CONTINUING EDUCATION PET Imaging of Osteosarcoma*jnm.snmjournals.org/content/44/6/930.full.pdf ·...

CONTINUING EDUCATION

PET Imaging of Osteosarcoma*Winfried Brenner, MD, PhD1; Karl H. Bohuslavizki, MD, PhD2; and Janet F. Eary, MD1

1Division of Nuclear Medicine, University of Washington Medical Center, Seattle, Washington; and 2Department of NuclearMedicine, University Hospital Eppendorf, Hamburg, Germany

During the past decade the clinical value of PET imaging hasbeen investigated for many different tumors. As knowledge ofthe advantages and limitations of this modality increased, PEThas gained acceptance in tumor imaging. 18F-FDG PET is nowsuccessfully used and approved for procedure reimbursementin many types of cancer—for example, lung cancer, melanoma,lymphoma, head and neck tumors, brain tumors, esophagealcancer, and colorectal cancer. In osteosarcoma, the introduc-tion of neoadjuvant chemotherapy has dramatically improvedsurvival rates, thus changing the demands for state-of-the-artimaging to provide detailed information on tumor staging andgrading, evaluating treatment, and detecting recurrences. In thisreview, the available literature on PET imaging in osteosarcomapatients is critically summarized with respect to diagnosis, stag-ing, therapy monitoring, and follow-up focusing on the clinicallyused tracers 18F-FDG and 18F-fluoride ion. Potential and prob-able indications are outlined. Because of the relatively smallnumber of patients enrolled in clinical trials published to date,further research needs to be done in larger, prospective patientseries to determine the full utility of PET in osteosarcoma.

Key Words: osteosarcoma; 18F-FDG; 18F-fluoride ion; PET; met-abolic imaging

J Nucl Med 2003; 44:930–942

Despite the fact that osteosarcoma represents only 0.1%of all tumors, it is the second most frequent malignantprimary bone tumor after myeloma. The incidence has nosex- or race-based predilection and is estimated to be about2 or 3 per 106 persons. More than 80% of all cases presentin patients between 5 and 25 y of age. A second lower peakincidence occurs in the fifth and sixth decades (1). Etiolog-ically, osteosarcoma can be divided into 2 categories: pri-mary and secondary types. Primary osteosarcoma predom-inantly affects the metaphyseal portion of the long bones ofthe extremities, with approximately 30% of cases occurringin other skeletal locations (1). The fundamental nature of

osteosarcoma is yet unknown. In contrast, secondary osteo-sarcoma often arises in locations of Paget’s disease, fibrousdysplasia, and multiple chondromas or is associated withretinoblastoma. It is also observed after radiation therapy,with most of the cases developing within 7–15 y afterirradiation. Outcome is usually poor in secondary osteosar-coma as compared with primary osteosarcoma, and themajority of these tumors is located in the truncus, cranio-facial, or even extraskeletal (1).

CLASSIFICATION AND STANDARD DIAGNOSTICPROCEDURES

According to the clinical staging criteria of the UnionInternationale Contre le Cancer (UICC) in 1997, osteosar-coma patients are divided into 6 groups based on the TNMstage and histologic grading (Tables 1 and 2) (2). Althoughosteosarcoma is a heterogeneous disease with a large rangeof pathologic presentations (Table 3), at the time of primarydiagnosis as many as 75% of all patients are classified asclinical stage IIB. This presentation consists of a histologicgrade 3 or 4 with tumor extension to the periosteum withoutevidence of lymph node and distant metastases (Fig. 1)(1,3). However, in 80% of these patients occult metastasesmust be presumed on the basis of the experience in theprechemotherapy era that these patients will develop metas-tases within months, which are predominantly located in thelungs (Fig. 2). Moreover, osteosarcoma frequently metasta-sizes to second bone sites, which occurs in 10%–20% ofpatients with metastatic disease, whereas lymph node in-volvement is rarely seen. The prognosis of osteosarcomawas poor before the development of effective chemother-apy, with 80% of the patients dying within 2 y (4). Intro-duction of multiagent chemotherapy has improved survivalrates, reaching 60%–70% in recent years (4,5).

Because the therapeutic management of osteosarcoma aswell as treatment of recurrent disease has been significantlyimproved with aggressive chemotherapeutic regimens, ac-curate tumor staging and restaging after treatment havebecome increasingly important in osteosarcoma patients.The pretherapeutic diagnostic work-up usually starts withconventional radiography of the tumor-suspicious bone andsubsequent biopsy. The diagnosis of osteosarcoma is thenbased on characteristic histologic features in combinationwith typical radiographic findings. MRI of the entire sus-

Received Aug. 29, 2002; revision accepted Dec. 11, 2002.For correspondence or reprints contact: Winfried Brenner, MD, PhD, Divi-

sion of Nuclear Medicine, University of Washington Medical Center, 1959 N.E.Pacific St., P.O. Box 356113, Seattle, WA 98195-6113.

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pected bone is performed to define the degree of penetrationof the tumor surrounding soft tissue as well as to estimatethe local tumor infiltration into bone marrow (6–9). Arte-riography has been used for presurgical treatment planningto assess possible vascular involvement (10) but is usuallyreplaced by MRI and color-coded duplex sonography now-adays. Furthermore, CT of the chest and conventional bonescanning are necessary (5,11) because metastases of osteo-sarcoma are known for their early hematogenous spreadwith predilection for the lungs and the skeleton. Posttreat-ment follow-up imaging consists of radiography or CT ofthe chest in 6-mo intervals. This is especially importantbecause the treatment of lung metastases is still potentiallycurative by complete surgical resection of lung nodules.MRI and bone scanning are used to distinguish postopera-tive changes from residual or recurrent tumor tissue afterlocal surgical treatment. Because osteosarcoma metastasesusually incorporate bisphosphonates, bone scanning can beused for follow-up examinations to detect both osseous andnonosseous metastases.

