Normal Skeletal Standardized Uptake Values Obtained from Quantitative Single-Photon Emission Computed Tomography/Computed Tomography: Time-Dependent Study on Breast Cancer Patients

Introduction

Over the last many years, Tc-99m methylene diphosphonate (Tc-99m MDP) has been widely used as a bone scintigraphy agent in the diagnosis of many pathological conditions such as metastatic bone disease, stress fractures, degenerative changes, or other similar conditions.[123] It is known that skeletal metastases often happen with breast cancer.[45] Tc-99m MDP rapidly enters into extracellular fluid after intravenous injection and is immediately taken up by the bone, where it binds with the hydroxyapatite mineral component of the osseous matrix by the process of chemisorption.[5] Gamma camera is a widely used instrument in nuclear medicine which uses two-dimensional planar imaging for qualitative analysis of the uptake of tracer in bone tissue. However, due to the lack of depth information in planar whole-body scans, it is a difficult task to estimate the absolute value of tracer uptake from bone tissues. Later single-photon emission computed tomography (SPECT) was used in quantitative analysis of tracer uptake in bone tissue, where images were obtained from a fixed range of body and have been interpreted using the relative intensity of tracer uptake instead of quantitative analysis of tracer concentration.[6] This problem was overcome by the technical development and wide acceptance of integrated Single SPECT/computed tomography (SPECT/CT) system made it clinically useful for the quantification.[3789101112]

Quantitative SPECT allows the estimation of standardized uptake values (SUVs), which can be used for the staging of disease and follow-up assessment.[13] SUV is a semi-quantitative parameter, frequently used for the quantification of uptake of tracer.[1314] It is defined as the ratio of activity per unit volume of interest (VOI) to the activity per unit whole body volume.[511] The SUV can be measured as patient's body weight (SUVbw), lean body mass (SUVlbm), or body surface area (SUVbsa).[814] Concerning SUV measurement, however, SPECT/CT has not been exploited as much as positron emission tomography/CT (PET/CT). In PET/CT, SUV is widely been used for quantification purposes.[1516171819] The overall effective dose received by the patient from standard ¹⁸F NaF PET/CT scans is higher as compared to Tc-99m MDP bone scan.[20] Besides, the easy availability and cost-effectiveness of Tc-99m MDP make it ideal for clinical use as compared to F-18 NaF.[21]

Although to establish and use quantitative SPECT as a biomarker to differentiate benign from malignant bone disease, it is important to determine the normal SUV values for each one of the skeletal systems. In PET/CT, normal SUV values for different skeletal sites are already established.[2223] However, due to the lack of popularity and standardization of SPECT/CT system, very few studies were performed to quantify and establish the normal SUV values for different skeletal sites in breast cancer patients.[924] The impact of postinjection acquisition time on SUV has already been studied in PET/CT.[252627] However, there is no study has been reported the possible impact of imaging time on SUV values obtained using quantitative SPECT/CT with Tc-99m MDP.

The primary aim of our study was to estimate the SUV value from normal bones or skeletal sites in breast cancer patients using Tc-99m MDP-SPECT/CT bone scans. Moreover, postinjection acquisition time-dependent changes in SUV values were also studied. Furthermore, the correlation between SUVs and patient parameters such as age, body mass index (BMI), administered activity, and alkaline phosphatase (ALP) was also evaluated.

Materials and Methods

Image quantification

Image quantification was performed using Q.Metrix software (supplied by GE Healthcare), which converted activity concentration values into SUV. After processing, data were loaded into the software. Information regarding acquisition parameters, camera sensitivity, patient information, administered activity, and scan time was entered into Q.Metrix software [Figure 1]. SUVs were measured in the unit of body weight (BW) g/ml. These measured SUV values of Tc-99m MDP were demonstrated as SUV maximum (SUVmax) and SUV mean (SUVmean). The SUVmax was defined as the pixel value with the highest activity concentration within a VOI, whereas SUVmean was the mean pixel value of activity concentration within the VOI sampled:

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Figure 1

Q.Metrix processing; enter camera sensitivity (a), accept sensitivity (b), enter patient information (c), enter tracer information (d), accept all (e), load patient information from previous study (f) and load tracer information from previous study (g)

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A manual delineation technique opted for SUV measurement. Delineation of VOI was made around visually normal skeletal sites of SPECT/CT images: Skull, scapula, sternum, ribs, cervical spine, thoracic spine, lumbar spine, pelvis, humerus, and femur. The size of VOI was carefully monitored in all image sections (axial, sagittal, and coronal) of the bone [Figure 2].

