Extraosseous distribution of 99mTc-diphosphonates during bone scintigraphy: review of the literature with case series presentation.

PURPOSE: Technetium-99m (99mTc)-diphosphonates represent the most common radiopharmaceutical used for bone scintigraphy. Even if the uptake in bone tissue has been widely explored, atypical uptake could be seen in soft tissue malignancies during bone scintigraphy. Increased vascularization and endothelium permeability represent front-row players in the biodistribution of the tracer, albeit other causes have been identified such as trauma, necrosis, the presence of calcification in metastasis, the pH of the tissue and consequently the type of ion concentration. CONCLUSION: The aim of this paper is to summarize the state of art of atypical soft tissue uptake seen in cancer tissues. The research was conducted on PubMed. The analysis of the literature suggests that calcium metabolism and ionic saturation have a pivotal role in the biodistribution of bone tracers. This phenomenon ranks in a complex scenario that includes carcinogenesis and cancer environment aspects. We also report two cases in our Institution in which atypical uptake in cancer tissues was observed.

Comparison of bone single-photon emission computed tomography (SPECT)/CT and bone scintigraphy in assessing knee joints.

BACKGROUND: This study attempted to compare the radiopharmaceutical uptake findings of planar bone scintigraphy (BS) and single photon emission computed tomography (SPECT)/computed tomography (CT) performed on knee joints. METHODS: We retrospectively included 104 patients who underwent bone SPECT/CT and BS 4 h after the intravenous administration of technetium-99m-hydroxymethylene diphosphonate (99mTc-HDP) for pain in the knee joint. The uptake degree of each of the knee regions (medial femoral, lateral femoral, medial tibial, lateral tibial, and patellar area) in planar images and SPECT/CT were evaluated by visual (grades 0 to 2) and quantitative analyses (uptake counts for planar image and standardized uptake values [SUVs] for SPECT/CT). RESULTS: The uptake grades assessed visually on the planar images differed significantly from the uptake grades on SPECT/CT images in all areas of the knee (all p < 0.001), and SPECT/CT imaging revealed a larger number of uptake lesions than those noted in planar imaging for each patient (3.3 ± 2.0 vs 2.4 ± 2.3, p < 0.0001). In all regions of the knee, all of the quantitative values, including uptake counts obtained from the planar image as well as the maximum SUV (SUVmax) and mean SUV (SUVmean) obtained from SPECT/CT, showed statistically higher values as their visual grades increased (all p < 0.001). However, when analyzed for each area, only the SUVmax showed a significant difference by grade in all knee regions. Quantitative uptake values obtained from planar images were moderately correlated with SUVs of SPECT/CT images (r = 0.58 for SUVmean and r = 0.53 for SUVmax, all p < 0.001) in the total knee regions. Looking at each area, there was a significant but low correlation between the uptake counts of the planar images and the SUVs on SPECT/CT in the right lateral tibial region (r = 0.45 for SUVmean, r = 0.31 for SUVmax, all p < 0.001). CONCLUSIONS: In assessing knee joints, the findings of planar images and SPECT/CT images differ both visually and quantitatively, and more lesions can be found in SPECT/CT than in the planar images. The SUVmax could be a reliable value to evaluate knee joint uptake activity.

Dosimetric considerations of 99mTc-MDP uptake within the epiphyseal plates of the long bones of pediatric patients.

