j nucl med-1988-kern-181-6

ositron emission tomography (PET) is a diagnosticimaging technique that is capable of estimating tissuemetabolism, noninvasively (1-2). Glucose metabolismhas been evaluated in brain tumors with PET using thepositron emitting glucose analog fluorine-18-2-fluoro2-deoxy-r-glucose (FDG) (36).Poorly-differentiated,rapidly growing cerebral neoplasms have higher rates ofglycolysis than well-differentiated, slowly growing tumors (36). Since the relationship between rate ofglucose metabolism and tumor biology appears to applyto many tumors ( 7-11), PET measurements of glucoseutilization rate (GUR) may be an useful method ofnoninvasively categorizing grade of malignancy.

The PET-FDG technique has been used to imagecertain somatic tumors, including breast carcinoma(12) and metastatic liver cancer (13). Blood flow andoxygen utilization in human extremity sarcoma hasbeen determined with PET and oxygen-15 methods(14). To date, no report has appeared regarding PETimaging of human extremity musculoskeletal tumors

ReceivedDec. 31, i986; revisionaccepted July 30, 1987.For reprintscontact: S. M. Larson,MD, Nuclear Medicine

Dep CC, Bldg 10, Rm lC4OI, 9000 Rockville Pike, Bethesda,Md.

. Present address: Medicina NucleareIstituto di Scienze Ra

diologiche,2nd MedicalSchool,Naples,Italy.

with FDG. This study was performed with the goal ofimaging human extremity musculoskeletal tumors using PET and FDG. We correlated glucose utilizationrate as measured by PET with histopathologic gradingof these tumors. The results obtained support the useofPET as a noninvasive method of preoperative assessment of human musculoskeletal tumors.

MATERIALS AND METHODS

Patient PopulationFive patients with musculoskeletal tumors referred to the

National Cancer Institute or to an orthopedic oncologist(M.M.)wereentered into the study after obtaininginformedconsent. Their ages rangedbetween 12 and 63 yr; four weremale, and one was female. Several patients had small mcisional biopsies performed at other hospitals prior to referralfor definitive treatment, and other patients had no tissuediagnosis prior to scanning. There were no clinically evidentchanges in the tumor site in those patients who underwentincisional biopsy prior to imaging. All patients underwentPET scanningprior to tumor resection.The clinicaldata onthese five patients is presented in Table 1.

Positron Emission TomographyPatients were studied under IND #23195 (S. M. Larson,

MD, Sponsor).Patients were kept fasting for 6 hr prior toscanning. PET studies were performed using the ECAT II

181Volume29 Number2 February1988

Metabolic Imaging of Human ExtremityMusculoskeletal Tumors by PETKenneth A. Kern, Arturo Brunetti, Jeffrey A. Norton, Alfred E. Chang,Martin Malawer, Ernest Lack, Ronald D. Finn, Steven A. Rosenberg, andSteven M. Larson

Surgery Branch, NC!, DCT; Nuclear Medicine Department, CC; and Anatomic PathologyBranch, NIH, Bethesda, Maryland

Themeasurementofglucoseutilizationrate(GUR)bypositronemissiontomography(PET)using18F-2-fiuoro-2-deoxy-D-glucose(FDG)is a valuablemethodto assessthe gradeofmalignancy of brain tumors. We have designed a feasibility trial to determine whether PETcouldbeusedto imageandpredictthegradeofmalignancyofhumanextremitymusculoskeletal tumors. Five patients with extremity tumors (four soft-tissue tumors and oneosteogenictumor)werestudied.PeakandmeanapparentOURsweredeterminedin thetumorregion.Alltumorsweresubsequentlyresectedandgradedina standardfashionusingtheNCIgradingsystem.PeakapparentGUR5rangedfrom3.3 mg/iOOg/minto 15.2mg/i00g/min,with the highestvaluesfoundin the highgradetumors.Althoughthe numberofpatientsstudiedwassmall,a goodcorrespondencewasshownbetweenGURsandhistopathologicgrading.Our resultsindicatethat PETcanbe usedto imageandevaluatethemetabolic activity of human musculoskeletal tumors.

J Nuci Med 29:181186,1988

only. by Indonesia: J of Nuclear Medicine Sponsored on February 17, 2015. For personal usejnm.snmjournals.org Downloaded from

PETApparent

glucoseutilizationrate(mg/PatientAge

(yr),1009/mm)no.sexLocationSize (cm)Pathologic diagnosisPeakMean163,M(L)migh12x14Malmgnantfibroushis

tiocytoma, Grade Ill15.189.10222,

M(L) Thigh1 1 x 15Malignant fibroushistiocytoma, Grade II6.05

4.50324,

MR)t Thigh8 x 9Myxoid liposarcomaGradeI4.41

3.24438,

M(L) Femur7 x 13Cystic giantcelltumor3.702.76512,F(R)CaIf6x11Plexiformneurofibroma

(benign)3.352.64.

