(Tl) SPECT/CT. Quantitative analyses of the he CZT SPECT/CT images were performed, and the potential application of SUVs in parathyroid disorders was preliminarily explored. We present this article in accordance with the STARD reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2397/rc) (24).

Methods

Phantoms

Two phantoms were acquired: (I) a uniform phantom (filling volume: 6,820 mL); and (II) a National Electrical Manufacturers Association (NEMA) International Electrotechnical Commission (IEC) phantom with six spherical inserts (filling volume without spheres: 9,807 mL, sphere diameters: 10, 13, 17, 22, 28, and 37 mm; total sphere volume: 51.4 mL).

To obtain the calibration factor, a cylindrical uniform phantom was used. The uniform phantom was filled with 446 MBq of sodium pertechnetate [^99mTc] solution (^99mTcO4−). The radioactivity measurement was performed using an activity meter (CRC-25R Capintec, Inc., Florham Park, New Jersey, United States) that undergoes regular inspection and calibration on an annual basis. The measurement was conducted three times, and the average value was taken. The calibration factor was calculated using Eq. [1], which is expressed as follows:

Calibrationfactor=meancounts(cnt)activityperstarttime(Bq/mL)∗voxelsize(mL)∗scanduration(min)[1]

In the NEMA IEC phantom, the activity concentrations of the background and the spheres were examined and compared with the true activity loaded into the phantom. In the NEMA IEC phantom, the spheres-to-background activity concentration ratio was 9.8:1. At the start of the acquisition, the activity inside the phantom was 268 MBq, corresponding to an actual sphere activity concentration of 0.255 MBq/mL, and a background activity concentration of 0.0259 MBq/mL. The volumes of interest (VOIs) were delineated on CT, including the six hot spheres and five nearby background spheres.

The recovery coefficient (RC) was then calculated using Eq. [2], which is expressed as follows:

RC=meanactivityconcentrationinspheresphereactivityconcentrationatstarttime[2]

Clinical patients

Patients with hyperparathyroidism (HPT) who underwent parathyroid scans at Department of Nuclear Medicine, Ruijin Hospital from July 2023 to August 2024 were included in the study. All the patients willing to undergo additional SPECT/CT imaging were included in the study and signed the informed consent form for the collection of imaging and clinical data (ethics committee reference number: 2025-93). A total of 85 patients with elevated parathyroid hormone (PTH) (23.81±21.42 pmol/mL) were enrolled in the study, of whom 62 were female and 23 were male. The patients had an average age of 48 years. Among them, 59 patients had evaluable lesions with positive ^99mTc-MIBI uptake. The basic characteristics of the patients are set out in Table 1. Twenty-four patients underwent parathyroid surgery after imaging studies. Among them, three patients had parathyroid hyperplasia, one patient had parathyroid carcinoma with metastasis, and the remaining 20 patients had parathyroid adenomas. Additionally, six patients were diagnosed with multiple endocrine neoplasia (MEN) through comprehensive clinical evaluation or genetic testing.

The patients were injected with 925–1,111 MBq of ^99mTc-MIBI, and routine planar imaging was performed 15 minutes later using the NaI(Tl) system. Two hours after injection, SPECT/CT imaging was performed sequentially: first on the NaI(Tl)-based system, and then on the CZT-based system (GE HealthCare, Starguide) over 13 minutes. Image reading was performed using a GE workstation (Xeleris), and two experienced nuclear medicine physicians interpreted all the images separately. Based on the suspicious low-density lesions observed on CT, both physicians conducted a visual assessment of the tomographic images. Uptake exceeding that of the mediastinal blood pool was considered positive. The physicians were aware of the patients’ medical histories but were blinded to the imaging system used. In case of disagreement between the physicians, a third more senior physician was invited to make the interpretation.

