The value of ¹²³I-MIBG xSPECT/CT quantitative parameters in the diagnosis of bone metastasis in pediatric neuroblastoma patients

Introduction

Neuroblastoma (NB) is the malignant tumor with the highest mortality rate in children, and accounts for approximately 15% of all pediatric malignancy-related deaths (1). It can occur in any part of the sympathetic nervous system; however, the majority of primary tumors (65–70%) occur in the abdomen, most commonly in the adrenal glands (2). Studies have shown that patients with primary sites in the adrenal glands have a higher risk of recurrence and metastasis than those with primary sites in other locations (3). NB is highly susceptible to distant metastasis, most commonly in the bone, distant lymph nodes, and liver (4). Under the International Neuroblastoma Staging System (INSS) (5), NB with bone metastasis is classified as stage IV, which necessitates adjustments in the treatment plan, and indicates a potential unfavorable prognosis for patients. Therefore, the early detection of bone metastasis is crucial for the subsequent treatment and prognosis of children with NB.

The routine evaluation of bone metastasis in NB primarily includes X-ray, computed tomography (CT), and magnetic resonance imaging (MRI), all of which are non-specific examinations. These methods can assess the location of metastatic lesions, and the relationship between lesions and surrounding tissues, but usually cannot accurately determine the nature of the lesions. Functional imaging modalities of nuclear medicine, such as ^99mTc-methylene diphosphonate (^99mTc-MDP) bone scintigraphy and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography-computed tomography (PET/CT) scans, can be used to evaluate the location, extent, and activity of residual lesions with respect to the metastatic characteristics of NB, but these modalities have low accuracy, and are prone to false positives or false negatives.

¹²³I-metaiodobenzylguanidine (MIBG) is currently the preferred radiopharmaceutical method for imaging pediatric NB due to its high sensitivity and specificity (6,7). A variety of semi-quantitative scoring systems have been developed to assess tumor load and to quantify response to therapy, of which the Curie score, which can be used to determine patient prognosis and the efficacy of NB treatment, is the most widely used (8). However, it is based on ¹²³I-MIBG planar imaging, which may yield false-negative results due to its limited spatial resolution, and physiological or non-neoplastic MIBG uptake is not always easy to distinguish from pathological uptake, which could potentially lead to false-positive results (9). ¹²³I-MIBG single-photon emission computed tomography/computed tomography (xSPECT/CT) can significantly improve the accuracy of NB diagnosis; however, due to background noise, it is also relatively difficult to identify NB metastatic lesions and monitor prognosis based only on a visual analysis of MIBG planar or tomographic imaging (10). Thus, further research needs to be conducted to determine how to identify bone metastatic lesions using relatively objective indexes, and thus improve the specificity and accuracy of diagnosis.

Siemens xSPECT/CT technology is based on the Symbia Intevo system. This new high-definition bone imaging technique uses segmented CT information to reconstruct reference frames and integrate data from large matrix SPECT acquisitions. This technology enhances the resolution of SPECT/CT, and allows for the quantification of MIBG uptake to obtain standardized uptake values (SUVs) and other parameters (11). Due to the continuous improvement of image reconstruction algorithms and the application of complex compensation techniques in the correction of photon attenuation and scattering, quantitative xSPECT/CT can now accurately restore the display of internal radiation distribution of the lesion and improve the detection of small lesions, which has led to significant progress in its clinical applications (12). Quantitative xSPECT/CT has demonstrated varying degrees of diagnostic value of ^99mTc-MDP in screening for bone metastases from various malignant tumors, such as prostate cancer (13), lung cancer (14), and breast cancer (15). However, there is still a lack of research on the use of ¹²³I-MIBG xSPECT/CT imaging in the diagnosis of NB metastasis.

Therefore, this study analyzed the quantitative parameters of bone metastasis of NB and further investigated the value of quantitative ¹²³I-MIBG xSPECT/CT imaging in diagnosing bone metastasis in pediatric NB patients. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1251/rc).

Methods

Patients

A retrospective cohort study was conducted on 414 pediatric patients with NB and clinical suspicion of bone metastasis who underwent quantitative ¹²³I-MIBG xSPECT/CT imaging at Beijing Friendship Hospital from March 2022 to December 2023. To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) have a diagnosis of NB based on pathological or clinical criteria; (II) be aged <18 years; and (III) have undergone treatment according to the Multidisciplinary Treatment Guidelines for NB developed by the Chinese Children’s Cancer Group of the China Anti-Cancer Association (16). Patients were excluded from the study if they met any of the following exclusion criteria: (I) had an unclear diagnosis of NB or had other tumors; (II) had incomplete medical records; and/or (III) were unable to cooperate with the follow-up.