Skeletal scintigraphy is most performed in pediatric patients using the radiopharmaceutical 99mTc labelled methylene diphosphonate (99mTc-MDP). Reference biokinetic models for 99mTc-MDP indicate 50% of the administered activity is uniformly localized to the interior bone surfaces (trabecular and cortical regions), yet imaging data clearly show some preferential uptake to the epiphyseal growth plates of the long bones. To explore the dosimetric consequences of these regional activity concentrations, we have modified mesh-type computational phantoms of the International Commission on Radiological Protection (ICRP) reference pediatric series to explicitly include geometric models of the epiphyseal growth plates (2 mm in thickness) within the left/right, distal/proximal ends of the humeri, radii, ulnae, femora, tibia, and fibulae. Bone mineral activity from the ICRP Publication 128 biokinetic model for 99mTc-MDP (ICRP 2015) was then partitioned to the growth plates at values of 0.5%, 4.4%, 8.3%, 12.2%, 16.1%, and 20%. Radiation transport simulations were performed to compute 99mTc S-values and organ dose coefficients to the soft tissues and to bone site-specific regions of spongiosa. As the percentage of bone activity assigned to the growth plates was increased (from 0.5% to 20%), absorbed doses to the soft tissue organs, active bone marrow, bone endosteum (BE), as well as the detriment-weighted dose, were shown to decrease from their nominal values (no substantial growth plate activity), while epiphyseal plate self-doses increased. In the 15 year old male phantom, moving from 0.5% to 20% relative bone activity within the epiphyseal plates resulted in a 15% reduction in active marrow (AM) and BE dose, a 10% reduction in mean soft tissue and detriment-weighted dose, and a 6.3-fold increase in epiphyseal plate self-dose. In the newborn female phantom, we observed a 18% decrease in AM and BE dose, a 10% decrease in mean soft tissue dose, a 15% decrease in detriment-weighted dose, and 12.8-fold increase in epiphyseal plate self-dose. Increases (to 3 mm) and decreases (to 1 mm) in the assumed growth plate thickness of our models were shown to impact only the growth plate self-dose. Future work in differential quantification of 99mTc-MDP activity-growth plates versus other bone surfaces-is required to provide clinically realistic data on activity partitioning as a function of patient age, and perhaps skeletal site. The phantom series presented here may be used to develop more optimized age-related guidance on 99mTc-MDP administered activities to children.

Intense 99mTc-MDP Uptake in the Abdominal Soft Tissue Secondary to Subcutaneous Insulin Injection.

A 65-year-old woman with known breast cancer presented with lower back pain over 1 month. Multiple sclerotic foci of increased tracer uptake in the bones were noted on the Tc-MDP bone scintigraphy and SPECT/CT images, suggesting osteoblastic metastasis. Unexpectedly, symmetric Tc-MDP activity was visualized in the soft tissue near the umbilical area, corresponding to the sites of insulin injection.

Iatrogenic Lung Microembolism Resulted in Extraosseous Uptake of 99mTc-MDP.

A 61-year-old woman diagnosed with left breast cancer underwent a bone scan for the evaluation of possible bone metastases. Multiple foci of elevated activity were noticed in the spine and pelvis. In addition, a focus of intense activity was observed in the right lung on the SPECT/CT images without corresponding anatomic abnormality.

Extensive Extramedullary Hematopoiesis in Thalassemia: Soft Tissue Uptake on 99mTc-MDP SPECT/CT.

We report the case of a 45-year-old man with thalassemia major referred for a bone scan as a workup for generalized bone pain. Tc-MDP SPECT CT showed multiple elongated soft tissue masses along the inner aspects of ribs and along both sides of dorsal spine with calcification and mild tracer uptake. There was also a large lobulated presacral soft tissue mass displacing the bladder and involving the adjacent pelvic bone. Biopsy of mildly avid tracer uptake in pelvic soft tissue mass was extramedullary hematopoiesis confirmed by biopsy.

Maximum standardized uptake value from quantitative bone single-photon emission computed tomography/computed tomography in differentiating metastatic and degenerative joint disease of the spine in prostate cancer patients.