TREATMENT AND OUTCOME

According to the Cooperative Osteosarcoma StudyGroup, the standardized therapeutic management of osteo-sarcoma includes neoadjuvant chemotherapy followed bywide resection of the primary tumor, which is still consid-ered the only reliable step to ensure local tumor control(4,12). Today, limb-sparing procedures are most often per-formed rather than amputations in patients with tumors ofthe limbs (13–15). However, as compared with ablative

surgical procedures, limb-sparing surgery itself has a 3- to5-fold increased risk of local relapse, which significantlyworsens prognosis (16,17). According to the data of theCooperative Osteosarcoma Study Group (3,18), the overallsurvival rate after 5 y is 68%, whereas prognosis of patientswith a local relapse deteriorates dramatically with a survivalrate after 5 y of only 21%. Therefore, effective multidrugpre- and postoperative chemotherapy is mandatory to re-duce the risk of local relapse. Preoperative, neoadjuvantchemotherapy, however, also provides an important prog-nostic factor in osteosarcoma because a greater degree ofdrug-induced tumor necrosis is associated with a signifi-cantly higher survival rate (12,18). Necrosis of �90% of thetumor mass is considered as a good therapy response. More-over, chemotherapy treats potential metastatic spread. Afteradjuvant chemotherapy, fewer lung metastases have beenobserved and the metastases appear later than in the pre-chemotherapy era. Combined treatment protocols increaseddisease-free and overall survival rates after 5 y in patientswith no detectable metastases initially from 20% in the caseof surgery only to 60%–70% with the use of neoadjuvantchemotherapy (3,4). Because osteosarcoma is relatively re-sistant to radiation therapy, this treatment modality is usedmainly in inoperable tumors or when a complete surgicalresection cannot be achieved, as may be the case in tumorsof the spine. Patients with tumor relapse usually have lungmetastases only. As long as these metastases are completelyresectable by surgical metastasectomy, there is still a 20%–

TABLE 1Histologic Tumor Grading of Osteosarcoma

Tumor grade Tumor differentiation

G1 Well differentiatedG2 Moderately differentiatedG3 Poorly differentiatedG4 UndifferentiatedGx Not assessable

TABLE 2Clinical Staging of Osteosarcoma Based

on Tumor Grade and TNM

Tumor grade TNM Clinical stage

G1,G2 T1 N0 M0 IAG1,G2 T2 N0 M0 IBG3,G4 T1 N0 M0 IIAG3,G4 T2 N0 M0 IIBAny G Any T, N1 M0 IVAAny G Any T, any N, M1 IVB

Stage III is not defined.

TABLE 3Classification of Osteosarcoma

Classification %

Primary high-grade, intramedullary 75Mixed pattern (73%)Bone rich/sclerosing (9%)Cartilage rich (5%)Spindle cell richMalignant histiocyte richTelangiectaticSmall cell rich (Ewing-like)Benign giant cell richEpitheloid cell rich

Primary low-grade, intramedullary 4–5Fibrous dysplasia-like (50%)Nonossifying fibroma-like (25%)Osteoblastoma-like (15%)Chondromyxoid fibroma-like (10%)

Secondary intramedullary 6Multifocal 1–2Intracortical 0.2Juxtacortical 7–10

Parosteal (65%)Periosteal (25%)High-grade surface (10%)

Osteosarcoma of jaw 6

Classification according to Mirra (1).

PET IMAGING OF OSTEOSARCOMA • Brenner et al. 931



50% chance of cure in selected cases (19). Therefore, earlydetection of small lung metastases is one of the most chal-lenging and critical tasks in the follow-up of osteosarcomapatients.

PET

Because both the management and the outcome of osteo-sarcoma have been improved by the introduction of reliablestaging systems (Table 4) as a basis for adequate therapy(20,21), sophisticated diagnostic procedures are importantto ensure accurate tumor staging and restaging. Therefore,

apart from conventional, well-standardized anatomic imag-ing procedures, metabolic PET imaging became the focus ofongoing research by assessing its potential utility in sar-coma patients (22)—for example, for determining the met-abolic rates of osteosarcoma (23–28), monitoring of neoad-juvant therapy response (29–32), and differentiating viablesarcoma from posttreatment changes (33–36). The mostwidely used PET tracer for osteosarcoma is 18F-FDG. Theother clinical PET tracer with reported utility for osteosar-coma imaging in patients is 18F-fluoride ion (18F), whereas18F-labeled monoclonal antibodies (37), 18F-fluoromi-

FIGURE 1. Maximum intensity projec-tions of truncus and extremities of patientwith primary high-grade mixed pattern os-teosarcoma of left humerus. Intense traceraccumulation of 18F-FDG is evident at pri-mary tumor site with second focus of lessuptake (arrow) above, suggesting a skipmetastasis. LAO � left anterior oblique;RAO � right anterior oblique.

FIGURE 2. Maximum intensity projec-tions of truncus of patient after therapy ofosteosarcoma of right tibia and newly di-agnosed small lung mass detected by con-ventional radiography in follow-up study.Focal accumulation of 18F-FDG in right api-cal lobe (arrow) confirms viable tumor tis-sue. LAO � left anterior oblique; RAO �right anterior oblique.




sonidazole (38), 18F-labeled RGD-containing glycopeptide(39,40), 3H-thymidine (38), 13N-methionine (41), and PETof p53 transcriptional activity in osteosarcoma (42) havebeen used only in animal studies.