A total of 125 patients were enrolled in the study. The following clinical data were recorded: age, sex, weight, height, primary tumor site, histologic type and stage, MYCN amplification, 11q aberration, neuron specific enolase (NSE) level one week before xSPECT/CT imaging, and current treatment status. The INSS (17) and the Children’s Oncology Group Classification were used to determine stage and histologic type respectively. All patients were followed-up for a minimum period of six months.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the local ethical review board of Beijing Friendship Hospital of Capital Medical University (No. 2022-P2-314-01). Informed consent was obtained from all the patients’ parents or legal guardians.

xSPECT/CT acquisition

The ¹²³I-MIBG xSPECT/CT imaging was performed using the xSPECT/CT system (Siemens Symbia Intevo T16). To close the thyroid gland, Lugol’s iodine solution was administered from 3 days before to 2 days after the imaging procedure. Patients received an intravenous injection of ¹²³I-MIBG at a dose of 5.2 MBq/kg (37–370 MBq), adjusted based on their age, height, and weight. Details of the full syringe, empty syringe, and injection time were simultaneously recorded. Anteroposterior whole-body planar imaging with ¹²³I-MIBG and local xSPECT/CT were performed 24 hours post-injection.

xSPECT/CT was primarily used to characterize suspicious lesions or lesions that could not be identified by planar imaging. In instances in which planar imaging yielded negative results, local xSPECT/CT imaging of the surgical area was conducted. SPECT data acquisition involved acquiring images with 60 steps of 10 s/step, 360°, and a 256×256 matrix. The CT scanning parameters were as follows: tube voltage: 110 keV; tube current: 90 mA; slice thickness: 3 mm; and pitch value: 0.8 mm. The acquired xSPECT images underwent post-processing using SyngoMIVB21A software; iterative reconstruction following CT attenuation correction was applied before fusion with the CT images to generate the final xSPECT/CT images.

Image analysis

The images were assessed by two experienced nuclear medicine physicians (with more than 5 years of experience each) using the workstation (Syngo Multimodality Workplace, Siemens) without access to original scan reports or other clinical information, and any discrepancies were resolved through mutual discussion until consensus was reached. For the analysis, cubic volumes of interest >10 mm were placed on the cross-sectional, sagittal, and coronal planes of the regions with bone abnormalities, and abnormal radiotracer accumulation was identified on the CT images (Figure 1). The software automatically calculated the maximum standardized uptake value (SUVmax), average standardized uptake value (SUVavg), minimum standardized uptake value (SUVmin), and peak standardized uptake value (SUVpeak) of the lesions. The SUV formula is expressed as follows:

Figure 1 Representative ¹²³I-MIBG xSPECT/CT images of a patient with positive bone metastasis results. In a 7-year-old girl diagnosed with NB in the left adrenal gland, xSPECT/CT revealed enhanced contrast uptake in the lateral wall of the orbit (A), spine (B) and pelvis (C). The larger one in the right iliac bone corresponded to the SUVmax, SUVavg, SUVmin, and SUVpeak values of 9.34, 7.48, 4.99, and 8.98 respectively; subsequently confirming the presence of bone metastasis. ¹²³I-MIBG, ¹²³I-metaiodobenzylguanidine; xSPECT/CT, single-photon emission computed tomography/computed tomography; NB, neuroblastoma; SUVmax, maximum standardized uptake value; SUVavg, average standardized uptake value; SUVmin, minimum standardized uptake value; SUVpeak, peak standardized uptake value.

SUV = specific activity of the region of interest (kBq/mL) × weight (kg)/injection dose (MBq).

A diagnosis of bone metastasis was established based on the following: (I) a pathological diagnosis (based on local bone biopsy); (II) imaging examination results, including ¹²³I-MIBG imaging, ¹⁸F-FDG PET/CT, ultrasound, enhanced CT and MRI; and (III) the patient’s medical history and long-term follow-up results. The selection criteria for normal bone relied on lumbar vertebrae 3 as the reference standard, characterized by the uniform distribution of radioactivity, and the absence of abnormal changes in CT scans. In cases where L3 was affected, adjacent lumbar vertebrae L1–2 were used as the reference standard (18).

