Introduction
The skeleton has been identified as the most frequent site for tumors to metastasize to after the treatment of primary breast cancer [
1,
2]. A previous study has stated that 13.6% of patients diagnosed with stages I–III breast cancer will have skeletal or bone metastases at 15-year follow-up [
3]. The ribs, spine, pelvis, and upper bones of the arms and legs are among the most common sites for secondary bone metastases from primary breast cancer.
In addition to initial investigation methods such as blood cell count tests, bone scans (i.e., bone scintigraphy) can also be conducted for accurate early detection of bone metastases. A bone scan is a type of nuclear medicine-based imaging that provides an entire skeletal visualization based on the activity of a radionuclide tracer within a short amount of time. Two of the most widely used bone scan instruments are gamma cameras and single-photon emission computed tomography (SPECT), both of which are used with
99mTc-methylene diphosphonate (MDP) tracer [
4]. Conventionally, the interpretation of bone scan images has been based on a qualitative approach alone, whereby the images produced are evaluated using relative intensity values rather than absolute tracer concentration values [
5]. However, the development of advanced imaging modalities, specifically the integrated SPECT/computed tomography (SPECT/CT) method, has been reported to help users obtain more information on skeletal tracer distribution due to the complementary anatomical mapping provided by the additional CT unit [
6]. Moreover, the improved computing power of the SPECT/CT method has allowed for the implementation of more sophisticated image reconstruction algorithms (i.e., attenuation and scatter correction), thus enabling quantitative analysis via standardized uptake values (SUVs) to be performed [
5,
7].
In recent years, the introduction of SUVs into the SPECT/CT method has offered a more accessible tool for diagnostic purposes in comparison with the expensive and less available positron emission tomography (PET) method. In general, an SUV is a semiquantitative biomarker that assesses the tissue concentration of a radionuclide tracer measured by the scanner and divides it by the activity injected divided by body size [
8,
9]. Due to the development of the quantitative SPECT/CT technique, clinicians are now expected to be able to better differentiate metastasis and degenerative changes from the expected physiology and incidental uptake [
10,
11]. This could also prevent patient mismanagement [
12,
13]. However, regardless of the protocol published on quantitative SPECT/CT (with the earliest protocol validated on humans having been released almost 10 years ago [
14]), its clinical application until now has been slow and not widely implemented [
11].
Furthermore, few researchers have studied the measurement of SUV in SPECT/CT bone scans with
99mTc tracers thus far [
4-
6,
8,
13]. Therefore, the chief purpose of this study is to report the SUV measured for the normal vertebrae of breast cancer patients undergoing
99mTc-MDP bone scans via a SPECT/CT machine. Additionally, we also investigate the possible cutoff SUV that could be utilized to differentiate degenerative joint disease (DJD) of the spine, which constitutes benign changes, from normal vertebrae.
Discussion
Metastases of the bone are known to not show any discernible uptake patterns during scanning [
17]. The same can be said for normal bone, as the SUV
mean and SUV
max for each vertebral level are different and possess a considerably wide variability. A low CoV indicates a small value dispersion, while a high CoV suggests a large value dispersion. Based on the results obtained in this study, the SUV
mean produced a lower CoV compared with the SUV
max in all three SUV variations (BW, BSA, LBM), although the differences were rather modest. The SUV
max is known as the standard SUV assessment method in quantitative molecular imaging (especially PET) because of its simplicity, reproducibility, resistance to partial-volume issues in tumors, and immunity to interobserver variability [
9,
13,
18]. The SUV
max is commonly reported in the literature, which has led to the assumption that it is the best quantitative biomarker parameter. However, it has a high dependence on the statistical quality of the images produced and, hence, is susceptible to noise [
19,
20]. Since CoV values illustrate the noise level in acquired data, it could be asserted that SUVs with a lower CoV (in this case, the SUV
mean) can be utilized as an optimal reference for normal bone. Recent paper of Arvola et al. [
5] supports this observation, as they found higher variability in the SUV
max values compared with those of the SUV
mean in both
99mTc-hydroxyethylene diphosphonate SPECT/CT and 18F sodium fluoride PET/CT scans. Therefore, despite contradicting earlier reports on the best SUV for normal bone SPECT/CT imaging [
8], the SUV
mean could also serve as an alternative in quantifying tracer uptake.