18F-FDG

Physiology18F-FDG is the most widely used PET tracer in oncology

and the most commonly used tracer for osteosarcoma im-aging (Figs. 3, 4, and 5). 18F-FDG PET studies produceimages that represent the rate of glycolysis in tissues: Theglucose analog 2-18F-FDG undergoes membrane transportand phosphorylation by hexokinase to 18F-FDG-6-phos-phate similar to the pathway of glucose metabolism toglucose-6-phosphate. However, whereas glucose-6-phos-phate is metabolized in the normal glycolysis pathway,18F-FDG-6-phosphate is not a substrate for further metabo-lism. Because 18F-FDG is not able to diffuse back across thecell membrane after phosphorylation nor can phosphoryla-tion be reversed to a significant extent, 18F-FDG is trappedin the cell in proportion to the rate of glycolysis. This

metabolic pathway enables 18F-FDG to be used for quanti-tative metabolic imaging. Common quantitative proceduresfor 18F-FDG imaging in tumor (27) are the standard uptakevalue (SUV) (43), graphical analysis (44–46), and nonlin-ear regression analysis based on a 3-compartment model for18F-FDG (47). The tumor SUV is a semiquantitative param-eter that represents the metabolic activity in a static imageas measured by region-of-interest (ROI) technique and cor-rected for both the injected activity per kilogram of bodyweight and the blood glucose level. Two different types ofSUV are known that represent different biologic informa-tion. The average tumor SUV is the mean of all pixel-relatedSUV values within an ROI as a statistical measure of tumormetabolism in general. However, in heterogeneous tumorssuch as osteosarcoma, the maximum SUV—that is, thehighest single SUV value within an ROI—is thought to bemore reliable to describe biologic features because the high-est uptake areas determine tumor grade. Patlak analysis andthe more sophisticated nonlinear regression analysis allowtrue quantitative calculation of kinetic parameters but re-

FIGURE 3. Coronal (A), transverse (B), and sagittal (C) projec-tions of telangiectatic high-grade osteosarcoma in right distalfemur. Initial 18F-FDG SUV was 6.5 in this rather homogeneoustumor.

TABLE 4Surgical Staging System by Enneking et al. (20)

Tumorgrade Tumor site Stage

Low Intracompartmental* IALow Extracompartmental† IBHigh Intracompartmental IIAHigh Extracompartmental IIBLow or high Metastasis (regional or distant) III

*Intramedullary without breaching cortex.†Tumor extends beyond cortex.Only 2 tumor grades are used, either high or low.

FIGURE 4. Coronal (A) and transverse (B) projections of pri-mary high-grade, mixed-pattern osteosarcoma in right proximalhumerus. Pretherapeutic maximum SUV was 16.2 in this largeand inhomogeneous tumor with low 18F-FDG uptake in tumorcenter. According to high SUV, overall survival in patient waspoor.

FIGURE 5. Coronal (A) and transverse (B) projections of smallperiosteal osteosarcoma in right distal fibula reveal initial 18F-FDG SUV of 1.6.




quire dynamic PET in combination with arterial or venousblood sampling.

First Imaging StudiesBecause glycolysis is enhanced in most malignancies,

inflammatory lesions, and some benign tumors, 18F-FDGhas been widely used for tumor imaging. In the 1980s, when18F-FDG PET studies began to focus on oncology, a reportwas published on the usefulness of 18F-FDG in osteosar-coma imaging. In 1988, Kern et al. (22) successfully imaged4 patients with soft-tissue tumors and 1 patient with anosteogenic tumor using 18F-FDG PET. Although the numberof patients was very small in this study, the highest 18F-FDGuptake values were found in high-grade tumors. Similarfindings were reported by Adler et al. in 1991 (23) for 25patients with musculoskeletal tumors including 2 patientswith osteosarcoma. In grade 3 tumors, 18F-FDG uptake wassignificantly higher than in grade 1 tumors or benign le-sions, demonstrating a positive correlation (r � 0.83) oftumor grade and 18F-FDG uptake. In 1993, Hoh et al. (48)successfully detected tumor lesions with intense 18F-FDGuptake in 3 of 4 osteosarcoma patients. In 1 patient withrecurrent disease at the resected primary site, the 18F-FDGstudy was negative. That lesion, however, consisted ofalmost entirely necrotic tissue and contained only micro-scopic foci of tumor.

Thus, these early PET studies already demonstrated thefeasibility of detecting osteosarcoma with 18F-FDG and laidthe basis for further investigations. Osteosarcomas gener-ally showed intense 18F-FDG uptake. Semiquantitative find-ings suggested a correlation of tumor 18F-FDG uptake andhistologic grading, whereas normal bone was characterizedby relatively low 18F-FDG uptake. Subsequent studies de-scribing tumor 18F-FDG PET in osteosarcoma patients in-vestigated the impact of this imaging modality on tumorgrading, staging (i.e., diagnosis of tumor presence and ex-tension as well as metastatic spread), therapy monitoring,and detection of recurrences during follow-up.

Osteosarcoma Tumor GradingMany publications on the use of 18F-FDG PET in osteo-

sarcoma patients describe tumor uptake as a measure ofmetabolic activity and, thus, of tumor grade. Early studiesby Kern et al. (22) and Adler et al. (23) reported higheruptake values in high-grade tumors. In short, all of thepublished papers show a correlation of histologic grading ortumor aggressiveness with 18F-FDG uptake, measured astumor-to-background ratio (TBR), SUV, or kinetic model-ing analysis results. However, at present, the published18F-FDG imaging results do not suggest avoiding tumorbiopsy to differentiate benign from malignant lesions be-cause of overlaps in 18F-FDG uptake in both processes. Toour knowledge, only 1 publication so far has shown nocorrelation between the metabolic rate of glucose consump-tion and the biologic aggressiveness, making it impossibleto differentiate between benign and malignant bone tumors(49). Both the SUV and the Patlak-derived metabolic rate of

FDG (MRFDG) showed a wide overlap between 19 malig-nant and 7 benign bone tumors (the mean maximum SUV inmalignant tumors ranged from 2.93 to 16.06 vs. 2.23–12.27in benign tumors). However, in this study by Kole et al. (49)2 observations are quite interesting: First, osteosarcomaswith low MRFDG responded poorly to subsequent chemo-therapy, whereas 1 patient with a high MRFDG respondedwell; and, second, osteosarcomas revealed relatively lowMRFDG as compared with malignant fibrous histiocytoma orlymphoma.