Statistical analysis

The continuous variables are reported as the mean ± standard deviation, or the median and interquartile range. The categorical variables are reported as the count and percentage. A Spearman correlation analysis was conducted to assess the association between the normal SUV and physical variables. Intergroup comparisons were conducted using the Mann-Whitney U test, while multi-group comparisons were conducted using the Kruskal-Wallis H test. Receiver operating characteristic (ROC) curves were constructed to determine the optimal cut-off values of the SUVs for distinguishing between metastatic and normal lesions, with corresponding area under the curve (AUC) values, sensitivity, and specificity derived. A univariate analysis was performed of the clinical information and imaging characteristics of the patients, after which, any statistically significant variables were included in the multivariate logistic regression analysis. The statistical analyses were carried out using SPSS 26.0 software. All the statistical tests were two-sided, and a significance level of P<0.05 was considered statistically significant.

Results

Clinical parameters

Based on the inclusion and exclusion criteria, 125 pediatric patients with NB who underwent ¹²³I-MIBG xSPECT/CT imaging were included in the study. The study cohort comprised 75 girls and 50 boys. The patients had an average age of 5.94 years (0.6–9 years) (Figure 2). All the patients received standardized treatment based on their risk group classification. The primary tumor sites included retroperitoneum (61 cases in the adrenal region, and 25 cases outside the adrenal region), as well as other regions (39 cases). Among the NB patients, 65 were diagnosed with NB and 60 were diagnosed with ganglioneuroblastoma. Pathological grading revealed that the majority of tumors were classified as high risk (n=98), while a smaller proportion fell into other grades, with 22 classified as median risk, and five classified as low risk (Table 1). Ultimately, a total of 329 metastatic lesions were confirmed to be bone metastases at final diagnosis.

Figure 2 Flow diagram of patient inclusion, with reasons for exclusion, and the total study population. ¹²³I-MIBG, ¹²³I-metaiodobenzylguanidine; xSPECT/CT, single-photon emission computed tomography/computed tomography.

Differences among the SUV measurements of metastatic subzones

The SUVmax, SUVavg, SUVmin, and SUVpeak of all bone metastatic lesions were significantly higher than those of normal bone lesions (P<0.0001). The children’s metastatic sites were categorized based on the Curie score, with 69 bone metastatic lesions in the head (zone 1), 175 in the trunk (zones 2–5), and 85 in the limbs (zones 6–9) (Table 2). Nevertheless, no statistically significant difference was observed in the SUV measurements of bone metastatic foci among the different subzones (P>0.05).

Value of 123I-MIBG xSPECT/CT in the evaluation of NB bone metastasis

The ROC curves of the SUVmax, SUVavg, SUVmin, and SUVpeak were generated based on measurements of normal bone and bone metastasis (Figure 3). The diagnostic utility of the SUV in discriminating between normal bone and lesions was assessed, and the AUC values of the SUVmax, SUVavg, SUVmin, and SUVpeak, were 0.946 [95% confidence interval (CI): 0.921–0.971], 0.962 (95% CI: 0.939–0.984), 0.953 (95% CI: 0.928–0.978), and 0.959 (95% CI: 0.936–0.982), respectively. The sensitivity was 91.2%, 88.4%, 93.3% and 91.2%, and the specificity was 90.2%, 95.9%, 89.4% and 92.7% for the SUVmax, SUVavg, SUVmin, and SUVpeak, respectively. All these differences reached statistical significance with P values <0.0001. The optimal diagnostic thresholds identified for the SUVmax, SUVavg, SUVmin, and SUVpeak were 0.39, 0.36, 0.19 and 0.35, respectively. The ROC curves comparing different metastatic sites in children according to Curie score partitioning were also analyzed. Ultimately, among all the partitions examined, the SUVavg had the highest diagnostic efficacy (Table 3). Additionally, we observed a total of 332 sites of radiotracer distribution on ¹²³I-MIBG xSPECT/CT imaging, of which 325 cases were consistent with the final diagnosis. The visual analysis demonstrated a specificity of 94.6% for diagnosing bone metastasis of NB, while the SUVavg parameter exhibited a specificity of 95.9%.

Figure 3 ROC curves depicting SUV measurements for the detection of bone metastasis in NB. SUVmax, maximum standardized uptake value; SUVavg, average standardized uptake value; SUVmin, minimum standardized uptake value; SUVpeak, peak standardized uptake value; AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic; SUV, standardized uptake value; NB, neuroblastoma.

