PET Imaging of the Skeleton 21

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A number of applications of PET in skeletal disorders have become apparent in the last decade. With the gener- alized growth of oncologic applications, there has been particular interest in assessing the skeleton for metastatic disease with the bone tracer ¹⁸F-ﬂuoride and the metabolic tumor agent ¹⁸F-ﬂuorodeoxyglucose (FDG). There are also some early data on the use of FDG in the evaluation of primary bone tumors.

In benign skeletal disorders, quantitative dynamic ¹⁸F- ﬂuoride PET scanning can be used to measure a number of parameters related to regional metabolism of bone in both global and focal skeletal diseases, but the use of this tracer has not been described in qualitative imaging evaluation of benign disorders. There is a possible role for FDG in the evaluation of infection within the skeleton, and the hypoxia tracer ¹⁸F-ﬂuoromisonidazole has been assessed in anaerobic skeletal infection.

Radiopharmaceuticals and Uptake Mechanisms

18F-Fluoride

18F-Fluoride was ﬁrst described as a bone imaging agent in the 1960s (1) but was subsequently replaced by ^99mTc- labeled diphosphonate compounds that were more suit- able for gamma camera imaging. With improvement and increased availability of PET scanners, allowing high-resolution imaging of the skeleton, there is now renewed interest in the use of ¹⁸F-ﬂuoride for clinical and research applications.

The mechanism of uptake of ¹⁸F-ﬂuoride is similar to other bone-speciﬁc tracers used in nuclear medicine.

Accumulation depends on regional blood ﬂow and to a greater extent on regional osteoblastic activity. ¹⁸F- Fluoride is preferentially deposited at sites of high bone turnover and remodeling (2) by chemisorption onto bone surfaces, exchanging with hydroxyl groups in hydroxyap-

atite crystals of bone to form fluoroapatite. Blood flow and the capillary permeability–surface area product (PS) determine the clearance of fluoride by total bone tissue (bone mineral, bone marrow, and associated extracellular fluid spaces). Net clearance by bone mineral is influenced by osteoblastic activity, which increases accumulation by means of local bone mineralization and also by the relationship between blood flow and bone formation. At low blood flow, passage of ¹⁸F-fluoride from the vascular space to bone tissue is limited by perfusion, but at high blood flow, diffusion becomes the limiting factor.

This difference means that the unidirectional, single- passage extraction efficiency (E) is close to unity at low flow rates, so that ¹⁸F-fluoride clearance by total bone tissue approximates blood flow (3). However, at high blood flow E decreases and clearance underestimates blood flow (4, 5).

18F-Fluorodeoxyglucose

It has been known for many years that malignant cells have a higher glycolytic rate than normal tissue (6) so that the glucose analogue FDG preferentially accumulates in a number of tumors, although uptake is not speciﬁc to malignant tissue. Uptake of FDG is also related to tumor hypoxia, which is probably also mediated by an increase in glycolysis (7). FDG is transported into tumor cells by the glucose transporter membrane proteins GLUT 1–GLUT 5. GLUT 1 in particular is expressed in many malignant tumors (8).

In the skeleton, it is assumed that FDG is taken up di- rectly into tumor cells and does not result from skeletal reaction to tumor as with ¹⁸F-ﬂuoride, which accumulates on the mineralizing surface of bone rather than the tumor itself. The mechanisms of uptake and the information available from FDG uptake in the skeleton are therefore quite different from ¹⁸F-ﬂuoride. FDG is currently the most commonly used tracer in oncologic PET imaging, and because uptake of this tracer is not restricted to the 317

21

PET Imaging of the Skeleton

Gary J.R. Cook, Ignac Fogelman, and Ora Israel

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18F-Fluoromisonidazole

18F-Fluoromisonidazole is one of a number of labeled compounds that have been synthesized which incorporate a 2-nitroimidazole moiety as a bioreductive molecule (9).

The nitro group undergoes one-electron reduction in viable cells to produce a radical anion. In hypoxic cells, this intermediate is further reduced to species that react with cellular components and are trapped within the cell.

In normoxic conditions, reoxidation rapidly takes place and the compound eventually diffuses out of the cell.

These compounds have been most extensively evaluated in the context of tumor and myocardial hypoxia but may have a role in the investigation of anaerobic infection of bone (10, 11).

Malignant Skeletal Disease

Skeletal Metastases

High image contrast between normal and diseased bone is achievable by PET imaging as early as 1 h following in- jection of ¹⁸F-ﬂuoride, and this method has been evaluated in the investigation of bone metastases (12–17).

In breast cancer, both sclerotic and lytic bone metastases have been reported to show increased uptake of ¹⁸F- ﬂuoride (15), as is also seen with conventional nuclear medicine bone tracers such as ^99mTc-methylene diphosphonate (MDP). Lytic metastases, more frequently en- countered in most cancers, are caused by osteoclastic bone resorption that is stimulated by tumor-derived cy- tokines, and this is nearly always accompanied by local reactive bone formation and hence uptake of bone tracers.

Sclerotic metastases occur when newly formed bone is laid down without prior resorption, and these are characteristically associated with marked uptake of bone tracers.