This is in contrast to the findings of Eary et al. (26), whoreported that osteosarcomas displayed the highest MRFDG

values beside the malignant fibrous histiocytoma. Thus, therelatively low MRFDG values, at least in the case of osteo-sarcoma, might be an explanation for the poor correlationbetween tumor uptake and grading observed by Kole et al.(49). Also, in contrast to the findings of Kole et al., Griffethet al. (50) could correctly separate 10 malignant from 10benign lesions of soft-tissue masses by measuring tumoruptake ratios. In line with these findings, Dehdashti et al.(51) were able to define intraosseous lesions in 25 patientsas either benign or malignant in all cases but one using acutoff SUV value of 2.0.

Several papers on tumor grading of bone and soft-tissuesarcomas by means of quantitative 18F-FDG PET werepublished by Eary et al. (24,26), Eary and Mankoff (52),and Folpe et al. (53). Despite a high correlation of the SUVand the Patlak-derived metabolic rate of 18F-FDG with acorrelation coefficient of 0.94 in 42 soft-tissue and bonysarcomas (52), MRFDG was more sensitive for determiningtumor grade in a subsequent study (26). Although an over-lap between the different groups of histologic grade wasfound with a wide range of variability in MRFDG within anyone group, the mean MRFDG values for the different groupswere significantly different in 70 patients with bone (13osteosarcomas) or soft-tissue sarcoma. Highly metaboli-cally active tumors with a low histologic grade may be thereason for the clinical experience that there is a subset oftumors in which the histologic grade does not predict out-come. In a recent paper, Eary et al. (24) proved the baselinemaximum tumor SUV as an independent and significantpredictor of overall survival by means of multivariate anal-ysis in 209 patients with different types and grades ofsarcoma (52 patients with osteogenic sarcoma). The P val-ues for the baseline maximum SUV were even lower thanfor histologic tumor grades, showing a higher significanceof baseline SUV for prediction of outcome as comparedwith conventional tumor grading. The authors, therefore,suggest performance of quantitative 18F-FDG PET becauseof its additional clinical information (Fig. 4).

Another important result is that often a marked hetero-geneity of 18F-FDG tumor uptake was observed, with areasof high metabolic activity often in the peripheral tumor parts(26). This information on tumor biology, provided by noother radiologic imaging modality, may be important toguide biopsy, because the highest grade areas determine the




histologic tumor grade and predict outcome. The accuracyof tumor diagnosis and histologic grading may suffer fromsampling error, particularly in large, heterogeneous tumors(Fig. 6). Non-PET–guided biopsy might miss the mostbiologically significant region, resulting in a false low pre-therapeutic tumor grading. In another study of the Earygroup, Folpe et al. (53) investigated the relationship of18F-FDG PET values and pathologic features in 89 patientswith soft-tissue tumors or osteosarcoma: They found asignificant positive correlation between the tumor SUV andthe histopathologic grade, tumor cellularity, Ki-67 labelingand mitotic activity, and overexpression of p53. Becausethese parameters, either independent or nonindependentpredictors of outcome, are associated with higher tumorgrade, shortened overall survival, and development of dis-tant metastases, the results suggest a significant role forquantitative 18F-FDG PET in the management of sarcomapatients in terms of reliably separating low-grade tumorsthat are usually treated by surgery from intermediate orhigh-grade sarcoma that undergo preoperative neoadjuvantchemotherapy. The 18F-FDG tumor uptake values can beused as pathologic surrogates obtained noninvasively. How-ever, Folpe et al. (53) pointed out some limitations of18F-FDG PET. Because of the wide overlap of SUV values,although the mean group values are significantly different,PET is not able to distinguish between grade II and IIItumors. Furthermore, some benign highly cellular and pro-liferative tumors, such as giant cell tumor of bone, havehigher SUV values than grade I sarcomas. Their conclusion,therefore, is that PET scans will not obviate the need forbiopsy and tissue diagnosis in soft-tissue and bone masses,whereas PET is helpful to guide biopsy.

Similar results stressing the heterogeneity of tumor up-take reflecting different tumor activity areas and necrosisare reported by Lodge et al. (27), who studied the kinetics of18F-FDG tumor uptake over time using the SUV, Patlakanalysis, and nonlinear regression analysis to measure 18F-FDG tumor concentrations in benign and malignant soft-tissue masses. The most important result of this study is thedifference in time–activity curves between high-grade sar-comas, reaching the peak tumor activity as late as 4 h after18F-FDG injection, and benign and low-grade tumors, witha peak activity within the first 30 min after injection. TheSUV measured at 4 h after injection was as useful asMRFDG, reaching a sensitivity of 100% and a specificity of76% for the detection of high-grade sarcomas, whereasneither quantitative approach was able to distinguish low-grade sarcomas from benign lesions, as already shown byother authors (23,52,53). In a line with the findings of Lodgeet al., Schulte et al. (54) reported on 202 patients with bonelesions, 44 of them with osteosarcoma, in whom a cutofflevel of 3.0 of the TBR yielded a sensitivity of 93% and aspecificity of 67% to detect malignancies. Again, the au-thors were not able to clearly differentiate aggressive benignlesions from low-grade malignant bone tumors. Using asimilar study setting, Aoki et al. (55) also observed a sig-nificant difference in the mean SUV between malignant anda wide variety of benign bone disorders in 52 patients.Although osteosarcomas presented relatively high SUV val-ues, giant cell tumors, fibrous dysplasia, sarcoidosis, andLangerhans cell histiocytosis reached the same high SUVlevels. Thus, a cutoff level of SUV could not be set to safelydistinguish between these benign lesions and osteosarcoma.As mentioned by the authors, a possible explanation for thehigh SUV values observed in these benign lesions is thecomposition of many of these lesions of either monocyte/macrophage–derived cells or fibroblasts, which are knownto have high levels of 18F-FDG metabolism. This finding isalso true for inflammatory lesions. As a consequence of high18F-FDG uptake levels in inflammation, Watanabe et al.(56) found high SUV values in sites of osteomyelitis. Theimaging studies showed a sensitivity of 100% and a speci-ficity of 77% for 18F-FDG PET in diagnosing malignantbone lesions with an accuracy of 83% using an SUV cutoffof 1.9. However, osteomyelitis and malignant bone tumorscould not be differentiated. Interestingly, in 18 bone lesions,the highest SUV values—even higher than in osteosar-coma—were observed in bone metastases.