Acquisition parameters

For the NaI(Tl) system, low-energy high-resolution collimators were fitted for acquisition. SPECT was acquired first using a 128×128 matrix with 1.00× zoom and a 15% energy window centered on the 140 keV photopeak. A total of 32 steps were acquired, with a time of 12 seconds per step. The CT scan was then performed (130 kV, 3-mm slice thickness, and a 500-mm field of view), and an automatic exposure control system (CARE Dose) was applied for the tube current. The total acquisition time was 8 minutes.

Subsequently, SPECT/CT on the full-ring CZT system was immediately performed. SPECT was acquired first using a 15% energy window centered on the 140 keV photopeak. Each detector contains seven CZT modules, each with 16×16 pixels measuring 2.46 mm in size and a thickness of 7.25 mm. The axial coverage is 27.5 cm. The CT scan was then performed (120 kV, 80 mAs, 2.5-mm slice thickness, and a 500-mm display field of view). The data were recorded in list mode. The total acquisition time was 6 minutes, and a 3-minute tomographic image was reconstructed using new projections generated from list-mode data.

Reconstruction

Both the OSEM and BSREM algorithms were systematically used with the manufactures’ default attenuation correction (AC) and scatter correction (SC) and resolution recovery (RR). The reconstruction parameters of both algorithms are set out in Table 2.

Quantitative parameters

VOI delineation: To quantitatively evaluate imaging quality, counts were obtained from three distinct anatomical regions—the thyroid bed (normal thyroid tissue), cervical muscles (ipsilateral sternocleidomastoid muscle), and the mediastinal blood pool (thoracic aorta)—and used as references for calculation. VOIs for both lesions and reference regions were delineated as 10-mm spheres on CT images. Mean pixel value sand standard deviations were then measured to compute the quantitative parameters.

Calculation of coefficient of variation (CV) and contrast-to-noise ratio (CNR) (25,26): CV was calculated using the standard deviation and mean pixel values of the reference regions, while the CNR was calculated using the standard deviation and mean pixel values of both the lesion and all reference regions {Eqs. [3,4]}. The equations are expressed as follows:

CV=standarddeviationhealthytissuemeanpixelvaluehealthytissue∗100%[3]

CNR=meanpixelvaluelesion−meanpixelvaluehealthytissuestandarddeviationhealthytissue[4]

Calculation of SUV: SUV refers to the ratio of the activity concentration of the imaging agent in local tissues to the average injected activity in the whole body. The patient’s height, weight, injection dose, and injection time were recorded. Lesion areas were delineated using a 10-mm diameter spherical VOI, and the SUV_max and SUV_mean of each lesion were calculated. For patients with multiple lesions, only the SUV of the lesion with the highest uptake was recorded.

Statistical analysis

Quantitative values are expressed as the mean ± standard deviation. The Kruskal-Wallis test was used to compare differences in CV and CNR values under the three imaging conditions, followed by pair-wise comparisons between each data pair, with Bonferroni correction applied for multiple comparisons. The Mann-Whitney U test was used to compare SUVs between patients with and without MEN. For all tests, a P value <0.05 was considered statistically significant difference. The statistical analyses were performed using SPSS 24.0 software (IBM Corporation^®, Armonk, NY, USA).

Ethical considerations

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (No. 2025-93) and informed consent was obtained from all the patients.

Results

Phantoms

The calibration factor was 0.0648 (count/min/Bq). For the ^99mTc NEMA IEC phantom, the full-ring CZT system showed a higher CNR compared to the NaI(Tl) system under the same reconstruction parameters (OSEM 4i10s), especially in spheres with larger diameters. A comparison of images obtained through different reconstruction parameters revealed that the 10 mm-diameter sphere was poorly shown under conventional OSEM reconstruction. With the increase in the number of iterations, the 10-mm sphere shown by the OSEM reconstruction gradually became clearer, but the noise increased. While under the BSREM reconstruction, although there was no significant improvement in the CNR value, the sphere appeared more clearly visually, which may be related to a more uniform background (CV: OSEM 20i10s: 19.9%, BSREM 20i10s: 17.9%) (Figure 1).