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Figure 2

(a) Tc-99m methylene-diphosphonate single-photon emission computed tomography/computed tomography maximum intensity projection image and (b) 3D volume segmentation for different bone parts

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Results

A total of 60 patients having a history of breast cancer were divided into four groups, i.e. I^st (2 h), II^nd (3 h), III^rd (4 h), and IV^th (5 h) based on postinjection acquisition time (for each group; n = 15). The characteristics of patients in each group are listed in Table 1. However, no significant difference in patients age, BMI, ALP, creatinine, and administered activity between all four groups was noted (P = 0.46, 0.89, 0.84, 0.82, and 0.99, respectively). Comparisons of different demographic and clinical parameters of all groups are mentioned in Table 3. The box and whisker plots of parameters between all four groups are shown in Figure 3.

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Figure 3

Comparison of baseline parameters between imaging groups. No significant difference noted in age (a) P = 0.46, BMI (b) P = 0.89, administered activity (c) P = 0.99, ALP (d) P = 0.84 and creatinine (e) P = 0.82 between all four groups. BMI, body mass index; ALP, alkaline phosphatase

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We have observed different normal SUVmax and SUVmean values for various skeletal sites [Figures 4 and 5]. Overall, study results show that thoracic, lumbar, and pelvis exhibit the highest SUVmax and SUVmean values as compared to rest skeletal sites. However, the lowest SUVmax and SUVmean values among all skeletal sites were observed in humerus and ribs, respectively. The highest values of the SUVmax and SUVmean among all of the skeletal sites were observed in lumber and thoracic vertebra (8.89 ± 2.26 and 2.89 ± 0.58) for Group I and in the pelvis and thoracic (9.6 ± 1.32 and 3.04 ± 0.64), (10.93 ± 3.91 and 3.65 ± 0.97), (11.33 ± 2.67 and 3.65 ± 0.22) for Groups II, III, and IV, respectively. Meanwhile, the lowest values of the SUVmax and SUVmean among all of the skeletal sites were observed in humerus and ribs (3.22 ± 0.67 and 0.97 ± 0.18), (5.16 ± 1.82 and 1.18 ± 0.16) for Group I, IV and in humerus (3.17 ± 0.58 and 0.85 ± 0.26), (3.98 ± 1.12 and 1.04 ± 0.28) for Group II and III, respectively. Detailed average normal SUVmax and SUVmean values for different skeletal sites are mentioned in Table 4.

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Figure 4

Distribution of SUVmax values quantified in Group I (a), Group II (b), Group III (c), and Group IV (d). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmax, maximum standardized uptake value

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Figure 5

Distribution of SUVmean values quantified in Group I (a), Group II (b), Group III (c), and Group IV (d). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmean, mean standardized uptake value

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Although overall COV values of SUVmax were comparably lower in Group II in contrast to rest imaging groups, the overall COV values of SUVmean were comparably lower in Group IV in contrast to rest groups. The highest COV values of the SUVmax and SUVmean among all of the skeletal sites were observed in sternum and femur (0.39 and 0.32) for Group I and in the skull (0.34 and 0.35), (0.45 and 0.45), (0.40 and 0.40) for Groups II, III, and IV, respectively. Meanwhile, the lowest COV values of the SUVmax and SUVmean among all of the skeletal sites were observed in cervical and pelvis (0.08 and 0.16) for Group I, scapula and pelvis (0.08 and 0.13) for Group II, scapula (0.13 and 0.12) for Group III, and in ribs and thoracic (0.05 and 0.06) for Group IV, respectively. Detailed COV values for each skeletal site are also mentioned in Table 4.

Comparison of SUVs for each skeletal site between groups shows an increase in SUVmax and SUVmean value with postinjection acquisition time [Figures 6-9]. As per our observation, III^rd and IV^th imaging groups relatively show higher SUVs as compared to the rest imaging groups. We have observed a significant difference (P < 0.05) in SUVmax for sternum, cervical, humerus, ribs, and pelvis sites concerning time. However, a significant difference (P < 0.05) was noted in SUVmean for all skeletal sites concerning time.