Although PET shows superior quantitative accuracy over planar or single photon emission computed tomography (SPECT) gamma camera imaging, it is unlikely that quantification of uptake of ¹⁸F-fluoride uptake, as a non- specific bone agent, would be able to differentiate benign from malignant focal skeletal lesions. Using a relatively crude index of uptake (lesion to normal ratios), it has not been possible to differentiate benign from malignant lesions (13). Dynamic measurements of regional skeletal

quisition of tomographic images, ¹⁸F-ﬂuoride PET imaging has potential advantages over conventional bone scintigraphy in detecting bone metastases. Schirrmeister and colleagues (17) have compared ¹⁸F-ﬂuoride PET with

99mTc-MDP in 44 patients with varied primary cancers (prostate, lung, and thyroid), using computed tomography (CT), magnetic resonance imaging (MRI), and ¹³¹I- scintigraphy as reference methods. It was found that all known metastases were detected by ¹⁸F-fluoride PET and nearly twice as many benign and malignant lesions were identified by PET than by ^99mTc-MDP bone scans. It was also possible to correctly classify a larger number of lesions as benign or malignant with ¹⁸F-fluoride (97%) compared to ^99mTc-MDP (80.5%) because of the superior spatial localization of the former, particularly in the spine.

In a further study of patients with breast cancer, the greater accuracy of ¹⁸F-ﬂuoride PET led to a change in management in 4 of 34 patients compared to conventional

99mTc-MDP bone scans (16).

It is possible that some of the benefit of ¹⁸F-fluoride PET derives from the better spatial resolution and tomographic images compared to planar bone scintigraphy. A further study by Schirrmeister et al. (18) in patients with lung cancer showed a significant advantage in diagnostic accuracy for ¹⁸F-fluoride PET compared to planar bone scintigraphy but only a small, nonstatistically significant advantage compared to bone scintigraphy augmented with SPECT. ¹⁸F-Fluoride PET led to a change in management in 11% of patients compared to planar bone scintigraphy.

In a subsequent study, ¹⁸F-ﬂuoride PET was found to be more effective than SPECT but was associated with higher incremental costs (19). It remains to be seen whether routine PET bone scanning by ¹⁸F-ﬂuoride PET would be cost effective across a broader spectrum of malignancies.

With the advent of combined PET/CT, it is likely that the anatomic and structural information available from the CT component will enhance the diagnostic accuracy compared to ¹⁸F-fluoride PET alone, as has been confirmed in an initial study by Even-Sapir et al. in which the specificity of PET/CT was significantly greater than PET (97% versus 72%; P less than 0.001) (Figure 21.1) (20).

Because the uptake of FDG is within tumor cells and not on bone mineral surface, measurement of quantitative indices of FDG and ¹⁸F-ﬂuoride uptake is attractive, as there is the potential to grade lesions, infer prognosis, and monitor response to treatment. This potential has not been explored so far.

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PET Imaging of the Skeleton 319

The possible role of FDG in the evaluation of skeletal metastases has been explored in a number of studies. On a patient-by-patient basis, the sensitivity for detecting metastases was found to be the same as ^99mTc-MDP in non-small cell lung cancer, but FDG-PET correctly confirmed the absence of bone metastases in a larger number of cases [specificity of 98% (87/89) compared to 61% (54/89)] (21). The most likely explanation for these observations is that uptake of FDG is more specific for tumor and does not accumulate in coincidental benign skeletal disease such as osteoarthritis. Subsequent studies in lung cancer have shown advantages of FDG-PET over bone scintigraphy with regard to overall accuracy (22, 23).

In a similar study of 145 patients with a variety of cancers, FDG-PET demonstrated higher sensitivity and speciﬁcity on a lesion-by-lesion basis (24). This improved sensitivity may result from detection of metastases at an earlier stage, when only bone marrow is involved, as well as the better spatial and contrast resolution offered by PET.

FDG-PET is not more sensitive than bone scintigraphy for the detection of all bone metastases. In breast cancer, a higher false-negative rate has been described in the skeleton compared to other sites (25, 26). In a group of patients with breast cancer and progressive disease, a signiﬁcantly higher number of metastases was reported overall with FDG-PET (Figure 21.2), but it was noted that a subgroup with predominantly sclerotic disease showed fewer lesions by PET than by conventional ^99mTc-MDP bone scintigraphy (27). Sclerotic metastases showed lower uptake than lytic metastases in terms of standardized uptake value (SUV) (Figure 21.3). It has also been noted in a number of reports that FDG was less accurate in assessing skeletal disease in prostate cancer, a tumor that produces predominantly sclerotic bone metastases (28, 29).

A number of possible explanations have been advanced for the lower uptake of FDG in sclerotic bone metastases.

It may be that this type of metastasis is metabolically less active. This explanation would be supported by the ﬁnding of a better prognosis in breast cancer patients with sclerotic bone metastasis than those with lytic metastasis (27). Sclerotic metastases are relatively less cellular (30), so that smaller tumor volumes may account for the lower uptake of FDG. In addition, more aggressive lytic disease might be expected to outstrip its blood supply, rendering the metastasis relatively hypoxic, a property that is associated with increased FDG uptake in some cell lines (7). In a different study, the sensitivity for detection of bone metastases was no different between FDG-PET and bone scintigraphy, but FDG-PET showed a higher speciﬁcity (97.6% versus 80.9%) (31).

In lymphoma, where skeletal involvement is predominantly marrow based rather than in cortical bone, FDG- PET has shown greater sensitivity than conventional bone scintigraphy (32) (Figure 21.4). As bone marrow staging of lymphoma is limited to iliac crest biopsy, which in- volves obvious sampling errors, it has also been suggested that FDG-PET might replace bone marrow biopsy as a

staging procedure, with the added advantage that other tissues will be imaged at the same time (33, 34). For assessing bone marrow response to treatment, the situation may be more difﬁcult with FDG, because it is known that chemotherapy and granulocyte colony-stimulating factors cause benign, diffuse increase in marrow activity (35, 36) (Figure 21.5). Similarly, in other malignancies where bone scintigraphy characteristically has a lower sensitivity as a result of predominantly lytic skeletal disease, including multiple myeloma and renal cell carcinoma, FDG-PET has been reported as showing greater accuracy in assessing the extent of skeletal involvement (37–39).

