Predicting Malignancy Grade with PET in Non-Hodgkin's Lymphoma

Miriam Rodriguez, Suzanne Rehn, Hkan AhlstrOm, Christer Sundstrm and Bengt Glimelius Departments ofDiagnostic Radiology, Oncology and Patho1o@; and the PET Centre, University of Uppsala, AkademL@ka Sjukhuset, Uppsala, Sweden

NHL). These patients have a poor prognosis. More Our goal was to determine whether PET with 11C-methionine intensive treatment is given if the disease takes a more and/or 18FDGcould predict malignancygrade in non-Hodgkin's progressive course or if transformation occurs (2). lymphoma(NHL).Methods: Twenty-three palientswith high In contrast, high-gradeNHL has aggressive tumorswith grade, low-grade or transformed low-grade NHL were investi high proliferation rates. When the proliferation rates of gated.Standardized uptakevalues(SUV),transportrate and high- and low-grade NHL were compared, high-grade tu
mass influx values were calculated both for the whole tumor [mean regions of interest, (ROl)1and for the tumor area with the highestlevels ofactivity, comprisingfour contiguouspixelswithin mors yielded much higher values, although great variability is seen between and within prognostic groups (3). Treat

take values correlated well with each other for both tracers, except for the mean ROI SUV and transport rate of 11C-methi onine. Quantifications of mean ROI uptake and hot spots were strongly correlated. Conclusion: The results of this study to gather with previous findings from other studies indicate that 18FDGbut not 11C-methionine can predict malignancygrade in NHL Furtherstudies witha largerseriesof patients are needed.

eachtumorand designated as a hotspot.Results: Both1'C- ment of high-grade NHL has a curative intention. About methionine and18FDG detected alltumors. Inaddition, 18FDG 40% of patients can achieve long-term remissions using discriminated betweenhigh-andlow-grade NHL whereas11C- various combinations of cytostatic agents (2). methionine did not With 18FDG,three transformed low-grade In most cases, NHL gradingis easily made when appro NHLSbehaved in an intermediate manner. All quantitative up priate biopsy specimens have been taken. In certain pa
tients, great difficulties may be encountered in such sam

KeyWords:positron emissiontomography; non-Hodgkin's lym phoma; tumor staging

J Nucl Med 1995; 36:1790-1796

pling. This is particularly evident in cases where the disease is limited to intrathoracic and/or intra-abdominal locations only or when adequate tissue sampling may not easily be accomplished without surgery. Additionally, the transformationoflow-grade lymphomas to high-gradeones may occur unpredictably, sometimes requiring multiple
sampling for disclosure (4). Therefore, in vivo prediction of malignancy grade by an easy and reproducible method

would be of great clinical value. In parallel with increased proliferation, glucose and methionine metabolism and cell membrane transport are usually increased in neoplastic tissue (57). In head on-Hodgkin's lymphoma (NHL) consists of heteroge and neck cancer and malignant lymphomas, 8FDG up neous groups of neoplasms (1). Clinically, there are two take, as analyzed by PET, correlates to proliferation major NHL groups: high-grade and low-grade. Within rates (8,9). these groupings several subtypes exist; therefore differ The potential role of PET for detecting and grading ma entiating between low-grade and high-grade NHL is lignant lymphomas and predicting prognoses is limited. clinically important. Although low-grade NHL is usu Okada et al. (10) reported that 8FDG uptake could be ally considered to be incurable, it often progresses slowly and patients have long survival rates. Treatment useful for prognostic prediction in patients with malignant
is therefore often deferred until symptoms occur and
lymphoma in the head and neck region. In another study,

then frequently consists of single-drug cytostatic ther apy or radiotherapy if the symptoms are only local. For low-grade NHL, some tumors may have a more aggres sive course and some tumors may transform into high grade NHL (transformed or secondary high-grade

in which C-methionine and 8FDG uptake was compared

in NHL, Leskinen-Kallio et al. (11 ) found that C-

methionine was a better tracer for identifying tumors than 8FDG, but 8FDG was superior in predicting ma lignancy grade (11). The aim of this study was to further evaluate the diag
nostic accuracy of PET using C-methionine and 8FDG, determining whether either of the tracers could reliably

Received Oct21,1994; revision accepted Apr.12,1995. Diagnostic Radk@logy, Akaderniska Sjukhuset, S-75185 Uppsala, Sweden.
For correspondence or reprints contar@tMiam Rodriguez, MD, Department of

predict the grade of malignancy in NHL.

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TheJournal ofNudearMedicine Vol.36 No.10 October 1995

TABLE1
Patient Characteristicsand Clinical Data PatientAgeMalignancyHIStOIO@YMethionineFDGno.(yr) WF Sex gradeKiel

Stage

CT

MRI

PETPET x x x x x x

x 156MHighNUDNUDIAAbdomen255FHighNUDNUDlIBAbdomenAbdomen370MHighd.CB(0)lIlANeck474MHighd.CB(G)IVAAbdomen547FHi

x x x x x x x x x x x x x x x x 550MLowf.CB-CC(B)IVBNeck1659MLowCLL(A)IVANeck1769MLowCLI(A)WAAxilla1886MLowCLL(A)IVAGroin1955FLowf. x x x x x x x x x x NUD = unclassifiable; d.CB = diffusecentroblastic lymphoma; CC = centrocytic lymphomaCB-CC= centrocytic centroblastic lymphoma; f CB-CC= fohoularcentrocytic centroblastic lymphornaCU. = lymphocytic lymphoma; (A) = smalllymphocytlc; (B) = follicular predominan@y small-cleaved cell (E = small-cleaved cell (0 = largecellnoncleaved WF = Working Formulation.