OBJECTIVE: Qualitative interpretation in bone scan is often complicated by the presence of degenerative joint disease (DJD), especially in the elderly patient. The aim of this study is to compare objectively 99mTc-MDP tracer uptake between DJD and osseous metastases of the spine using semi-quantitative assessment with SPECT SUV. METHODS: Bone scan with SPECT/CT using 99mTc-MDP was performed in 34 patients diagnosed with prostate carcinoma. SPECT/CT was performed based on our institutional standard guidelines. SUVmax based on body weight in 238 normal vertebrae visualized on SPECT/CT was quantified as baseline. A total of 211 lesions in the spine were identified on bone scan. Lesions were characterized into DJD or bone metastases based on its morphology on low-dose CT. Semi-quantitative evaluation using SUVmax was then performed on 89 DJD and 122 metastatic bone lesions. As most of the bone lesions were small in volume, the effect of partial volume effect (PVE) on SUVmax was also assessed. The corrected SUVmax values were obtained based on the recovery coefficient (RC) method. RESULTS: The mean SUVmax for normal vertebrae was 7.08 ± 1.97, 12.59 ± 9.01 for DJD and 36.64 ± 24.84 for bone metastases. The SUVmax of bone metastases was significantly greater than DJD (p value < 0.05). To assess for diagnostic accuracy, receiver operating characteristic (ROC) curve was performed. The area under the curve (AUC) was found to be fairly high at 0.874 (95% CI 0.826-0.921). The cutoff SUVmax value ≥ 20 gave a sensitivity of 73.8% and specificity of 85.4% in differentiating bone metastases from DJD. The corrected SUVmax for both DJD and bone metastases was smaller with a mean of 6.82 ± 6.02 and 24.77 ± 20.61, respectively. The cutoff SUVmax value was also lower with a value of 10, which gave a sensitivity of 73.8% and specificity of 86.5%. CONCLUSION: SPECT SUVmax was significantly higher in bone metastases than DJD. Semi-quantitative assessment with SUVmax can complement qualitative analysis. A cutoff SUVmax of ≥ 20 can be used to differentiate bone metastases from DJD. Partial volume effect should be taken into consideration in the quantification of small lesion size.

Comprehensive molecular imaging of malignant transformation of giant cell tumour of bone reveals diverse disease biology.

Malignant transformation of giant cell tumour of the bone is extremely rare. In addition, bone transformation in giant cell tumour may occur in different phases. With conventional X-rays, CT scans or MRIs, it may be challenging to distinguish among different phases of bone transformation, normal bone, soft tissue disease and bone disease (benign vs malignant lesions) and changes in multiple organs such as lung, liver and lymph nodes unless every lesion is biopsied, which is not practical. Molecular imaging with different isotopes (Tc-99m phosphonate, 2-deoxy-2-(18F)fluoro-d-glucose and sodium fluoride-18) may help to better characterise the disease. We hypothesised that molecular imaging could offer qualitative and quantitative characterisation of all stages of bone formation, destruction, reactivity or neoplasia in a patient with giant cell tumour of the bone, and we present the first case of molecular imaging where bone formation was seen in multiple soft tissues, such as lungs, muscles, lymph nodes and liver.

Increased Muscular MDP Activity in the Lower Extremities Caused by Multiple Arterial Thromboses.

Many reasons could lead to abnormal increased extraosseous tracer uptake on Tc-MDP bone scintigraphy. A 75-year-old man was referred a bone scintigraphy to evaluate his chest pain. The images revealed rib fractures. In addition, increased MDP activity in the muscle of the lower extremities was noted. The abnormal increased uptake in the muscles was likely related to the arterial thromboses revealed by vascular ultrasonography. The patient received interventional embolectomy.

99mTc-Methyl-Diphosphonate Binding to Mineral Deposits in Cultures of Marrow-Derived Mesenchymal Stem Cells in Osteogenic Medium.

IMPACT STATEMENT: The work is notable for describing a highly sensitive, quantitative, and nondestructive method for evaluating the in vitro amount of mineral accompanying different types of osteogenic differentiation of mesenchymal stem cells in a monolayer cell culture. What is so unique and useful about the method is that it has the potential to be used to define the kinetics of the differentiation process, reflected in the mineralization, without destroying the monolayer. Therefore, it remains intact for further experiments.

Effects of bone cement filling in rabbit proximal femoral medullary cavity on distal femoral blood flow and metabolism.