L =Left.tA = Right.

TABLE IGlucose Utilization Rates in Extremity Tumors

scanner (EG & 0 ORTEC, now CTI, Oak Ridge, TN). ECATII has 66 sodium iodide crystals arranged in a hexagon,producing one slice per scan. The PET scans were acquired inmedium resolutionacquisition mode, usinga medium resolution reconstruction filter. In this mode, the inplane resolution is 1.7 cm and the slice thickness is 2 cm.

All tumors were large relative to the inplane and Z-axisresolution of the ECAT-Il scanner (Table 1). The location ofthe tumor was determined by inspection and palpation in allcases. The midpoint of the tumor was obtained, a line wasdrawn across the tumor, and two parallel lines were drawn at2 cm above and 2 cm below the midpoint. Using the horizontal laser line, the ECAT was positioned at the level of thecephalad slice. Before scanning was begun, the patients position was stabilized in relationship to the scanning bed usingsand-bags (out of field of view of scanner) and tape. Inaddition, it was determined that outlining the patient's bodycontour on an immobilized sheet fixed to the scanning bedwas a usefulmethod of maintaining patient position duringthe collection of data. In general, three planes were imaged:at the midpoint,at 2 cm abovethis point, and at 2 cm belowthe mid-plane slice. Transmission scans for attenuation correction were obtained with a gallium-68 source (1O@counts)in each patient studied prior to the injection of FDG.

PET scanswereacquiredbeginning35 mm after i.v. injection of 5 mCi of FDG into an arm vein. In a typicalemissionscan ofthe tumor region, @@-0.5l.Ox lO@counts were collectedper image, over 200-600 sec of acquisition time. Care wastaken to ensure that the patient did not change positionbetween transmission and emission scans.

Using a heating pad to warm the dorsum of the handopposite to the injection site, arterializedvenous blood was

sequentially drawn during the study. After injection of theFOG, 25 to 30 blood samples of 0.5 cc each were drawn at30-sec intervals for the first 5 mm; at 1-mm intervals beginning510mm postinjection; at 5-mm intervals beginning 1020mm postinjection; and at 10-mm intervals thereafter.

The apparentglucoseutilizationrate (OUR)wascalculatedusing the Sokoloff model (15), and an operational equationthat includes a k4or dephosphorylationcorrection term(16). The uptake of EDO in tumor was measured with thePET scannerat 3565mm postinjection.The integralof thetime-activity FDO plasma curve was used as the input function. Valuesfor the rate constantsand lumpedconstantcomefrom Phelps et al. (1 7). The lumped constant (LC) and graymatter transfer rate constants (Ks) used in the calculationswere: LC = 0.4 18, K1 = 0. 1020, K2 = 0. 1090, K3 = 0.0620,K4 =0.0068.

The mean and peak OURS were obtained using a region ofinterest (ROI) program available on the ECAT-II system(ORSAY ROIprogram).A variableROIwas usedthatencompassed the entire cross-sectional area of the tumor on thetransaxial image. In all cases, the tumor was readily demarcated from surrounding tissue. Care was taken to ensure thatthe edgesof the ROI werejust within the boundary of theapparent active metabolic zone of tumor. The mean OURwas computed as the average value on a pixel-by-pixel basiswithin the total region. The peak value was the maximumpixelvalue in that region.All of the availableimagingplaneson each patient were analyzed, and the peak values reportedin Table 1and Figure4 arethe highestvalues obtained amongthe available slices. The mean value reported is the meanvalue in the tumor region acquired from the transaxial slicecontaining the highest pixel value within the tumor ROI.

182 Kern, Bruneth, Nortonet al TheJournalofNuclearMedicine


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FIGURE 1Patient 3: Low-grade sarcoma of theright proximal thigh (myxoid liposarcoma, grade I).A: The CT scanshows the tumor as a relatively lowdensity area anterior to the femur. B:In thePETimagethetumor(arrow)shows inhomogeneous uptake ofFDGwithpeakapparentGURof4.41mg/i00 g/min and mean apparentGUR 3.24 mg/i 00 g/min. The levelofthePETimageisslightiysuperiorcompared to the CT image (b = bladder).

IBecause of the large size of these tumors (see Table 1), theROl was alwayslargein relationshipto the resolutionof theimaging equipment.

SurgeryAll patients underwent resection of tumor based upon

preoperative pathologic diagnosis determined by biopsy. PETresults were not used to determine the need for operation orits extent. After resection tumors were graded in a standardfashion using the NCI grading system (18). The pathologistsdid not know the results of PET prior to histologic grading ofthe resected tumor.

RESULTSAll tumors accumulated FDG and were evident as

hotspotsin the images. PET images are shown inFigures 13,along with the corresponding computedtomographic (CT) scans in three patients. CT scans areshown with the left-right orientation reversed to enableeasy comparison with the PET images.