MATERIALS AND METhODS Patients

Westudied23patients (14men,9women)whowerediagnosed
with NHL. Eleven patients had high-grade NHL, 9 low-grade and

PET Patients were examined with a whole-body PET camera that produces 15 simultaneous contiguous axial slices with a slice

thicknessof.5 mmand a resolutionof56 mm(14).Twenty-two

8FDG PET examinations and 11 C-methionine PET examina tions were performed. Ten patients were examined with both tracers (Table 1). All patients fasted for at least 4 hr before the study and the methionine or glucose plasma concentrations were measured be fore scanning.After a 10-mmtransmissionscan was obtained, the

3 transformed low-grade (Table1). All patientshadat leastone

tumor larger than 3 cm in diameter. The high-grade and trans formed NHL patients were consecutively enrolled from patients seen between June 1992and October 1993,whereas the low-grade NHL patients were selected from the patients in the oncology department.The low-gradeNHL groupconsisted of patientswith both an indolent and a more rapidlyprogressive course. Tumors

were graded accordingto the Kid classification(1); a classifica

tion was also made according to the Working Formulation (12).

tumor regionwas imagedafter rapid injectionof approximately 800MBqC-methionine (15) or 400MBq18}@W@ (16,17)intoa
peripheral vein. Immediately after injection, a dynamic scanning

Cr and MRI were performedin all patients for tumor stagingin

accordance with the Ann Arbor system (13) to evaluate a tumor size and determine tumor regions for the PET study (Fig. 1,

sequencewas started, consistingof 14(8FDG) or 16( C-methi

onine) frames with successively increasing acquisition times from 1 to 10 mm. During the examination, 13 (8FDG) or 12 (Cmethionine) plasma samples were taken from a peripheral vein, which was arterialized by warming (18), and analyzed for C or

Table 1). In 10 of the 11 patients with high-gradeNHL, PET

examinations were performed at the time of diagnosis, prior to

any therapy. One patient had a PET study duringrelapse,which

occurred 6 mo after the last chemotherapycourse. Among patients with low-grade NHL, three had PET studies at the time of diagnosis and before treatment was started, and one patient was examined 8 yr after diagnosis but never received any

8F concentration.
Image Reconstruction and Analysis

Imagereconstructionproduceda set of dynamicimages,each representinga quantitativeestimate of the radioactivityconcen

tration. A 128 x 128matrix and a 6-mm Hanning filter were used.

therapy.Fivepatientshadreceivedchemotherapybeforethe PET examination(four patients were treated with intermittentsingle agent therapy and one with combinationchemotherapyand/or
radiotherapy).One patienthad a PET examination 1 mo afterthe

Data were correctedfor attenuationand scatter (19). Carbon-li

methionine data were obtained from 14 to 45 mm and 8FDG data

were obtained from 30 to 50 mm postinjectionand summed to

produce an average image.

chemotherapycourse. None of the other four patients had re

ceived any treatmentwithin 5 mo priorto the PET examination.

The radioactivity concentration in the averageimagewas re

PET in Non-Hodgkin's Lymphoma Rodriguez et al.

1791

individual analyses of methionine metabolites, a standard correc

tion for metabolitescalculatedfromdata presentedby Hatazawa et al. (21) was applied to the plasma data. Hatazawa et al., however,recommend individual metabolite analyses.
For the SUV images, regions of interest (ROIs) representing viable tumor areas with the highest radioactivity were drawn according to a standardized procedure. This meant that in drawing

a ROl, a contour positionedhalfwaybetween the highesttumor

radioactivity and the surrounding tissues was followed. From

each ROl obtainedin this manner(designatedas mean ROI),the

mean tumor radioactivity value could be obtained. In addition to

this mean ROl, a region within each tumor comprising the four contiguous pixels with the highest levels ofactivity and designated

hotspotwas identified. Thus,corresponding SUVs andtransport rate values were estimated.

The transportrate values obtained for the mean ROI and the

hotspotweremultiplied byplasma levelvaluesof methionine and giucose, with a lumpedconstant of 0.4 (measuredfor the normal
brain and used in this study because the lumped constant for lymphoma is unknown) (22) for each patient to estimate the mass

influx of methionine [nmole/(mlmin)] and glucose [@tmole/(lOO

mimin)], respectively in the tumor area. Statistical Methods Differences in the distribution of values between the two groups were assessed with the Mann-Whitney U-test. Correlation between different parameters was measured with the Spearman

Rankcorrelation test. Theseanalyseswere performed with Stat View II (Stat View@1986)on a Macintoshcomputer.