OBJECTIVE: A rabbit model was used to evaluate the effects of bone-cemented hip arthroplasty on distal femoral blood flow and metabolism relative to that of the non-cemented contralateral leg. METHODS: The marrow cavity of the right hind femur was filled with bone cement. At each of the following time points, rabbits were randomly selected to receive an injection of one dose of 99mTc-methylene diphosphonate and then immediately scanned using a gamma camera: immediately postoperatively and at 4 and 8 weeks postoperatively. A BL-410 model biofunction experimental system was used to analyze the acquired images and determine the radioactive counts of each hind leg. RESULTS: The X-ray and photographic images of the right femoral bones confirmed successful filling of the marrow cavity with bone cement. The radioactive counts were significantly lower in the experimental than control legs at each time point. The ratio of the radioactive count of the experimental to control leg increased considerably at each time point, but each ratio was <1. CONCLUSION: Blocking the proximal femoral medullary cavity with bone cement was associated with significant lowering of the blood circulation of the femur and marrow, decreasing the distal femoral blood flow and bone metabolic rate.

Intense 99mTc-MDP Activity in an Elongated Sagging Gallbladder With a Partially Calcified Gallstone.

Intense activity was noted in the right middle abdomen on whole-body Tc-MDP bone scan images, which were obtained in a 78-year-old woman who had back pain. Further SPECT/CT images demonstrated that the intense activity was located in an elongated gallbladder. Partially calcified gallstone was also revealed on SPECT/CT images. Unexpectedly, the gallbladder activity was from the radioactive bile inside the gallbladder lumen, whereas the partially calcified gallstone was relatively photopenic.

Spleen Uptake on a Bone Scan.

We present a patient with spleen uptake on bone scanning that was due to sickle cell disease. We also discuss other etiologies for this finding.

Increased technetium-99 m hydroxy diphosphonate soft tissue uptake on bone scintigraphy in chronic kidney disease patients with secondary hyperparathyroidism: correlation with hyperphosphataemia.

In bone scan patients with dialysis-treated chronic kidney disease (CKD) and hyperparathyroidism, soft tissue accumulation of technetium-99 m hydroxy/methylene diphosphonate (Tc-99 m-HDP/MDP) has been reported primarily in case reports and usually explained by hypercalcaemia and/or hyperphosphataemia. As human vascular smooth muscle cells produce hydroxyapatite during cell culture with increased phosphate levels and as Tc-99 m-HDP/MDP primarily binds to hydroxyapatite, we hypothesized that soft tissue accumulation would be found in patients with hyperphosphataemia. We identified 63 CKD patients diagnosed with secondary hyperparathyroidism admitted for Tc-99 m-HDP bone scan. Baseline characteristics and mean concentrations of biochemical markers (including P-calcium and P-phosphate) taken 0-3 months prior to the bone scans were collected. Soft tissue uptake was detected on bone scans in 37 of 63 (59%) patients. Primary locations were in the heart (27/37 = 73%), muscles (12/37 = 32%), lung (9/37 = 24%) and gastrointestinal tract (6/37 = 16%), and 13 of 37 (35%) patients had simultaneous uptake in more than one location. Regarding biochemical markers, patients with soft tissue uptake only differed from patients without in terms of plasma phosphate levels (1·95 ± 0·15 (n = 37) versus 1·27 ± 0·08 (n = 26), P = 0·0012). All patients with myocardial uptake (n = 27) had a coronary arteriography-verified history of coronary artery disease (CAD), whereas CAD was only present in six of the 36 patients without myocardial uptake. In conclusion, dialysis-treated CKD patients with secondary hyperparathyroidism have a high incidence of soft tissue uptake, and this finding is strongly correlated with elevated phosphate, but not calcium values.

The effect of MRI contrast agents on hepatic and splenic uptake in the rabbit during (99m) Tc-MDP bone scintigraphy.