It would be anticipated that MRI would also be sensitive to marrow-based metastatic disease compared to bone scintigraphy. In a study of 39 children and young adults with Ewing’s sarcoma, osteosarcoma, lymphoma, rhabdomyosarcoma, melanoma, and Langerhan’s cell his- tiocytosis, sensitivity for the detection of bone metastases for FDG-PET was 90%, for whole-body MRI, 82%, and for bone scintigraphy, 71%, although FDG-PET showed the highest number of false-positive results (40).

Early data using FDG with combined PET/CT for evaluation of skeletal metastases in the spine have shown that having CT as an anatomic and structural correlate results in a higher speciﬁcity (41). PET/CT also allows the assessment of soft tissue extension of potential neurologic signiﬁcance (Figures 21.6, 21.7).

Skeletal metastases are notoriously difﬁcult to assess with regard to response to systemic therapies using current standard criteria depending on changes in radi- ographic appearances, a method that is accepted as being relatively insensitive compared to standard methods for monitoring soft tissue metastases. Assessing response with conventional bone scintigraphy is also limited by a slow change in bone activity or by the ﬂare response. Direct measurement of skeletal tumor viability with FDG-PET is therefore of potential interest. At the present time there are few data to support the use of FDG-PET in this role, but a preliminary study reported by Stafford and colleagues (42) showed a correlation in response as measured by tumor markers and that measured by serial FDG-PET.

Primary Bone Tumors

There are fewer published data regarding the role of PET in primary bone tumors than bone metastases. As in many other tumor types, there is a relationship between the uptake of FDG, whether measured by semiquantitative indices such as SUV or kinetic parameters such as the metabolic rate of FDG and tumor grade in soft tissue and bone sarcomas (43–45). Because of low uptake in low- grade sarcomas, FDG-PET may not be an adequate tool to differentiate low-grade sarcomas from benign lesions (46, 47). However, uptake of FDG does not generally reach a plateau for 3 to 4 h in malignant lesions whereas benign lesions show maximal uptake long before this (48). There

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is therefore the potential for better differentiation of benign from malignant sarcomas by scanning later than the conventional 1 h postinjection or by measuring changes in uptake between two time points.

In chondrosarcomas, a correlation between SUV and histopathologic stage has been described with an improvement in identifying patients at risk of local relapse and metastatic disease with higher SUVs (49). A further improvement in prognostic power was found when histo- logic tumor grade and SUV information were combined.

Similarly, high FDG activity has adverse prognostic signiﬁcance in osteosarcoma (50). For detecting skeletal metastases, it would appear that FDG-PET is more sensitive than conventional bone scintigraphy in Ewing’s sarcoma but relatively insensitive in osteosarcoma (51).

The value of FDG in the monitoring response of bone tumors to chemotherapy is unclear. Certainly there appears to be a reduction in uptake corresponding to tumor necrosis following neoadjuvant therapy (52), but uptake into benign reactive ﬁbrous tissue has been described that may cause difﬁculty in differentiating com- plete from partial response (53). However, FDG-PET may

be complementary to MRI in differentiating residual viable tumor from treatment effects (54). Good correlation between serial FDG-PET and histopathologic response has also been observed in pediatric bone sarcomas (55).

FDG-PET has also been used in the evaluation of residual or recurrent musculoskeletal tumors, and results suggest that it may be more sensitive than other tumor agents such as ^99mTc-sestamibi. In addition, it is possible that additional information may be gained by using both FDG and ^99mTc-sestamibi, where the former gives information on tumor viability and the latter gives information on the presence of multidrug resistance (56).

Benign Skeletal Disease

18F-Fluoride

Outside oncology, most of the reported work using ¹⁸F- ﬂuoride is in quantifying regional skeletal kinetics. The

a b

Figure 21.1.¹⁸F-Fluoride PET/CT images of a 73-year-old man with hormone refractory prostate cancer [Gleason 9; prostate-specific antigen (PSA), 37 ng/mL]. A sclerotic T9 metas- tasis and a pathologic rib fracture with an associated abnormal soft tissue mass are demonstrated on the PET (a) and PET/CT (b, c) images. (Courtesy Dr. Einat Even-Sapir, Souraski Medical Center, Tel-Aviv, Israel.)

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method was pioneered by Hawkins and colleagues (12) and has subsequently been used to quantify a number of indices of regional skeletal metabolism in normal subjects (12, 57, 58), metabolic bone diseases (59, 60), avascular necrosis of the hip (61), and surgical bone grafts of the maxilla and hip (62, 63), as well as measuring differences between trabecular and cortical sites within the same subject (57).