Diagnostic factors for NB bone metastasis

In the univariate analysis, tumor location, risk stratification, INSS stage, 11q aberration, NSE level, and SUV measurements were identified as statistically significant factors for diagnosing bone metastatic lesions. However, it should be noted that the effect estimates for some of these clinical factors were relatively small. In the multifactorial analysis, INSS stage, NSE level, and SUV quantitative measurements were significant risk factors in diagnosing bone metastatic lesions (Table 4).

Relationship between normal bone SUV and physical parameters

The normal bone SUV values did not show statistically significant differences across different physical parameters [i.e., gender, age, height, weight, and body mass index (BMI)] (P>0.05, Table 5).

Discussion

Our study investigated the potential use of ¹²³I-MIBG xSPECT/CT in the diagnosis of 329 bone metastatic lesions in 125 pediatric patients with NB. We observed that a focal MIBG uptake SUVavg >0.36 g/mL was highly indicative of metastasis in NB patients, and the quantitative analysis significantly enhanced the specificity of diagnosing bone metastasis in NB patients compared to the visual analysis. To our knowledge, this is the first study to show that quantitative parameters obtained from ¹²³I-MIBG xSPECT/CT can assist in the diagnosis of bone metastatic lesions of NB.

NB originates in the sympathetic nervous system and involves a wide range of sites, most often the adrenal gland (19). Studies have shown that patients with the primary site in the adrenal gland have a higher risk of recurrence and metastasis than patients with other primary sites (20,21). In this study, of the 125 children with bone metastasis, the primary site was the adrenal gland in 61 (48.8%) patients, which is consistent with figures from previous reports. NB exhibits a high susceptibility to recurrence and metastasis (21). The 5-year survival rate of NB patients with bone metastasis is approximately 41.3% (22). The detection of bone metastasis at any location leads to its classification as stage IV according to INSS, necessitating a modification in treatment approach. Some low-risk children experience spontaneous resolution; however, those classified as high risk face an unfavorable prognosis even after undergoing induction, consolidation, and maintenance therapy (23). Thus, the assessment of the occurrence of bone metastasis is of great importance in determining treatment strategies and prognostic outcomes.

The clinical diagnosis of bone metastasis typically involves a comprehensive analysis of CT, MRI, bone scintigraphy, and clinical symptoms during follow-up. However, the limited sensitivity of conventional imaging techniques poses challenges in the early detection of bone metastatic lesions and prolongs the diagnostic process. Consequently, there is an urgent need for a non-invasive and efficient method to enable the early diagnosis of bone metastatic lesions and the accurate evaluation of treatment efficacy.¹²³I-MIBG imaging, serving as a primary functional modality for assessing NB, exhibits superior sensitivity and specificity in detecting bone metastasis than ^99mTc-MDP bone scintigraphy (24), enhancing the characterization of the disease extent and distribution. Various semi-quantitative scoring systems, such as the Curie score, have been employed to systematically evaluate the severity and distribution of bone metastasis in NB (25). Planar imaging forms the basis of ¹²³I-MIBG assessment, where any uptake beyond the normal radiotracer distribution (particularly focal uptake) is indicative of disease infiltration. Recent studies have shown that ¹²³I-MIBG SPECT/CT can significantly enhance diagnostic sensitivity, specificity, and accuracy in NB diagnosis (10,26). However, conventional SPECT/CT lacks objective quantitative metrics and can only be analyzed qualitatively (27).

xSPECT/CT is an innovative iterative reconstruction algorithm developed on the basis of fusion SPECT/CT, which generates laminar images with voxel values representing activity. The voxel values can be converted to parameters by extracting the delineated volume from the image (28). It has shown varying degrees of diagnostic value in the screening of complex and small anatomical lesions (29), joint lesions (12), and bone metastases (13,30), and in the monitoring of compression fractures. Studies have confirmed that ^99mTc-MDP xSPECT/CT improves the diagnostic accuracy and consistency of diagnosing NB bone metastasis while enhancing clinical effectiveness. However, there is currently a lack of research on the use of ¹²³I-MIBG xSPECT/CT imaging for the diagnosis of NB metastasis.