Figure 1 Visualization and CNR values of spheres with various diameters under different reconstruction conditions. (A) A small sphere with different diameters shown under different reconstruction of NaI(Tl) OSEM 4i10s, CZT OSEM 4i10s, CZT OSEM 20i10s, and CZT BSREM 20i10s. (B) The CNR values of small spheres with different diameters under four different reconstructions. The arrow indicates the sphere with a diameter of 10 mm. BSREM, block sequential regularized expectation maximization; CNR, contrast-to-noise ratio; CZT, cadmium-zinc-telluride; D, diameter; NaI(Tl), thallium-activated sodium iodide; OSEM, ordered subset expectation maximization.

To verify the influence of different reconstruction algorithms on the quantitative accuracy of the CZT SPECT, we measured the RCs of different spheres (Table 3). The RCs of the BSREM algorithm were higher than those of the OSEM 4i10s algorithm for spheres of a fixed diameter, and were generally comparable to those of OSEM 20i10s, but slightly higher for the sphere with a diameter of 28 mm. For spheres with a diameter of more than 17 mm, the RCs of BSREM 20i10s exceeded 0.7.

Clinical patients

According to the physicians’ assessment, a total of 69 positive lesions in 85 patients were detected across all three imaging methods. All lesions exhibited varying degrees of positive uptake across the three different parathyroid imaging methods. The three methods showed completely consistent diagnostic ability. However, some small lesions with indistinct uptake were not clearly shown on the NaI(Tl) SPECT/CT images, requiring careful examination of the tomographic images by experienced physicians to make a diagnosis. As illustrated in the case shown in Figure 2, the 8-minute NaI(Tl) SPECT/CT image clearly displayed the right upper lesion, whereas the lower lesion was not clearly visualized. Conversely, both lesions are clearly displayed on the 3-minute and 6-minute CZT SPECT/CT images.

Figure 2 Images of a 27-year-old male patient (PTH: 29.08 pmol/mL; Ca: 3.07 mmol/L; ^99mTc-MIBI injection dose: 962 MBq). (A-C) Images acquired by NaI(Tl) SPECT/CT over 8 minutes. (D-F) Images reconstructed from the 3-minute acquisition of CZT SPECT/CT. (G-I) Images acquired by CZT SPECT/CT over 6 minutes. (A,D,G) The maximum intensity projection images. The red arrow indicates the right upper parathyroid lesion, and the yellow arrow indicates the right lower parathyroid lesion. CZT, cadmium-zinc-telluride; MIBI, methoxyisobutylisonitrile; NaI(Tl), thallium-activated sodium iodide; PTH, parathyroid hormone; SPECT/CT, single-photon emission computed tomography/computed tomography.

Among the 59 patients with positive imaging, differences in lesion visualization across different reference regions were further compared. Based on the practical considerations in clinical image reading, we compared the CV and CNR using the thyroid, cervical muscles and mediastinal blood pool as the reference regions, respectively. The results showed significant differences in the CV values of the thyroid and mediastinal blood pool across the three imaging methods (thyroid, P=0.043; cervical muscles, P=0.082; mediastinal blood pool, P<0.001). When the thyroid was used as the reference, the CV of the 6-minute CZT imaging was significantly lower than that of the NaI(Tl) SPECT/CT (P=0.022). The CV of the 3-minute CZT imaging was slightly lower than that of the NaI(Tl) SPECT/CT, but the difference was not significant (P=0.072). There was no significant difference between the 6-minute and 3-minute CZT imaging (P=0.550). When the cervical muscles were used as the reference, there was no significant difference in the CV between the NaI(Tl) SPECT/CT and CZT imaging (P values were 0.599 for 6-minute and 0.072 for 3-minute acquisitors, respectively); however, the CV for the 6-minute CZT imaging was significantly lower than that for the 3-minute CZT imaging (P=0.044). When the mediastinal blood pool was used as the reference, the CVs of both the 6-minute and 3-minute CZT imaging were both lower than that of the NaI(Tl) SPECT/CT (P values <0.001 for both), but no significant difference between the 6-minute and 3-minute CZT imaging was observed (P=0.102). Overall, for the thyroid and mediastinal blood pool references, the CZT SPECT/CT, whether using 6-minute or 3-minute acquisitions, had lower CVs than the conventional NaI(Tl) imaging. However, this advantage was not observed when using the cervical muscles as the reference.