By measuring plasma arterial activity and acquiring dynamic PET data over a skeletal region of interest, it is possible to calculate a number of parameters related to different aspects of bone metabolism. Hawkins et al. (12) described a three-compartment model and with the use of nonlinear regression analysis was able to determine the rate constants describing exchange of tracer between compartments as well as the macro-constant Ki, where

Ki= K1k3/(k2+ k3) (1) It was found that a three-compartment model, consisting of a plasma compartment, a central extravascular compartment, and a bone mineral compartment, ﬁtted the data better than a two-compartment model consisting of plasma and bone only. Subsequently, this model has been validated by using model-independent methods of

data analysis. It would appear that although the central compartment is an oversimplification, that is, it contains both bone marrow and bone extracellular fluid (ECF) as well as bone marrow cellular elements, this has little effect on parameter estimation, particularly Ki(58). This finding suggests that bone marrow ¹⁸F-fluoride is available for uptake into bone mineral, even if on a longer time scale than true bone ECF.

The two most important parameters are Ki(net plasma clearance of ﬂuoride by bone mineral; units, ml min^–1 ml^–1) and K1(plasma clearance of ﬂuoride by total bone tissue; units, ml min^-1ml^-1). The parameters k2, k3, and k4

are simple rate constants (units of min^–1). Kihas been shown to correlate with biochemical and histomorphome- tric parameters of bone formation and mineralization. K1

is related to blood ﬂow (Q) and E by the equation:

K1= Q • E (2)

If E is close to unity, as has been deduced from mea- surements on rabbit hindlimb (3), K1represents regional bone blood flow. The Renkin–Crone model of capillary diffusion (64) predicts that E is reduced at high rates of blood flow, as might be seen in trabecular sites. K1there- fore underestimates true regional blood flow in these cir-

c Figure 21.1. Contd. (c) ¹⁸F-Fluoride

PET/CT images of a 73-year-old man with hormone refractory prostate cancer [Gleason 9; prostate-specific antigen (PSA), 37 ng/mL]. A sclerotic T9 metastasis and a pathologic rib fracture with an associated abnormal soft tissue mass are demonstrated on the PET/CT.

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cumstances; this is supported by work from Piert and colleagues (65) who compared vertebral blood ﬂow in pigs measured with ¹⁵O-labeled water with K1for ¹⁸F-ﬂuoride determined as just described.

A number of potential clinical applications have been described for dynamic, quantitative ¹⁸F-ﬂuoride PET. One clinical problem in bone disease is the differentiation of

renal osteodystrophy patients with accelerated turnover from those with adynamic bone. Bone biopsy may be the only way of resolving this problem, and thus alternative noninvasive methods to determine bone turnover are at- tractive. Messa and colleagues (59), by measuring Kiin vertebrae of patients with renal osteodystrophy, were able to differentiate those with high turnover from those with b

a

Figure 21.2.^99mTc-MDP) bone scan (a) and FDG-PET scan (b) in a patient with breast cancer. The scans were performed 2 weeks apart with no intervening therapy. The bone scan is essentially normal, but the PET scan shows a number of skeletal metastases.

18FDG

b 18F-

a

Figure 21.3. Transaxial ¹⁸F-fluoride (a), FDG (b), and CT (c) scans demonstrate focally increased bone turnover in a sclerotic metastasis (arrows) but with no abnormal FDG activity.

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adynamic bone and were also able to show correlations between Ki and histomorphometric and biochemical indices of bone formation.

Schiepers et al. (60) studied the axial skeleton in a small number of subjects with a variety of metabolic bone diseases, including Paget’s disease and osteoporosis, by this method. Two subjects with Paget’s disease showed an ex- pected increase in both Kiand K1, reflecting an increase in both regional mineralization and blood flow. We have noted similar findings in seven patients with pagetic ver- tebrae (66). It was also noted that k4, describing the release of ¹⁸F-fluoride from bone mineral back to the extravascular compartment, was lower in pagetic vertebrae compared to adjacent normal vertebrae, suggesting that

18F-ﬂuoride remains more tightly bound to bone mineral in Paget’s disease, an observation also recorded by Fogelman and colleagues using the ^99mTc-MDP retention method (67).

Osteoporotic subjects show low values of vertebral Ki

(expressed in units of ml min^–1ml^–1) (58, 60), a ﬁnding b

a

Figure 21.4. FDG-PET (a) and PET/CT (b) scans in a patient with recurrent lymphoma. On the FDG-PET scan, abnormal focal uptake is seen (arrows), but it is not possible to confidently localize these lesions to the skeleton. The combined PET/CT scan allows accurate skeletal localization of the lesions, which had been unsuspected and changed management.

Figure 21.5. Diffuse increase in uptake of FDG seen in the bone marrow of a patient 2 weeks after completing chemotherapy is consistent with reactive changes rather than active lymphoma.

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a

b

Figure 21.6. A 47-year-old woman with metastatic breast cancer treated with chemotherapy 2 years previously pre- sented with increasing serum tumor markers. Planar bone scintigraphy (a) shows areas of abnormal uptake at the sacrum, T5, first left rib, a right anterior rib, and the right femoral neck. FDG-PET coronal slices (b) demonstrate patho- logic uptake in the sacrum, left first rib, and T5.

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ci

Figure 21.6. Contd. PET/CT images (c) show an active lytic metastasis in the pedicle of T4 (i), an active mixed sclerotic and lytic metastasis in the left first rib (ii)

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a b

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that is at odds with reports of increased bone turnover as measured by other methods (68). It is possible that there is a dissociation between global skeletal turnover and that measured in the predominantly trabecular site of the lumbar spine (58). It is clear that further work, perhaps with correlation with histomorphometric measurements, is required in osteoporotic subjects, before the full signiﬁcance of kinetic parameters derived by ¹⁸F-ﬂuoride PET is understood. However, using this method a direct metabolic effect of antiresorptive therapy on skeletal kinetics at the clinically important site of the lumbar spine has been observed in osteoporotic women (69).