Most SUVs are measured based on BW, since this is the most popular method. In this study, the BW skeletal SUV
mean and SUV
max were relatively low at 3.92±0.27 and 6.51±0.72, respectively. These values were regarded as commensurable to previously reported BW SUVs for normal vertebrae, e.g., 4.4±0.5, 4.6±1.7, and 5.9±1.5 for SUV
mean, and 7.1±0.4 and 7.6±2.4 for SUV
max [
8,
10,
21]. The SUV
mean and SUV
max for BSA and LBM also showed considerably low SUVs, decreasing in the order of BW, LBM, and BSA. However, none of the corrected SUVs showed a lower or higher mean CoV than those of the BW (as indicated in
Table 1). Since all three SUVs yielded an almost similar result, users should select the most appropriate SUV in bone SPECT/CT imaging. If the BW SUV is used to monitor the response of
99mTc in SPECT/CT scans, the BW should be measured with the same weighing scale at the facility rather than based on self-reported weight or patient charts [
9]. The scale should also be routinely calibrated to ensure its accuracy and precision in determining patients’ BW and SUV.
In this study, based on the Spearman correlation test, it was demonstrated that all SUVs showed a weak and no significant correlation with age (
p>0.05), similar to the results of Kaneta et al. [
8]. However, Cachovan et al. [
21] reported a significant negative correlation with age for all SUVs (BW and LBM) in healthy lumbar spines after
99mTc-diphosphonate-propanedicarboxylic acid SPECT/CT imaging (
p<0.001). These variations in SUV correlation with age across many published results might be due to differences in the ages of the study populations, attenuation correction method, sample size, type of radionuclide tracer, and SPECT/CT reconstruction method. The results in this study demonstrated a significant, moderate, and positive correlation between the BW SUV
max with weight (
p<0.05), somewhat similar to the results of Sugawara et al. [
22], which found a positive correlation between BWbased blood SUV with weight upon using 2-[fluorine 18]fluoro-2-deoxy-D-glucose PET scans (
p<0.001). This finding was likely due to the fat contribution to the BW SUV measurements [
23]. Therefore, it has been suggested to use the LBM SUV to quantify the uptake of tracer in heavier or obese patients as a correction method [
22].
A significant negative correlation between the BW SUV
mean with height was also found in this study. Bone density composition, in general, is higher in taller subjects compared with smaller subjects. This increase of bone density has been suggested to be a result of the rise in physical burden due to the high center of gravity [
8]. In a study by Axelsen et al. [
24], it was concluded that chemotherapy in breast cancer patients results in a significant bone mineral densitometry (BMD) loss due to an increase in bone turnover, leading to osteoporosis. Furthermore, Huang et al. [
25] also found that both the SUV
mean and SUV
max in osteoporotic patients are significantly lower compared with those in non-osteoporotic patients. Nonetheless, due to the retrospective design of the study, no correlations between the SUVs measured via the BMD assessment were able to be drawn. A reduction in the SUV from osteoporotic subjects might be recorded and, thus, not be representative of normal vertebrae. As such, future prospective studies incorporating BMD measurements are recommended.
Breast cancer therapy can affect normal bone homeostasis by altering the osteoclast and osteoblast functions [
26]. The mechanism of action of each treatment and its effect on bone may vary, which gives rise to variation of the SUVs. In this study, the BW SUV
mean and SUV
max were significantly higher in the treatment group as compared with the no-treatment group. To the best of our knowledge, no study has assessed the SUVs of normal bone preand post-therapy; thus, further research is highly needed.
Degenerative changes of the spine, especially in the elderly, are common and often mistaken for bone metastases during bone scans. Therefore, SUV acquisition could potentially be a useful parameter to differentiate bone lesions and normal vertebrae. In a recently published paper by Mohd Rohani et al. [
27] involving 34 prostate cancer patients utilizing SPECT/CT, a cutoff SUV
max value of 20 was suggested to distinguish between DJD and bone metastases of the spine. However, no cutoff SUV was proposed by the authors to discriminate DJD from normal vertebrae. The results from the current study suggested that no optimal cutoff point could be identified to differentiate DJD from normal vertebrae in both the SUV
mean and SUV
max. This finding is consistent with an earlier finding by He et al. [
28] stating that there are no statistical differences between degenerative changes and normal bone in the cervical and thoracic vertebral regions.
The implementation of quantitative SPECT/CT is deemed to be more challenging compared with PET imaging due to the former’s many technical limitations. Regarding bone SPECT/CT scans, quantitative uncertainties may appear because of tracer-drug interactions (e.g., with iron supplements), metal-induced artifacts from prostheses affecting the computed SUV, variations in hormone levels such as estrogen, and unknown rates of uptake and clearance from the blood [
11]. Other variables such as different radionuclide tracers with different photon energies, different collimators, and the use of different energy windows should also be considered when comparing results. The primary limitations of the current study are the small number of enrolled patients and the retrospective design, which hampered the sensitivity and specificity of the data. Moreover, SUV estimations from a completely healthy population without breast cancer were not included. Therefore, future prospective validation studies in a larger cohort are warranted to better define the SUVs of normal vertebrae.