Differences were also observed in the CNR values across the three imaging methods (thyroid, P=0.036; cervical muscles, P=0.402; mediastinal blood pool, P=0.003). When the thyroid was used as the reference, the CNR values of both the 6-minute and 3-minute CZT imaging were significantly higher than those of the NaI(Tl) SPECT/CT (P=0.033 and P=0.022, respectively), but no significant difference was observed between the 6-minute and 3-minute CZT imaging (P=0.599). When the cervical muscles were used as the reference, the CNR values of the 6-minute and 3-minute CZT imaging were slightly higher than that of the NaI(Tl) SPECT/CT, but neither showed a significant difference (P=0.033 and P=0.982, respectively). No significant difference was observed between the 6-minute and 3-minute CZT imaging (P=0.223). When the mediastinal blood pool was used as the reference, the CNR values of both the 6-minute imaging and 3-minute CZT imaging were higher than those of the NaI(Tl) SPECT/CT (P=0.001 and P=0.032, respectively). There was no significant difference between the 6-minute and 3-minute CZT imaging (P=0.182). The hyperfunctioning parathyroid glands imaged by the CZT SPECT/CT had a higher CNR than those imaged by the NaI(Tl) SPECT/CT, especially for lesions around the thyroid bed and in the mediastinum. Additionally, even with the imaging time reduced to 3 minutes, its CNR showed no significant difference compared to that obtained at 6 minutes (Figure 3).

Figure 3 Comparison of CV and CNR values under different imaging conditions using various reference regions. (A) Comparison of CV under 8-minute NaI(Tl) imaging, 3-minute CZT imaging, and 6-minute CZT imaging. (B) Comparison of CNR under 8-minute NaI(Tl) imaging, 3-minute CZT imaging, and 6-minute CZT imaging. *, P<0.05; **, P<0.01. CNR, contrast-to-noise ratio; CV, coefficient of variation; CZT, cadmium-zinc-telluride; NaI(Tl), thallium-activated sodium iodide.

Correlation between SUV and pathology characteristics

Based on the quantitative analysis capabilities of the full-ring CZT SPECT/CT system, we explored the potential application of SUV in differentiating parathyroid hyperplastic diseases with varying pathological characteristics. We found that, in patients diagnosed with MEN, the SUV of the parathyroid lesions with the highest uptake was significantly higher than that of the highest-uptake lesions in non-MEN patients, and this difference was statistically significant (SUVmax, P=0.009; SUVmean, P=0.006) (Figure 4).

Figure 4 Comparison of SUVmax and SUVmean between patients with and without MEN. *, P<0.05. MEN, multiple endocrine neoplasia; SUV, standardized uptake value.

Discussion

Phantom study

In this study, we first used a NEMA IEC phantom to compare lesion visualization between the NaI(Tl) SPECT/CT system and the CZT SPECT/CT system. Under the same reconstruction parameters, the full-ring CZT system exhibited a higher CNR than the NaI(Tl) system. The CNR value of images reconstructed with BSREM was higher than that of images reconstructed with OSEM under the same number of iterations in the full-ring CZT system. To evaluate the quantitative accuracy of the full-ring CZT system, RC was compared across different reconstruction methods. Notably, the RC under the BSREM 20i10s reconstruction was relatively high, exceeding 0.7 in spheres with a diameter of more than 17 mm.