Quantiﬁcation of regional skeletal metabolic indices also has potential clinical applications in orthopedics. A

pilot study has suggested that by measuring K1as an index of blood ﬂow in the femoral head following trauma, it may be possible to predict which patients will require surgical intervention rather than a conservative approach (61).

Two studies have also employed this method in assessing bone grafts, suggesting that it may be a useful method to monitor graft metabolism and incorporation (62, 63).

18F-Fluorodeoxyglucose

Accumulation of FDG is not speciﬁc to malignant cells, and observation of increased uptake into activated inﬂammatory cells (70, 71) has led to its use in the detec- c

Figure 21.7. Contd. (c) demonstrate pathologic uptake in both femora, the left proximal humerus, T4, and L5 (the left iliac crest is not visible on these slices).

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d

e f

Figure 21.7. Contd. FDG-PET/CT images show the intramedullary location of sites of disease in the femora and left humerus (d), an active lytic lesion in the right pedicle of T4 (e), and an intramedullary lesion in the left anterior iliac crest (f)

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tion of infection in humans (72). Early reports suggest that this application may be particularly successful in the skeleton (73, 74). Increased uptake of FDG occurs in both acute and chronic osteomyelitis (Figure 21.8), but care is required in image interpretation following surgical intervention when nonspeciﬁc uptake may be seen (75–78).

There is increasing evidence that FDG-PET may be helpful in assessing painful prostheses, although there is the potential for false-positive interpretation for infection if close attention is not paid to the pattern of uptake in painful hip prostheses (79–81). Here it has been suggested that a pattern of uptake in the interface between the prosthesis and bone is more predictive of infection than uptake around the head or neck of the prosthesis (82).

Accuracy has been reported as being better for hip pros- thetic infection compared to knee prostheses (83) (Figure 21.9).

It has been noted that increased uptake of FDG may also be seen in Paget’s disease, particularly in patients with more active disease as measured by serum alkaline phosphatase levels (84) (Figure 21.10). As the majority of patients with Paget’s disease are asymptomatic and may be unaware of the disease, there is the possibility of an oc- casional false-positive scan in patients being staged for cancer. Although osteosarcoma is only a rare complica- tion of Paget’s disease, the efﬁcacy of FDG-PET for differ-

entiating this tumor from benign pagetic changes may be diminished.

Conversely, it does not appear that benign degenerative disease in the spine or elsewhere causes uptake of FDG that would be mistaken for metastatic deposits, but uptake may be seen in inﬂammatory joint disease, particularly in the shoulder where uptake is assumed to be caused by inﬂammatory capsulitis or tendonitis. FDG- PET has been found to be very reliable in differentiating degenerative and infective vertebral endplate abnormalities detected on MRI, with no false positives or false nega- tives reported in one series of 30 patients (85). In the detection of bone metastases a potential false positive is caused by recent fractures (86–89). It has been suggested that measurement of SUV may help differentiate benign from pathologic malignant fractures. In a series of 20 patients, it was found that the mean SUV in those with benign fractures was 1.36 ± 0.49 whereas those with pathologic fractures had a mean SUV of 4.46 ± 2.12 (88).

It has been noted that it is rare for FDG uptake to persist longer than 3 month after trauma (89).

18F-Fluoromisonidazole

There is a limited literature on the potential use of this hypoxia selective tracer in skeletal infection. Its accumulation has been described in situations that commonly involve infection by anaerobic organisms, such as diabetic foot infection and osteomyelitis, as well as in odontogenic disease (10, 11).

Conclusion

The role for PET imaging of the skeleton is evolving. It is possible that ¹⁸F-ﬂuoride PET may have incremental value in detecting bone metastases over conventional bone scintigraphy, but this has yet to be established. A role may also exist for quantitative studies using ¹⁸F-ﬂuoride PET for research or clinical applications where there is a need to quantify regional skeletal metabolism.

FDG-PET is highly sensitive for detecting skeletal metastases in most cancers, and it is possible that the use of conventional bone scintigraphy may diminish as FDG- PET is used more routinely for cancer staging. There is a developing role for the use of this method also in primary bone tumors and in the detection of infection related to the skeleton.

g

Figure 21.7. Contd. and the left humerus (g).

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a

b

Figure 21.8. A 40-year-old woman with a previous history of osteomyelitis of the right foot complained of recurrent swelling and pain in the foot. FDG-PET (a) shows a focus of abnormal uptake in the right foot, localized to the second right metatarsal on the PET/CT images (b), consistent with recurrent osteomyelitis.

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a Figure 21.9. A 28-year-old woman with a left total hip replacement following an osteogenic sarcoma in childhood complained of pain related to the prosthesis.

Coronal FDG-PET images with attenua- tion correction (a),

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b

Figure 21.9. Contd. and without atten- uation correction (b) show foci of ab- normal uptake surrounding both the acetabular and femoral components of the prosthesis, consistent with infection.

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References

1. Blau M, Nagler W, Bender MA. A new isotope for bone scanning. J Nucl Med 1962;3:332–334.

2. Bang S, Baud CA. Topographical distribution of ﬂuoride in iliac bone of a ﬂuoride-treated osteoporotic patient. J Bone Miner Res 1990;5:S87–S89.

3. Wootton R, Dore C. The single-passage extraction of ¹⁸F in rabbit bone. Clin Phys Physiol Meas 1986;7:333–343.

4. Piert M, Zittel TT, Machulla, HJ et al. Blood ﬂow measurements with [(15)O]H₂O and [18F]ﬂuoride ion PET in porcine vertebrae. J Bone Miner Res 1998;13:1328–1336.