Osteosarcoma Staging and RestagingAlthough 18F-FDG PET showed a very high sensitivity in

detecting primary osteosarcoma lesions (49,54,57), it is notconsidered a diagnostic tool to prove the presence of osteo-sarcoma. 18F-FDG PET, however, is gaining importance forinitial characterization of biologic features of osteosarcomain terms of tumor grading and treatment planning. Plainradiographs and MRI are the first-line diagnostic tools (10).MRI is the technique of choice for defining the intra- and

FIGURE 6. Coronal (A) and sagittal (B) projections of largeprimary high-grade chondroblastic osteosarcoma in right pelvis.Maximum SUV in tumor with heterogeneous 18F-FDG uptakewas 7.4.




extraosseous extent of a bone tumor (58). Only in children,there might be an indication for 18F-FDG PET to detectintraosseous skip metastases (59) in cases of unequivocalMRI findings due to the physiologic red blood marrowdistribution in the long bones in children, which may impairthe detection of bone metastases (10,60). These small le-sions can be missed by conventional bone scanning (61).However, up to now, no data are available to support thishypothesis as the basis for recommending 18F-FDG PET forthat indication.

Because lymph node metastases are very rare in osteo-sarcoma (1), the value of imaging modalities capable ofdetecting lymph node involvement is rather limited.

Clinical experience showed that in 80% of the patientswith no detectable metastases at the time of diagnosis,occult metastases must be presumed, which are predomi-nantly located in the lungs. Early detection of lung metas-tases, therefore, is important to improve survival becausethere is a real chance of cure by surgical metastasectomy.Today, the method of choice for detection of lung metasta-ses is spiral high-resolution CT and, because of this tech-nique, the number of lung metastases detected during initialstaging has almost doubled (4). Nevertheless, many of thesepresumed metastases have sizes in the submillimeter rangeand are not detectable. Another common problem is thedifferentiation of a single or few lung lesions as benignversus metastasis by CT, especially when lesions are rela-tively small. Schulte et al. (30) reported on lung metastasesdetection in 4 of 27 osteosarcoma patients with no false-positive or false-negative findings according to the CT data.These results suggest a 100% sensitivity and specificity for18F-FDG PET compared with CT but no superiority of PETwith regard to lung metastases. Similar findings were de-scribed by Lucas et al. (36) in soft-tissue sarcomas. How-ever, in this study, 18F-FDG PET as a whole-body imagingdevice was able to detect 13 other sites of metastases notshown by CT or MRI because of the limited body area ofscanning. Franzius et al. (62) compared the results of 32osteosarcoma patients with a total of 49 18F-FDG PET scanswith spiral CT: The sensitivity, specificity, and accuracy of18F-FDG PET for lung metastases was 50%, 100%, and92%, respectively; for CT the corresponding results were75%, 100%, and 96%. The conclusion of this study was thatthe sensitivity of 18F-FDG PET for lung metastases wasunsatisfactory, especially in small lesions of �9 mm. How-ever, similar to previous findings, 15 additional lesions(bone and soft-tissue metastases) were found by PET, whichwere not detected by conventional staging. These findingswere confirmed by a more recent paper from this group (63).

Osteosarcoma frequently metastasizes to secondary bonesites in 10%–20% of patients with metastatic disease. Dataon the benefit of 18F-FDG PET for detecting osseous me-tastases in osteosarcoma patients, however, are very sparsewith only few patients being imaged so far. Franzius et al.presented successful detection of all sites (n � 6) of boneinvolvement in a recent publication (63). This is in contra-

diction to their earlier study reporting that none of 5 me-tastases identified by bone scanning in osteosarcoma couldbe identified by 18F-FDG PET (64). In another study fromthis group that compared bone scanning, MRI, and 18F-FDGPET in children with primary bone tumors, there was only1 case presenting a single bone metastasis from osteosar-coma. This lesion showed no 18F-FDG uptake (65). Despitereports on increased sensitivity and specificity of 18F-FDGPET for detecting bone metastases in various cancers andsoft-tissue sarcomas compared with conventional bonescanning, 18F-FDG PET cannot be recommended for iden-tification of bone metastases in osteosarcoma patients on thebasis of the data provided so far.

For osteosarcoma metastases located outside the lungsand bones, no systematic data that compare 18F-FDG PETwith other imaging modalities are available. Only a fewcases have been reported (36,62,63). That might be due tothe fact that such metastases can be only detected by CT orMRI when they are located in the scanning field of interest.In contrast to this limitation of CT and MRI, whole-bodyimaging is considered the great advantage of 18F-FDG PETby several authors (30,36,62).