The peak and mean GUR for the five tumors wasdetermined. These values are listed in Table 1. Peakapparent OUR varied between 3.3 mg/l00 g/min and

. 15.2 mg/i g/min. Mean apparent GUR varied be

tween 2.6 mg/lOO g/min and 9.1 mg/lOO g/min, andthe rank order was identical for the five patients. Therewas good correspondence between increasing peak andmean GUR and increasing grade ofmalignancy. Figure4 is a scatter pli of peak OUR compared with gradeof tumor. There was a step-wise correspondence between grade oftumor and increasing OUR. Because ofthe small numbers in this preliminary study, we did notperform formal correlation analysis.

DISCUSSIONPET determinations of OUR have been used to

predict the biologic behavior ofcertain types of cerebralneoplasms. For example, DiChiro et al. have imaged

Volume29 Number2 February1988 183


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FIGURE 2Patient2: Intermediate-gradesaxcoma of the left proximal thigh (malignant fibrous histiocytoma,gradeII). A: The CT scanshowsa largetumor mass in the antero-medial regionof the leftthigh.B: In the PETscan the tumor mass is shown as anarea of relatively high FDG uptakewith a peak apparent GUR of 6.05mg/iOO g/min and mean apparentGUR of 4.50 mg/i00 g/min.Utiletracer uptake is observed at the leveloftherightthigh,consistentwiththefact that normal resting muscle hasextremely low glycolitic actMty.

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over 300 cases ofbrain tumors and have shown a strongcorrelation of tumor grade with OUR (4,6,19). Additionally, Patronas and DiChiro have reported that OURreflects the prognosis in patients with giiomas (5). Patients with tumors exhibiting high GUR by PET havea much lower mean survival time than patients withtumors showing low GUR (5).

Theoretically, musculoskeletal tumors (particularlysarcomas) are excellent candidates for FDG-PET imaging, since glucose uptake rates in extremity sarcomasare known to be high (20). In two of the tumors fromthe present study, glucose 6-phosphatase enzymatic activity was measured, and found to be very low (KernKA, Norton JA, personal communication). The deoxyglucose method as originally described by Sokoloff(15) is valid in principle under conditions where glucose

6-phosphatase activity is low during the evaluationperiod.

We are aware that the values for OUR obtained inthis study are approximate, since the lumped constantand the transfer rate constants for the operational equation are not known for human musculoskeletal tumors.The values of tumor OUR reported here are estimatesbased upon the lumped constant (LC) and the kinetictransfer constants of gray matter (k's) in the same waythat Di Chiro et al. have used LC and gray matter k'sfor the determination of GUR in cerebral tumors (6).Such estimates ofGUR, although admittedly imperfect,appear to serve as a useful index of tumor metabolicactivity in human brain tumors. Our preliminary resultssuggest that a similar set of approximations may beused to compute estimates of OUR that may correlate

1 84 Kern, Bruneth, Norton et al TheJournalofNudearMedicine


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FIGURE 3Patient 1: High grade sarcoma of theleft proximal thigh (malignant fibroushistiocytoma, grade Ill). A: The CTscan shows a large tumor mass inthe antero-medial region of the leftthigh.B: InthePETscanthe lateralportion of the tumor mass shows avery high FDG uptake with a peakapparentGMR of i 5.18 mg/i00 g/mmand mean apparent GMR of 9.i 0mg/i00 g/min.

with important differences in the tumor biology ofhuman musculoskeletal tumors. As in cerebral giiomas,histopathologic grading is the single most important

. prognostic factor in patients with soft-tissue musculo

skeletal tumors (21).This is the first reported study of PET-FDO imaging

of human extremity musculoskeletal tumors. This feasibiity study indicates that these tumors accumulateFDO and are readily imaged with good contrast bypositron tomography. Further prospective studies areplanned to assess the clinical contribution of PET studies in the assessment ofhuman musculoskeletal tumors.

TumorGrade ACKNOWLEDGMENTSFIGURE 4Scatter plot of apparent peak glucose utilization rates@ The authorsthank Dr. Giovanni Di Chiro for his valuableversustumorgrade.Glucoseutilizationratesareincreased commentsandadviceindesigningthisstudy.in tumors of higher malignant grade. A. Brunettiis a recipientof a FogartyFellowship.

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Volume29 Number2 February1988 185


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1 86 Kern, Brunetti, Norton et al TheJournalof NuclearMedicine


1988;29:181-186.J Nucl Med.

A. Rosenberg and Steven M. LarsonKenneth A. Kern, Arturo Brunetti, Jeffrey A. Norton, Alfred E. Chang, Martin Malawer, Ernest Lack, Ronald D. Finn, Steven

Metabolic Imaging of Human Extremity Musculoskeletal Tumors by PET

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