5. Blake GM, Park-Holohan SJ,Cook GJR, Fogelman I. Quantitative studies of bone using ¹⁸F-ﬂuoride and ^99mTc-methylene diphosphonate. Semin Nucl Med 2001;31:28–49.

6. Warburg O. On the origin of cancer cells. Science 1954;123:306–314.

7. Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med 1995;36:1625–1632.

8. Yamamoto T, Seino Y, Fukumoto H, et al. Overexpression of facili- tative glucose transporter genes in human cancer. Biochem Biophys Res Commun 1990;170:223–230.

9. Nunn A, Linder K, Strauss HW. Nitroimidazoles and imaging hypoxia. Eur J Nucl Med 1995;22:265–280.

bi bii

ai aii

Figure 21.10.^99mTc-MDP bone scan (a) demonstrates Paget’s disease in the left femur and in the upper thoracic spine; increased activity is also shown on a FDG-PET scan (b).

(18)

14. Hoegerle S, Juengling F, Otte A, et al. Combined FDG and [F- 18]ﬂuoride whole-body PET: a feasible two-in-one approach to cancer imaging? Radiology 1998;209:253–258.

15. Petren-Mallmin M, Andreasson I, Ljunggren, et al. Skeletal metastases from breast cancer: uptake of 18F-ﬂuoride measured with positron emission tomography in correlation with CT. Skeletal Radiol 1998;27:72–76.

16. Schirrmeister H, Guhlmann A, Kotzerke J, et al. Early detection and accurate description of extent of metastatic bone disease in breast cancer with ﬂuoride ion and positron emission tomography. J Clin Oncol 1999;17:2381–2389.

17. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus ¹⁸F PET. J Nucl Med 1999;40:1623–1629.

18. Schirrmeister H, Glatting G, Hetzel J, et al. Prospective evaluation of the clinical value of planar bone scans, SPECT and (18)F-labeled NaF PET in newly diagnosed lung cancer. J Nucl Med 2001;42:1800–1804.

19. Hetzel M, Arslandemir C, Konig HH, et al. F-18 NaF PET for detection of bone metastases in lung cancer: accuracy, cost-effectiveness and impact on patient management. J Bone Miner Res 2003;18:2206–2214.

20. Even-Sapir E, Metser U, Flusser G, et al. Assessment of malignant skeletal disease: initial experience with ¹⁸F-fluoride PET/CT and comparison between ¹⁸F-fluoride PET and ¹⁸F-fluoride PET/CT. J Nucl Med 2004;45:272–278.

21. Bury T, Barreto A, Daenen F, Barthelemy N, Ghaye B, Rigo P.

Fluorine-18 deoxyglucose positron emission tomography for the detection of bone metastases in patients with non-small cell lung cancer. Eur J Nucl Med 1998;25:1244–1247.

22. Cheran SK, Herndon JE, Patz EF. Comparison of whole-body FDG- PET to bone scan for detection of bone metastases in patients with a new diagnosis of lung cancer. Lung Cancer 2004;44:317–325.

23. Hsia TC, Shen YY, Yen RF, et al. Comparing whole body ¹⁸F-2-deoxyglucose positron emission tomography and technetium-99m methylene diphsophonate bone scan to detect bone metastases in patients with non-small cell lung cancer. Neoplasma 2002;49:267–271.

24. Chung JK, Kim YK, Yoon JK, et al. Diagnostic usefulness of F-18 FDG whole body PET in detection of bony metastases compared to

99mTc-MDP bone scan. J Nucl Med 1999;40:96P.

25. Moon DH, Maddahi J, Silverman DH, Glaspy JA, Phelps ME, Hoh CK. Accuracy of whole-body ﬂuorine-18-FDG PET for the detection of recurrent or metastatic breast carcinoma. J Nucl Med 1998;

39:431–435.

26. Gallowitsch HJ, Kresnik E, Gasser J, et al. F-18 ﬂuorodeoxyglucose positron emission tomography in the diagnosis of tumour recur- rence and metastases in the follow-up of patients with breast carcinoma: a comparison to conventional imaging. Invest Radiol 2003;38:250–256.

27. Cook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastases in breast cancer by FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol 1998;16:3375–3379.

28. Shreve PD, Grossman HB, Gross MD, et al. Metastatic prostate cancer: initial ﬁndings of PET with 2-deoxy-2-[F-18]ﬂuoro-D- glucose. Radiology 1996;199:751–756.

33. Carr R, Barrington SF, Madan B, et al. Detection of lymphoma in bone marrow by whole-body positron emission tomography. Blood 1998;91:3340–3346.

34. Moog F, Bangerter M, Kotzerke J, et al. 18-F-Fluorodeoxyglucose- positron emission tomography as a new approach to detect lym- phomatous bone marrow. J Clin Oncol 1998;16:603–609.

35. Cook GJ, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18-ﬂuoro-2-deoxyglucose positron- emission tomography scanning: potential for error in interpretation. Semin Nucl Med 1996;26:308–314.

36. Hollinger EF, Alibazoglu H, Ali A, et al. Hematopoietic cytokine- mediated FDG uptake simulates the appearance of diffuse metastatic disease on whole-body PET imaging. Clin Nucl Med 1998;23:93–98.