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Figure 6

Box and whiskers plot showing the distribution of SUVmax values in patient groups; (a) skull (P = 0.25), (b) scapula (P = 0.24), (c) humerus (P = 0.0002), (d) sternum (P = 0.0001), (e) ribs (P = 0.0004) and (f) cervical (P = 0.0001). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmax, maximum standardized uptake value

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Figure 7

Box and whiskers plot showing the distribution of SUVmax values in patient groups; (a) thoracic (P = 0.23), (b) lumber (P = 0.21), (c) pelvis (P = 0.03) and (d) femur (P = 0.32). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmax, maximum standardized uptake value

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Figure 8

Box and whiskers plot showing the distribution of SUVmean values in patient groups; (a) skull (P = 0.03), (b) scapula (P = 0.0002), (c) humerus (P = 0.03), (d) sternum (P = 0.0001), (e) ribs (P = 0.0001) and (f) cervical (P = 0.0003). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmean, mean standardized uptake value

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Figure 9

Box and whiskers plot showing the distribution of SUVmean values in patient groups; (a) thoracic (P = 0.001), (b) lumber (P = 0.006), (c) pelvis (P = 0.002), and (d) femur (P = 0.0001). The top and bottom of the boxes represented the first and third quartile, end of whiskers represented minimum and maximum values of data and horizontal line inside the boxes represent median. SUVmean, mean standardized uptake value

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Tables 5-8 show the relation between the SUVs and age, BMI, administered activity and ALP. All SUVs of different imaging groups show weak and no significant correlation with age, BMI, administered activity and ALP.

Discussion

Technological evolution and advances in molecular imaging have made quantitative measurements vastly important in the staging of various diseases, differentiation of metastasis from degenerative changes, and also in the evaluation of various treatment responses.[30] The advancement in reconstruction algorithms and the use of various corrections techniques have made SPECT feasible as similar to PET for the quantification.[631] A major challenge with SPECT/CT is the reduction of total acquisition time. However, recent studies reveal that bone SPECT/CT is diagnostically equal to NaF PET/CT and the imaging can also be executed with low acquisition time.[3233] There are no studies that reported the normal SUV values for various skeletal sites using Tc-99m MDP SPECT/CT bone scan on breast cancer patients having no metastatic or degenerative bone diseases. Moreover, this is the first study to demonstrate time-dependent changes on normal SUVs with SPECT/CT.

The results of our study show wide variability in different normal SUV values for various skeletal sites. Here we evaluated different SUVs including SUVmax and SUVmean based on patient BW, which is the most popular method. However, SUVmean is being used as useful alternatives because of the limitations of SUVmax, which is restrictive to noise and statistical changes in data.[34] In our study, the values of SUVmax and SUVmean of all groups were relatively higher in thoracic, lumbar and pelvis as compared to ribs, humerus, and femur. Our results are supported by the results of Win AZ and Aparici CM, which suggested the highest SUV values in vertebrae as compared to humerus and femur.[22] The most likely reason being that higher trabecular density bones show higher blood flow and metabolism lead to higher uptake values.[35363738] Furthermore, weight-bearing and excess mechanical stress bones such as thoracic vertebra, lumber vertebra, and pelvic bones enhance osteoblastic activity lead to higher uptake.[39] Another fluoride-based PET study also revealed that cortical bone-like humerus usually has a lower level of bone metabolism, whereas lumbar spine is excess in trabecular bone.[40]

The phosphonate group of MDP tend to have lesser accumulation in the hydroxyapatite structure of the appendicular skeleton (e.g. humerus and femur) than in the axial skeleton (e.g. vertebrae and pelvis). Win and Aparici measured SUVmax values from Na18F PET/CT studies performed at 60 min postinjection on 11 patients free of cancer or any metabolic disease.[22] Their results were found in good agreement with our study results predominantly for Group II. Here, we observed <10% difference in SUVmax values for skeletal sites, i.e. cervical, thoracic, lumber, and sternum. The differences in SUVs can be resulted from differences in instrumentation, acquisition parameters, and reconstruction techniques.[41] In our study, highest mean SUV value was found in thoracic spine for all four groups. A study by Li et al. suggested that the SUVmean values in the humerus and femur are around 15%–25% of the total value in the spine.[42] However, mean SUV values in the humerus and femur for Group II were found marginally higher in our study, which falls within 25%–35% of value in the thoracic spine (3.04). Meanwhile, values in the humerus and femur for rest imaging groups fall within 35%–45% of value in thoracic spine. Moreover, we have found that SUVmax values in the humerus and femur for all four groups fall within a range of 40%–60% of the total value in the thoracic spine.