Our study validated the use of a novel algorithm in xSPECT/CT reconstruction, which effectively enhanced the specificity of bone metastasis diagnosis in NB patients. This advancement facilitates disease monitoring and prognosis evaluation in pediatric patients. Quantitative xSPECT/CT enables the accurate differentiation of the physiological uptake of surrounding lesions (e.g., orbit, ribs, and sacrum) by reducing image background noise. Consequently, it improves the precise diagnosis of bone metastatic lesions to some extent. This cut-off value offers additional diagnostic value, as a focal MIBG SUVavg uptake >0.36 g/mL is highly indicative of metastasis in NB patients, and thus could help clinicians to accurately identify bone metastasis in NB. This finding further strengthens the clinical significance of MIBG imaging in the diagnosis of bone metastatic lesions in NB patients. In this study, we employed the Curie score for the semi-quantitative assessment of MIBG uptake in systemic bone metastatic lesions. However, it should be noted that due to varying lesion sizes, potential partial volume effects between different subdivisions might influence visualizer uptake measurements. Nevertheless, we found no statistically significant differences in the SUV values among these regions.

We also found that tumor stage, NSE level, and the SUV measurement parameters of ¹²³I-MIBG xSPECT/CT were significant factors influencing the diagnosis of bone metastasis. Our study included pediatric NB patients who were at different treatment stages according to the consensus protocol for NB diagnosis. This variability might have affected the uptake of MIBG in bone metastatic lesions. Previous treatments could potentially induce sclerosis, reduce vascularity, or cause other alterations in the tumor microenvironment, all of which can influence the uptake of imaging agents (14). However, the treatment status of the children was not identified as a significant influencing factor in the diagnosis of bone metastatic lesions in our study. The changes in the SUVs observed for bone metastatic lesions may provide more valuable guidance for NB patients in clinical practice; this aspect will be explored in future investigations. Additionally, Rogasch et al. were the first to undertake a stratified study of pediatric NB patients based on quantitative parameters obtained from the primary tumor site using ¹²³I-MIBG xSPECT/CT. This approach is closely associated with the selection of subsequent treatment regimens and prognosis evaluation in children (31). Therefore, investigating whether the metabolic parameters of bone metastasis have additional prognostic value for NB is crucial and will be further investigated in our follow-up study.

This study provided the first validation of the diagnostic value of quantitative ¹²³I-MIBG xSPECT/CT imaging for bone metastatic lesions in pediatric NB patients. However, it is important to acknowledge certain limitations associated with this study. First, its retrospective design and small sample size restrict the generalizability of the findings. Second, only body sites in the field of view of ¹²³I-MIBG xSPECT/CT were compared, and lesions without corresponding tomographic images were excluded from the final analysis. The study highlights the reliance of nuclear medicine physicians on subjective judgments, which could introduce variability and potential bias in the diagnostic outcomes. Third, most of the bone metastatic lesions were not pathologically confirmed; thus, continued follow-up is required to further support and validate these findings. Fourth, it should be noted that there was no significant correlation between the quantitative parameters of normal bone in ¹²³I-MIBG xSPECT/CT imaging and the overall condition of pediatric patients; this discrepancy may be attributed to factors such as patient characteristics and the contrast agent used. Finally, 10% of NB are MIBG non-avid, and ¹²³I-MIBG imaging has relatively low spatial resolution. We primarily focused on MIBG-avid lesions, and did not consider MIBG non-avid lesions. In the future, we intend to conduct a larger scale prospective study and incorporate other imaging examinations to make the conclusions of the study more comprehensive.

Conclusions

The use of ¹²³I-MIBG xSPECT/CT scintigraphy has incremental value in the diagnosis of NB metastasis, and can serve as a diagnostic aid for visual assessments. An SUVavg >0.36 g/mL in suspicious bone regions of NB patients is highly indicative of metastasis. Moreover, the specificity of the quantitative analysis in diagnosing NB bone metastasis was better than that of the visual analysis; thus, it can be used to improve the accuracy of diagnosing metastatic bone lesions.

Acknowledgments

The authors would like to thank the staff at the Nuclear Medicine Department, Beijing Friendship Hospital, Affiliated to Capital Medical University for their assistance in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1251/rc

Funding: This study was supported by grants from the Natural Science Foundation of Beijing (No. 7232031), and the National Natural Science Foundation of China (No. 82272034).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1251/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 (as revised in 2013). This retrospective cohort study was approved by the local ethical review board of Beijing Friendship Hospital of Capital Medical University (No. 2022-P2-314-01). Informed consent forms were signed by all participating patients’ parents or legal guardians.

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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