37. Jadvar H, Conti PS. Diagnostic utility of FDG PET in multiple myeloma. Skeletal Radiol 2002;31:690–694.

38. Orchard K, Barrington S, Buscombe J, et al. Fluoro-deoxyglucose positron emission tomography for the detection of occult disease in multiple myeloma. Br J Haematol 2002;117:133–135.

39. Wu HC, Yen RF, Shen YY, et al. Comparing whole body ¹⁸F-2-de- osxyglucose positron emission tomography and technetium-99m methylene diphosphonate bone scan to detect bone metastases in patients with renal cell carcinomas: a preliminary report. J Cancer Res Clin Oncol 2002;128:503–506.

40. Daldrup-Link HE, Franzius C, et al. Whole-body MR imaging for detection of bone metastases in children and young adults: comparison with skeletal scintigraphy and FDG PET. Am J Roentgenol 2001;177:229–236.

41. Metser U, Lerman H, Blank A, et al. Malignant involvement of the spine: assessment by ¹⁸F-FDG PET/CT. J Nucl Med 2004;45:279–284.

42. Stafford SE, Gralow JR, Schubert EK, et al. Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy.

Acad Radiol 2002;9:913–921.

43. Eary JF, Conrad EU, Bruckner JD, et al. Quantitative [F- 18]ﬂuorodeoxyglucose positron emission tomography in pretreat- ment and grading of sarcoma. Clin Cancer Res 1998;4:1215–1220.

44. Eary JF, Mankoff DA. Tumor metabolic rates in sarcoma using FDG PET. J Nucl Med 1998;39:250–254.

45. Kern KA, Brunetti A, Norton JA, et al. Metabolic imaging of human extremity musculoskeletal tumors by PET. J Nucl Med 1988;29:181–186.

46. Adler LP, Blair HF, Makley JT, et al. Noninvasive grading of musculoskeletal tumors using PET. J Nucl Med 1991;32:1508–1512.

47. Kole AC, Nieweg OE, Hoekstra HJ, et al. Fluorine-18- ﬂuorodeoxyglucose assessment of glucose metabolism in bone tumors. J Nucl Med 1998;39:810–815.

48. Lodge MA, Lucas JD, Marsden PK, et al. A PET study of ¹⁸FDG uptake in soft tissue masses. Eur J Nucl Med 1999;26:22–30.

49. Brenner W, Conrad EU, Eary JF. FDG PET imaging for grading and prediction of outcome in chondrosarcoma patients. Eur J Nucl Med Mol Imaging 2004;31:189–195.

50. Franzius C, Bielack S, Flege S, Sciuk J, Jurgens H, Schober O.

Prognostic signiﬁcance of (18)F-FDG and (99m)Tc-methylene diphosphonate uptake in primary osteosarcoma. J Nucl Med 2002;43:1012–1017.

51. Franzius C, Sciuk J, Daldrup-Link HE, Jurgens H, Schober O. FDG- PET for detection of osseous metastases from malignant primary

(19)

bone tumours: comparison with bone scintigraphy. Eur J Nucl Med 2000;27:1305–1311.

52. Schulte M, Brecht-Krauss D, Werner M, et al. Evaluation of neoadjuvant therapy response of osteogenic sarcoma using FDG PET. J Nucl Med 1999;40:1637–1643.

53. Jones DN, McCowage GB, Sostman HD, et al. Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using ﬂuorine-18-FDG PET. J Nucl Med 1996 37:1438–1444.

54. Bredella MA, Caputo GR, Steinbach LS. Value of FDG positron emission tomography in conjunction with MR imaging for evaluat- ing therapy response in patients with musculoskeletal sarcomas.

AJR Am J Roentgenol 2002;179:1145–1150.

55. Hawkins DS, Rajendran JG, Conrad EU, Bruckner JD, Eary JF.

Evaluation of chemotherapy response in pediatric bone sarcomas by [F-18]-ﬂuorodeoxy-D-glucose positron emission tomography.

Cancer (Phila) 2002;94:3277–3284.

56. Garcia R, Kim EE, Wong FC, et al. Comparison of ﬂuorine-18-FDG PET and technetium-99m-MIBI SPECT in evaluation of musculoskeletal sarcomas. J Nucl Med 1996;37:1476–1479.

57. Cook GJR, Lodge MA, Blake GM, Marsden PK, Fogelman I.

Differences in skeletal kinetics between vertebral and humeral bone measured by ¹⁸F-ﬂuoride PET in postmenopausal women. J Bone Miner Res 2000;15:763–769.

58. Frost ML, Fogelman I, Blake GM, Marsden PK, Cook GJR.

Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis. J Bone Miner Res 2004;19:1797–1804.

59. Messa C, Goodman WG, Hoh CK, et al. Bone metabolic activity measured with positron emission tomography and [¹⁸F]ﬂuoride ion in renal osteodystrophy: correlation with bone histomorphometry.

J Clin Endocrinol Metab 1993;77:949–955.

60. Schiepers C, Nuyts J, Bormans G, et al. Fluoride kinetics of the axial skeleton measured in vivo with ﬂuorine-18-ﬂuoride PET. J Nucl Med 1997;38:1970–1976.

61. Schiepers C, Broos P, Miserez M, et al. Measurement of skeletal ﬂow with positron emission tomography and ¹⁸F-ﬂuoride in femoral head osteonecrosis. Arch Orthop Trauma Surg 1998;118:131–135.

62. Berding G, Burchert W, van den Hoff J, et al. Evaluation of the incorporation of bone grafts used in maxillofacial surgery with [¹⁸F]ﬂuoride ion and dynamic positron emission tomography. Eur J Nucl Med 1995;22:1133–1140.