In the present study, the SUVmean value for normal pelvis in all imaging groups was also found lower than thoracic and lumbar vertebra. A study by Kaneta et al. found SUV mean values of pelvis lower than vertebral body.[3] Furthermore, Wang et al. demonstrated normal SUVmax and mean value in the normal pelvis which was 3.8 and 2.07, respectively.[7] Our study results reveal SUVmean value in the normal pelvis of Group II is about 2.86 which were found in the same extent as obtained by them. Meanwhile, we have observed higher SUVmax values in pelvis about 9.6 as compared to their results. The possible reason is the technique used for delineation of VOI in pelvis images, where we included the sacroiliac joint as a part of the pelvic surface. Another study also revealed SUVmax and SUVmean values in vertebrae with 6.51 and 3.92, respectively.[8] Although their results were in good accordance with our SUV results in Group II, which were about 7.99 and 2.87, respectively. Moreover, these values were also observed as compared to previously reported SUVs for normal vertebrae, for example, 7.1 ± 0.4 and 7.6 ± 2.4 for SUVmax, and 4.4 ± 0.5, 4.6 ± 1.7, and 5.9 ± 1.5 for SUVmean.[34344]

We used COV to see the dispersion in SUV values for different skeletal sites. It is known that the lower the COV value, the more accurate the measurement. SUVmax values in Group II, which was acquired at a standard time of 3 h postinjection showed less COV as compared to the rest imaging groups. We observed lower dispersion in SUV for all skeletal sites except the skull bone. Furthermore, our results demonstrate lower COV values of SUVmax at vertebral level in Group II, suggesting the smallest dispersion as compared to SUVmean values. Our results are supported by the findings of Kaneta et al.[3]

Our study results show changes in SUVs concerning postinjection acquisition time. As the acquisition time is increasing, SUV difference is also increasing between imaging groups. Moreover, the highest differences in SUVs were found between Groups I and IV. We hypothesized that this is due to progressive changes in bone to background uptake ratio over a while.[45] The influence of postinjection acquisition time on SUVs has already been studied in PET/CT.[25262746] Our results were supported by a study where a percentage of activity retained in the background tissue decreased from 54.1% at 1 h postinjection to 22.4% at 4 h, whereas uptake of Tc-99m MDP in bone increased from 14.6% to 24.7%. Although, in the same period, urinary excretion of Tc-99m MDP was also increased from 31.3% to 52.9%.[4748]

In our study, we did not find any significant relation between SUVs and patient parameters, i.e. age, BMI, administered activity, and ALP. Our results were found in contrast with previous reports.[378] The main limitations of our study are the small sample size and differences in the target population in each imaging group. Moreover, SUV measurements from the entirely healthy population without any malignancy were not obtained. Therefore, in the future comparative study of SUVs at different times after injection can be performed in a larger population having the same subjects to better characterize the SUV for normal skeletal sites.

Conclusions

We concluded that Tc-99m MDP SPECT/CT is a feasible and viable option to quantify SUVs in normal skeletal sites. Our study shows variability in normal SUV values for different skeletal sites in breast cancer patients. Vertebral bodies and pelvis contribute the highest SUV values. If normal SUV values for metastatic prone skeletal sites are known, they can be used as a biomarker in the identification of disease level and the evaluation of treatment response and follow-up to cancer and other bone diseases. Furthermore, we concluded that SUVs change with postinjection acquisition time. The time dependency of SPECT/CT SUVs emphasizes the usefulness of routinely acquired images at the same time after Tc-99m MDP injection, especially in follow-up studies. However, more studies and references are needed to implement SUVs of bone in routine clinical practice.