Therapy MonitoringResponse to preoperative neoadjuvant chemotherapy is

the most important prognostic factor in osteosarcoma be-cause the degree of drug-induced tumor necrosis is highlycorrelated with disease-free survival after therapy (12,18).Thus, a method that is capable of reliably predicting earlytumor response would be of great benefit both for assessingtherapeutic outcome and for minimizing ineffective chemo-therapy with all of its side effects. Because biochemicalchanges in tumor are thought to occur earlier in response totreatment than morphologic changes, functional imaginghas high clinical utility (Fig. 7). Radiologic methods thatdescribe morphologic changes have been shown to be oflimited value for prediction of chemotherapy response (66).In 2000, Messa et al. (58) stated that 18F-FDG PET is themethod of choice for therapy monitoring among all of theavailable nuclear medicine procedures in their commentaryon musculoskeletal neoplasms. In the few studies publishedso far (29,30,32,65,67,68), a positive correlation of FDGuptake and viable tumor tissue has been shown, suggesting18F-FDG PET as a tool for assessing the efficacy of neoad-juvant chemotherapy. Jones et al. (29) investigated theimpact of 18F-FDG PET in treatment monitoring of soft-tissue and musculoskeletal sarcoma in 9 patients, 3 of themwith high-grade osteosarcoma. They observed a 25%–50%reduction of the peak and average SUV 1–3 wk after initi-ation of neoadjuvant chemotherapy in tumors with �90%necrosis and concluded that 18F-FDG PET would be usefulin this clinical setting. However, 18F-FDG uptake was alsoobserved in immature granulation tissue and a fibrouspseudocapsule of a treated tumor, indicating that postthera-peutic tumor uptake represents not only viable tumor tissuebut also benign, reactive tissue, resulting in a potential




overestimation of the remainder of the osteosarcoma. Agood correlation between the decrease in posttherapeuticTBRs and the histologic extent of tumor necrosis was alsoreported by Schulte et al. (30) in 27 patients with osteosar-coma undergoing neoadjuvant chemotherapy. A reductionin TBR of �40% detected responders with an accuracy of92.6%, although the extent of TBR reduction did not pre-cisely predict the quantitative amount of tumor necrosis. Nofalse-positive results were obtained—that is, classifying ahistologically proven responder as a nonresponder becauseof elevated TBR due to inflammatory processes. Nair et al.(67) confirmed the value of serial 18F-FDG PET for predict-ing the percentage of tumor necrosis induced by neoadju-vant chemotherapy in a study of 16 osteosarcoma patients.However, similar to the findings of Schulte et al. (30), thepercentage change of serial TBR failed to predict a 90% orhigher rate of tumor necrosis. However, visual assessmentand TBR values of the presurgical, postchemotherapy scanswere accurate in 15 of 16 patients. Contrary to these find-ings, Franzius et al. (32) reported a good correlation be-tween tumor necrosis and 18F-FDG uptake measured as apercent reduction of tumor-to-nontumor ratios in 11 patientswith osteosarcoma. Using a threshold of a 30% decrease inthis ratio, good responders (�10% viable tumor cells) could

be distinguished from poor responders in all cases. How-ever, the value of this study is limited by the small numberof only 2 persons with poor response. Hawkins et al. (68)demonstrated a significant correlation between the drop inSUV and tumor necrosis but found an even more accurateassociation of low postchemotherapy SUV and good histo-logic response in 18 osteosarcoma patients. However, bothparameters were imperfect at clearly distinguishing a goodresponse (�90% necrosis) from an unfavorable response in16% and in 27% of the patients using postchemotherapySUV and the drop in SUV, respectively. One reason for thismay be increased 18F-FDG metabolism caused by inflam-matory infiltrates or reactive fibrosis within the respondingtumor. Another possible explanation is also discussed by theauthors. The histopathologic evaluation averages the per-centage of tumor necrosis across the entire resected tumorspecimen, whereas maximum SUV values within the tu-mors were used for this study, representing the most activetumor tissue regardless of the size. Thus, the drop in theaverage SUV of the whole tumor might be more useful thanthe maximum SUV to predict the amount of necrosis. How-ever, to predict outcome, the maximum SUV is thought tobe more precise in delineating areas of insufficient therapyresponse.

Although the number of patients is still relatively small,18F-FDG PET seems to reliably predict tumor response inneoadjuvant chemotherapy (69). This would be of particularinterest because CT and MRI do not always reflect thequantity of residual viable tumor. Gadolinium enhancementis also present in immature scar tissue and nonmalignantreactive tissue (10,70,71). Although a new dynamic con-trast-enhanced MRI technique has been shown to improvedifferentiation of viable osteosarcoma tissue from tumornecrosis and to early identify patients at risk of recurrence(72–74), the clinical benefit of this method has yet to beproven.

Local Tumor RecurrencesBesides the detection of newly developed metastases

summarized above in the Staging and Restaging section,differentiation of fibrosis and posttherapeutic tissue changesdue to healing from residual tumor tissue or local relapse isthe most challenging task in the follow-up of osteosarcomapatients (Fig. 8). Reviewing the role of nuclear medicine inprimary bone and soft-tissue tumors, Abdel-Dayem (69)considered 18F-FDG PET to be more accurate than CT orMRI in the follow-up of treated bone and soft-tissue sar-coma patients for differentiating fibrosis from recurrence.Most of the papers supporting this statement, however,describe imaging results relating to soft-tissue tumors. Gar-cia et al. (33) found 18F-FDG PET helpful in differentiatingactive musculoskeletal sarcomas from posttreatmentchanges as confirmed by histology or long-term follow-upin 48 patients including 18 patients with osteosarcoma,yielding an overall sensitivity and specificity of 98% and90%, respectively. el-Zeftawy et al. (75) reported similar

FIGURE 7. Therapy monitoring in patient with primary high-grade, mixed-pattern osteosarcoma of left femur. Initial preche-motherapy SUV (A) was 10.8 in this large and heterogeneoustumor. 18F-FDG PET before third cycle of chemotherapyshowed decreased SUV of 4.1 (B), which dropped further to 1.5at end of chemotherapy before surgical resection (C). Accordingto large drop in SUV, good tumor response was found with�5% viable cells.




findings in 20 patients with bone and soft-tissue tumors.They concluded that 18F-FDG PET, besides CT and MRI,proved to have additional impact on the clinical manage-ment of these patients in helping to differentiate postoper-ative change from local recurrence. Moreover, detection ofall local recurrences in 6 osteosarcoma patients has beenreported by Franzius et al. (63). 18F-FDG was false-positiveonly in 1 case. In the same patient group, MRI also detectedall 6 recurrences but revealed 2 false-positive results. In astudy by Lucas et al. (36), comparing MRI and 18F-FDGPET, on detection of local recurrences after amputation inpatients with sarcomas, MRI had a higher sensitivity of88.2% compared with 73.7% for PET. However, in osteo-sarcoma, MRI is often hampered by imaging artifacts afterimplantation of a metallic prosthesis (10). In these patients,18F-FDG PET is expected to be superior to MRI for detec-tion of local recurrences. Furthermore, Lucas et al. found 13other sites of metastases by 18F-FDG PET, suggesting thatCT of the chest, MRI of the tumor region, and whole-body18F-FDG PET are necessary to define accurately the extentof disease.