The objective of this study was to investigate the effects of Omniscan® and Magnevist® on (99m) Tc-MDP uptake in rabbits during (99m) Tc-MDP bone scintigraphy. In Experiment Group 1, 30 healthy adult rabbits were randomized into six subgroups (n = 5); each subgroup experienced a different time interval between injections (30 min, 60 min, 120 min, 240 min, 360 min, 24 h). All six subgroups were injected first with Omniscan®, then with (99m) Tc-MDP. After 7 days, the same six subgroups were injected with normal saline followed by (99m) Tc-MDP at the same time intervals. In Experiment Group 2, 20 healthy adult rabbits were allocated randomly to four subgroups (n = 5); each subgroup experienced a different time interval between injections (30 min, 60 min, 120 min, 240 min). All four subgroups were injected first with Magnevist®, then with (99m) Tc-MDP. After 7 days, the same four subgroups were injected with normal saline followed by (99m) Tc-MDP. In all experiments, whole-body skeletal imaging was performed. Liver, spleen, and background were delineated to determine the target-to-background (T/B) ratio. Diffusely increased intake of the imaging agent was seen in the liver and spleen when the injection-time interval between Omniscan® and (99m) Tc-MDP varied from 30 min to 240 min and when the time interval between Magnevist® and (99m) Tc-MDP was 30 min-60 min. The imaging findings are consistent with the results of L/B and S/B ratios in each experiment group. Both Omniscan® and Magnevist® have an effect on (99m) Tc-MDP uptake during bone scanning; the main effect is diffusely increased hepatic and splenic activity.

Liver uptake on bone scanning: a diagnostic algorithm.

In this report, we present a case of liver uptake seen on a bone scan that was due to diffuse metastatic disease from breast carcinoma. We discuss possible etiologies for the uptake and offer an algorithm to narrow the differential diagnosis.

Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib.

BACKGROUND: Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging. METHODS: NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ((99m)Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann-Whitney test or Wilcoxon signed rank test. RESULTS: VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance (P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10(-6) mm(2)/s vs pretreatment ADC = 485±43×10(-6) mm(2)/s; P = .02 ). Tumor-associated uptake of (99m)Tc-MDP was statistically significantly reduced after 3 days of treatment (P = .02), sustained over 15 days treatment, and associated with a statistically significant (P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant (P = .001) increase in trabecular bone volume. CONCLUSIONS: The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.

Disparities in uptake pattern of (123)I-MIBG, (18)F-FDG, and (99m)Tc-MDP within the same primary neuroblastoma.

We report an unusual case of primary neuroblastoma in an 11-year-old girl. The superior portion of the tumor accumulated I-MIBG, Tc-MDP, and F-FDG. In contrast, the inferior portion of the tumor showed no abnormal F-FDG or Tc-MDP uptake, which usually indicates tumor necrosis. This inferior portion of the tumor, however, had intense I-MIBG activity, consistent with viable tumor rather than tumor necrosis.

Myocardial uptake of 99mTc-HDP and reduced perfusion on CT in subacute myocardial infarction.

A 65-year-old man with known bone metastases from prostate cancer and no cardiac history attended for a restaging bone scan (BS). Diffuse increased Tc-HDP activity in the heart was noted, new since a BS 3 months earlier. A restaging contrast-enhanced CT scan on the same day showed reduced myocardial perfusion in the anterior, apical, and septal walls. On direct questioning, he described an episode of severe exertional chest pain the day before. Myocardial infarction was confirmed and treated with primary percutaneous coronary intervention. New cardiac uptake on BS, raising the possibility of myocardial infarction, is a red alert for clinicians.

Intense splenic 99mTc-MDP uptake in a patient with myelofibrosis.

99mTc-MDP bone scan was performed in a 49-year-old woman with breast cancer. Whole-body bone scan showed multiple foci of increased MDP activity in the bone and intense splenic 99mTc-MDP uptake. Initial bone marrow aspiration in multiple locations yielded no blood cells. A subsequent bone marrow biopsy in the left anterior superior iliac spine showed myelofibrosis in addition to the known bone metastasis.