63. Piert M, Winter E, Becker GA, et al. Allogeneic bone graft viability after hip revision arthroplasty assessed by dynamic [¹⁸F]ﬂuoride ion positron emission tomography. Eur J Nucl Med 1999;26:615–624.

64. Renkin EM. Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 1959;197:1205–1210.

65. Piert M, Zittell TT, Machulla HJ, et al. Blood ﬂow measurements with [¹⁵O]H2O and [¹⁸F]ﬂuoride ion PET in porcine vertebrae. J Bone Miner Res 1998;13:1328–1336.

66. Cook GJ, Maisey MN, Fogelman I. Fluorine-18-FDG PET in Paget’s disease of bone. J Nucl Med 1997;38:1495–1497.

67. Fogelman I, Martin W. Assessment of skeletal uptake of 99mTc- diphosphonate over a ﬁve day period. Eur J Nucl Med 1983;8:489–490.

68. Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determi- nant of osteoporosis. J Bone Miner Res 1996;11:337–349.

69. Frost ML, Cook GJ, Blake GM, Marsden PK, Benatar NA, Fogelman I.

A prospective study of risedronate on regional bone metabolism and blood ﬂow at the lumbar spine measured by ¹⁸F-ﬂuoride positron emission tomography. J Bone Miner Res 2003;18:2215–2222.

70. Yamada S, Kubota K, Kubota R, et al. High accumulation of fluorine- 18-fluorodeoxyglucose in turpentine-induced inflammatory tissue.

J Nucl Med 1995;36:1301–1306.

71. Kubota R, Kubota K, Yamada S, et al. Methionine uptake by tumor tissue: a microautoradiographic comparison with FDG. J Nucl Med 1995;36:484–492.

72. Sugawara Y, Braun DK, Kison PV, et al. Rapid detection of human infections with ﬂuorine-18 ﬂuorodeoxyglucose and positron emission tomography: preliminary results. Eur J Nucl Med 1998;25:1238–1243.

73. Zhuang H, Yu JQ, Alavi A. Applications of ﬂuorodeoxyglucose-PET imaging in the detection of infection and inﬂammation and other benign disorders. Radiol Clin N Am 2005;43:121–134.

74. Crymes WB, Demos H, Gordon L. Detection of musculoskeletal infection with ¹⁸F-FDG PET: review of the current literature. J Nucl Med Technol 2004;32:12–15.

75. Zhuang T, Duarte PS, Pourdehand M, et al. Exclusion of chronic osteomyelitis with F-18 ﬂuorodeoxyglucose PET imaging. Clin Nucl Med 2000;25:281–284.

76. Kalicke T, Schmitz A, Risse JH, et al. Fluorine-18 ﬂuorodeoxyglu- cose PET in infectious bone diseases: results of histologically conﬁrmed cases. Eur J Nucl Med 2000;27:524–528.

77. Guhlmann A, Brecht-Krauss D, Suger G, et al. Fluorine-18-FDG PET and technetium-99m antigranulocyte antibody scintigraphy in chronic osteomyelitis. J Nucl Med 1998;39:2145–2152.

78. Guhlmann A, Brecht-Krauss D, Suger G, et al. Chronic osteomyelitis: detection with FDG PET and correlation with histopathologic ﬁndings. Radiology 1998;206:749–754.

79. Stumpe KD, Notzli HP, Zanetti M, et al. FDG PET for differentiation of infection and aseptic loosening in total hip replacements:

comparison with conventional radiography and three-phase bone scintigraphy. Radiology 2004;231:333–341.

80. Vanquickenborne B, Maes A, Nuyts J, et al. The value of (18)FDG- PET for the detection of infected hip prosthesis. Eur J Nucl Med Mol Imaging 2003;30:705–715.

81. Schiesser M, Stumpe KD, Trentz O, Kossmann T, Von Schulthess GK. Detection of metallic implant-associated infections with FDG PET in patients with trauma: correlation with microbiologic results. Radiology 2003;226:391–398.

82. Chacko TK, Zhuang H, Stevenson K, Moussavian B, Alavi A. The importance of the location of ﬂuorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses. Nucl Med Commun 2002;23:851–855.

83. Zhuang H, Duarte PS, Pourdehnad M, et al. The promising role of

18F-FDG PET in detecting infected lower limb prosthesis implants. J Nucl Med 2001;42:44–48.

84. Cook GJ, Maisey MN, Fogelman I. Fluorine-18-FDG PET in Paget’s disease of bone. J Nucl Med 1997;38:1495–1497.

85. Stumpe KD, Zanetti M, Weishaupt D, Hodler J, Boos N, Von Schulthess GK. FDG positron emission tomography for differentiation of degenerative and infectious endplate abnormalities in the lumbar spine detected on MR imaging. AJR 2002;179:1151–1157.

86. Fayad LM, Cohade C, Wahl RL, Fishman EK. Sacral fractures: a potential pitfall of FDG positron emission tomography. AJR 2003;181:1239–1243.

87. Shon IH, Fogelman I. F-18 FDG positron emission tomography and benign fractures. Clin Nucl Med 2003;28:171–175.

88. Kato K, Aoki J, Endo K. Utility of FDG-PET in differential diagnosis of benign and malignant fractures in acute to subacute phase. Ann Nucl Med 2003;17:41–46.

89. Zhuang H, Sam JW, Chacko TK, et al. Rapid normalization of osseous FDG uptake following traumatic or surgical fractures. Eur J Nucl Med Mol Imaging 2003;30:1096–1103.