Conclusions and Future Perspectives of 18F-FDGIn studies reviewed above, it is not yet possible to draw

definite indications for 18F-FDG PET in osteosarcoma be-cause the number of studies and the number of enrolledpatients are too small. Furthermore, the methods used forthe different studies—for example, time of PET study be-fore or after intervention, imaging procedure, and method of

quantification—differ per study. Because osteosarcoma is arare tumor, multicenter trials using well-defined diagnosticand therapeutic settings seem to be the appropriate tool toincrease the data on 18F-FDG PET for the various consid-erable indications suggested so far.

Primary Staging. For the basic work-up of bone lesions,plain radiographs and MRI are the first-line diagnostic toolsfor description and definition of extent of a bone tumor.High-resolution CT has been shown to be superior to 18F-FDG PET for detecting lung metastases, and 18F-FDG PETalso cannot be recommended for the search of bone metas-tases in osteosarcoma patients on the basis of the dataprovided so far. It seems more promising to evaluate theclinical benefit of 18F PET bone imaging for the latterpurpose. For primary staging, 18F-FDG PET has reducedutility. The exception may be in children, where there maybe an indication for 18F-FDG PET, or 18F PET, to detectintraosseous skip metastases in cases of unequivocal MRIfindings, although no data are yet available to support thishypothesis.

Tumor Grading and Prognosis. Because an overlap of18F-FDG uptake values between different tumor grades isreported, it is usually not possible to differentiate low-gradeand sometimes high-grade osteosarcoma from 18F-FDG–avid benign lesions, such as giant cell tumors or osteomy-elitis. Thus, the results do not permit avoiding biopsy.18F-FDG PET, however, is helpful for targeting biopsy inlarge, heterogeneous tumors to achieve a representativetumor specimen because the highest-grade areas determinethe histologic grade and subsequent biologic behavior. Thisinformation on tumor biology cannot be provided by otherradiologic imaging devices. Another interesting topic thatshould be further evaluated in clinical studies is highlymetabolically active but histologically low-grade tumors. Ina subset of tumors the histologic grade does not predictoutcome. Furthermore, initial high 18F-FDG uptake is pre-dictive of poor overall and event-free survival. Clinicalfollow-up studies in these patients will clarify whether18F-FDG PET is more accurate for prediction of outcomethan conventional clinical tumor grading.

Therapy Monitoring. 18F-FDG PET imaging data showreliability for prediction of tumor response to preoperative,neoadjuvant chemotherapy. This is of particular interestbecause CT and MRI images do not always detect thequantity of residual viable tumor. Further 18F-FDG PETstudies on larger patient populations are necessary to con-firm recent promising findings and to define the most suit-able parameter to predict the amount of tumor necrosis—that is, the percentage change of uptake or, simply, theposttherapeutic 18F-FDG uptake value. The influence ofinflammatory or healing processes on postchemotherapytumor uptake also has to be determined by correlatinghistologic findings with imaging results. Future studies needto define how early after the onset of chemotherapy is18F-FDG PET able to precisely predict tumor response. Thisdefinition would allow minimization of ineffective treat-

FIGURE 8. Coronal (A), transverse (B), and sagittal (C) projec-tions of locally relapsing osteosarcoma in left distal femur 7 moafter primary surgery. Area of pronounced 18F-FDG uptake(SUV, 3.4) is evident at proximal end of resection site, which washistologically confirmed as tumor recurrence.




ment and support an earlier change to alternative chemo-therapeutic regimens or even to surgery in case of unsuc-cessful chemotherapy. For an individualized risk evaluationto further improve therapy, new PET tracers might be help-ful—for example, 11C-verapamil. Because the majority ofrelapsing patients revealed Pgp-positive primary tumors, itwould be helpful to know the status of MDR1-inducedchemotherapy resistance (76–78). Other PET tracers forfurther characterization of biologic features might be 18F-misonidazole to define hypoxia, which influences angiogen-esis, proliferation, and glucose metabolism within the tu-mor, or 11C-thymidine to provide data on tumor DNAsynthesis and cell proliferation.

Patient Follow-Up. For differentiation between benignresidual mass lesions caused by posttherapeutic tissuechanges and residual tumor tissue or local relapse, 18F-FDGPET is considered to be highly sensitive and more accuratethan CT or MRI. In the case of osteosarcoma, MRI is oftenhampered by image artifacts after implantation of metallicprostheses. As stated for primary staging, there is no clearindication for 18F-FDG PET for detection of lung or bonemetastases. However, 18F-FDG PET was able to detectdistant metastases in addition to CT and MRI becausemetastases can be detected by these imaging modalities onlywhen they are located within the scanning field of interest.In contrast to this limitation of CT and MRI, whole-bodyimaging is considered the great advantage of 18F-FDG PETby many authors. They suggest that CT of the chest, MRI ofthe tumor region, and whole-body 18F-FDG PET are neces-sary to accurately define the extent of disease. This signif-icantly influences further therapy choices because it isknown that patients with metastatic spread benefit from bothsurgery and second-line chemotherapy (4).