Patients

This study explored the application of the full-ring CZT SPECT/CT in parathyroid imaging for the first time and conducted a comparison of its image quality with that of the conventional NaI(Tl) SPECT/CT. Although the final diagnostic results were similar between the full-ring CZT SPECT/CT and the NaI(Tl) SPECT/CT, the full-ring CZT SPECT/CT provided smoother images, and higher contrast for positive lesions when using the thyroid and mediastinal blood pool as references. Conversely, no statistically significant difference in lesion contrast was observed between the two systems when the cervical muscles served as the reference.

The full-ring CZT SPECT/CT system enables clinicians to more clearly distinguish parathyroid glands from surrounding tissues on SPECT images and may assist in diagnosing lesions in special locations, such as intrathyroidal parathyroid adenomas. These differences might be attributed to the application of the BSREM algorithm in reconstruction. No significant difference in the CNR were observed between the 6-minute and 3-minute acquisitions on the full-ring CZT SPECT/CT, indicating that comparable image quality could be achieved in a shorter time. In clinical applications, this allows physicians to reduce the imaging time, which is particularly beneficial for patients who have difficulty lying supine for an extended period.

Previous studies have explored the significance of SUV in SPECT/CT across various diseases, demonstrating its utility in diagnosing transthyretin fibril protein (ATTR) type cardiac amyloidosis, assessing vertebral fractures, and evaluating multiple bone metastases (19,27,28). However, research on its application in HPT is limited. This study found that the SUV of parathyroid lesions was significantly higher in the MEN patients than in the non-MEN patients. Since the uptake of MIBI is directly influenced by the number of mitochondria, membrane potential, and cellular metabolic activity, we speculate that this difference may be related to the effects of MEN-related gene expression on mitochondrial function (29).

Limitations

This study had a number of limitations. For the sake of practical clinical application, our study adopted the manufacturer-recommended parameters for both acquisition and reconstruction settings on the two SPECT/CT systems. As a result, the observed differences may stem from variations in acquisition and reconstruction methods rather than from the detectors themselves. A more rigorous comparison of crystal performance requires further investigation. All patients were first scanned on the NaI camera followed by the CZT camera. In addition, a 10-mm diameter VOI was used for segmentation in this study, which may have included background regions for some lesions smaller than 10 mm, potentially introducing bias in the comparison. Although a total of 85 patients were enrolled in our study, fewer than 50% of the patients ultimately underwent surgery and obtained a definitive pathological diagnosis. Consequently, there was insufficient reliable evidence to qualitatively determine some small lesions. In terms of the quantitative analysis, this study only conducted a preliminary exploration of its application in parathyroid imaging and did not further compare the quantitative capabilities of the two devices. We found that the SUV of lesions may be used to further differentiate parathyroid hyperplastic diseases of different etiologies; however, its utility in this regard requires additional cases and follow-up research. Previous research noted that the semi-quantitative analysis of ^99mTc-MIBI imaging can aid in the differential diagnosis of parathyroid adenomas and parathyroid carcinomas (30). In our patient group, only one patient had parathyroid carcinoma and had already undergone surgical resection of the primary lesion. Imaging revealed only two metastatic lymph nodes with mild uptake. Thus, the application of SUV analysis in parathyroid carcinoma also warrants investigation in a larger sample.

Conclusions

Compared with conventional NaI(Tl) SPECT/CT, the three-dimensional full-ring CZT SPECT/CT provides better lesion contrast in delayed ^99mTc-MIBI parathyroid imaging and has a shorter acquisition time. The quantitative analysis of ^99mTc-MIBI imaging shows potential for the differential diagnosis of parathyroid hyperplastic diseases, but further validation with a larger cohort is needed.

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-aw-2397/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-aw-2397/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-aw-2397/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by Ethics Committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (No. 2025-93) and informed consent was taken from all the patients.

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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