In conclusion, there are clinical settings in which 18F-FDG PET is already helpful for patient management inosteosarcoma:

● Predicting outcome as well as tumor response in neo-adjuvant chemotherapy

● Differentiating postoperative changes from residual tu-mor tissue or local relapse

● Whole-body imaging for detecting hematogenousspread during follow-up; in the case of diagnosed lungmasses, PET is helpful to differentiate benign frommetastatic lesions.

18F18F is a well-known bone-seeking tracer used for bone

imaging for 4 decades. However, there are only a fewpublications on 18F bone PET and even fewer on the use of18F PET in patients with osteosarcoma.

Physiology18F is extracted from plasma in proportion to bone per-

fusion (79–82) following a clearly defined physiologic pro-cess that allows quantitative studies of the skeletal system

using dynamic PET procedures (82). Hawkins et al. (83)suggested a 3-compartment, 4-parameter kinetic model for18F behavior consisting of the plasma space and an unboundand a bound bone compartment. Fluoride is taken up by thebones from the plasma into the unbound bone compartmentand then undergoes ionic exchange with hydroxyl groups inhydroxyapatite to form fluoroapatite (bound fraction). Flu-oride does not diffuse into mature bone but is incorporatedduring bone mineralization (84). The rate constants for theseprocesses (k1 and k2 for the forward and reverse capillarytransport to the unbound bone compartment, k3 for bindingto bone apatite, and k4 for the release from fluoroapatite) canbe measured by dynamic PET in combination with arterialor venous blood sampling over 60–90 min after injection of18F by using standard nonlinear regression methods. Ac-cording to this compartment model, the forward macropa-rameter 18F bone influx rate Ki � k1 � k3/(k2 � k3) can becalculated as a measure of bone metabolism (83,85–88).The influx rate can also be estimated by Patlak graphicalanalysis in good correlation with the modeling results(83,88). Unfortunately, no quantitative 18F bone PET studieson osteosarcoma for diagnostic purpose or for therapy mon-itoring have been published so far.

Imaging StudiesThe positron emitter 18F was introduced for bone scan-

ning using conventional gamma-camera systems by Blau etal. in 1962 (89). 18F was then approved by the Food andDrug Administration for clinical use and became the stan-dard agent for bone scanning until the development of99mTc-labeled bisphosphonates in the 1970s. A first reporton the use of 18F for skeletal PET in cancer patients waspublished by Hoh et al. in 1993 (90). Among 13 patientswith documented malignant bone lesions, 4 had osteosar-coma. The 3 highest tumor-to-normal bone activity ratios ofall the patients investigated were observed in untreatedosteosarcoma as compared with other malignant bone le-sions. In a patient with proven lung metastases of osteogenicsarcoma, Hoh et al. also found an increased 18F uptake inthese metastases. Interestingly, in 1 patient with osteosar-coma after treatment with chemo- and immunotherapy, thetumor activity ratio was clearly reduced to about one thirdof those observed in untreated osteosarcoma, suggestingquantitative PET with 18F as a useful tool for monitoringtherapy response. The only other clinical paper on the use of18F in osteosarcoma is a case report by Tse et al. (91) on apatient with a history of congenital polyostotic fibrous dys-plasia, metastatic osteogenic sarcoma, and a breast mass.This patient presented lung nodules with abnormal 18F up-take, which was interpreted as diagnostic for osteosarcomametastases.

Future Perspectives of 18FThus, a wide field of research remains to be performed for

18F in patients with osteosarcoma. Besides the unique po-tential of a more sensitive and specific tool than 18F-FDG todetect metastases to the lungs or second bone sites for both




primary staging and restaging, 18F may improve the sensi-tivity of conventional bone scanning in osteosarcoma pa-tients: Schirrmeister et al. (92–94) found a higher sensitivityand accuracy of 18F PET in detecting bone metastases invarious cancers as compared with conventional bone scan-ning. Therefore, it seems promising to prospectively eval-uate the clinical benefit of 18F bone PET in comparison withbone scanning for the diagnostic work-up in osteosarcomapatients.

Monitoring the response to neoadjuvant chemotherapywith 18F before surgical resection also seems to be a prom-ising field of interest. This might allow detection of viable,nonnecrotic, and, thus, chemotherapy-resistant parts of thetumor as a possible predictor for therapy outcome andprognosis. Another focus of research might be to monitorthe healing of bone grafts using 18F to early detect localrecurrences. Because 18F is mainly incorporated in newlymineralized bone, whereas no uptake in inflammatory cellsis to be expected, a differentiation of residual tumor orrecurrence from postsurgical fibrotic changes, inflamma-tion, or normal graft healing (Figs. 9 and 10) might be morereliable than by the use of 18F-FDG. However, whether 18Freally can provide additional relevant information to imag-ing with FDG has to be investigated in further prospectivepatient studies.

CONCLUSION

In osteosarcoma the introduction of neoadjuvant chemo-therapy has dramatically improved survival rates, changingthe demands for state-of-the-art imaging to provide detailedinformation on tumor staging and grading, treatment eval-uation, and detection of tumor recurrence. However, besidesthe studies published so far, it is not yet possible to drawdefinite conclusions resulting in approved indications forPET in osteosarcoma, mainly because of the small numberof patients enrolled. Further research needs to be done in

prospective studies in larger patient series to define thevarious indications that have been suggested as useful forosteosarcoma management. These indications are guidingbiopsy in large heterogeneous primary tumors, predictingtumor response in neoadjuvant chemotherapy, differentiat-ing postoperative changes from residual tumor tissue orlocal relapse, and whole-body imaging for detecting meta-static spread during follow-up.

ACKNOWLEDGMENT

This work was supported in part by National Institutes ofHealth grant ROI CA 65537.

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2003;44:930-942.J Nucl Med. Winfried Brenner, Karl H. Bohuslavizki and Janet F. Eary PET Imaging of Osteosarcoma

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