RESULTS All tumors detected by CT or MRI were clearly visual

ized by C-methionine and/or 8FDG (Figs. 2, 3). The uptakevalues of C-methionine and 8FDG for patients in each group, quantified as SUV, transport rate and mass influx, are shown in Figures 2 and 3, respectively. Mean values for the mean ROIs and hot spot, respectively, are presented in Table 2. The different quantitative tracer values correlated well with the hot spot (data not shown). Good correlationwas also found for the mean ROI, with the exception of the FiGURE 1. A@dal MRIand PETimagesofthe abdomenat corre methionine transportrate SUV (Figs. 4, 5). The uptake values for 8FDG were significantly higher sponding levels in a patient with high-grade NHL (A) MRI Ti weightedimageobtainedafter intravenousinjectionof gadolinium for high-gradethan low-grade NHL, whether recorded as
contrast depicts a large central tumor (arrows).L = liver,k = kidney, b = bowel. (B) PET 11CmethionineSUV imagevisualizestracer uptakeinthetumor(arrows), liver(L),kidneys(k)andbowel(b).Red andyellowcolorscorrespond to hightraceruptake.(C)PET18@ Suv imagevisualizestracer uptakein the tumor and kidneys(k). Redand yellowcolorscorrespondto hightraceruptake. SUV (p < 0.01), transport rate (p < 0.003) or mass influx

(p < 0.01). No such significant difference was seen for C-methionine uptakevalues (SUV p = 0.9, transportrate p = 0.1, mass influx p = 0.2). Uptake values varied con
siderably within the two prognostic groups, irrespective of

calculated to provide images of standardized uptake values (SUV): The concentration of radioactivity in the lesion was di vided by the ratio of totally administered radioactivity to body weight. Quantitative analyses were also performed on a pixel-by-pixel
basis according to the technique described by Patlak et al. (20),
generating images of tracer transport rate in tissues using plasma

the estimation method. For 8FDG, there were no overlap ping values between high-grade and low-grade NHL for transport rate, whereas this was the case for both SUV and mass influx estimations (Fig. 3). The few patients with transformed NI-IL had uptake values that behaved in an intermediate manner. In the transport rate calculations for 18FDG,two patients with transformedlymphomas hadval
ues higher than those of all low-grade tumors that fell

radioactivity as a reference. Because we were unable to perform

within the range of the high-gradevalues. No such clear

1792

The Journal of Nuclear Medicine Vol.36 No. 10 October 1995

A
10
8

U High-grade i@ Low-grade 1111 Tra.sformed

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FIGURE 2. Uptake 1C-methionine in patients withhigh-grade, low-gradeandtransformed low-gradeNHLquantifiedwith (A)SUV,

(B)transport rate(min1) and(C)massinflux[nmole/(mI . mm)].

Si I
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ii
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difference

was detected

for C-methionine (Fig. 2B), but

only one patient with transformed

NHL was studied.

DISCUSSION

FIGURE 3. Uptake of 18@J@@3 in each patientwith high-grade, low-grade andtransformed low-gradeNHLquantifiedwith (A)SUV, (B)transportrate(min1) and(C)massinflux[@unoIe/(iOO ml . mm)].

This study showed that both C-methionineand 8FDG, images. Leskinen-Kallio et al. (11) de as nonspecific tracers for metabolic activity, have high on C-methionine
sensitivity for detecting malignant lymphomas. Our results

differ from those reported by Leskinen-Kallio et al. (11), who found that low-grade NHL may not always be visu
alized on 8FDG PET images, whereas they are visualized

tected tumor location for the PET studies by palpation (except for one case of abdominal lymphoma where Cf was performed). We, however, consistently performed CT and/or MRI to determine tumor regions. Although Leski

PET in Non-Hodgkin's Lymphoma Rodriguez et al.

1793

TABLE 2 QuantitativeUptake Values Relatedto MalignancyGrade Met/M.AOl11C-Methionine hotspotT. Malignancy11C igradeSUV(min1)[nmole/(ml mm)]High rateMass. iT. rateMass. . mm)]SUV(min1)[nmole/(ml .

2.160.428 0.4653.12 3.15mean grade5.38 2.268.88 2.870.257 0.1874.50 s.d.Lowgrade6.523.070.1030.0471.600.888.503.540.1260.0592.001.18mean s.d.Transformedmean s.d.18FDG/M. spotSUVT. @
High grade

AOl18FDG rate
(min1)Mass.[junole/(ml. mm)]SUVT.

hot rate i 122.0 70.3 47.8 36.8

(min1)Mass. [mole/(prnl- mm)]

11.8 4.70 6.83 3.94 6.37 5.30 0.60 0.52 8.73 1.18 4.59 0.87

88.2 53.9 34.2 28.4

15.90 5.71 8.70 6.60 11.60 1.74

9.37 5.09 2.64 2.77 6.19 1.18

mean s.d. Lowgrade mean s.d.

Transformed

mean s.d. SUV= standardized uptakevalue;T. rate= transport rate;Mass.i = massinflux;M. AOl = meanregionof interest

nen-Kallio et al. (11) used ROIs with at least 43 pixels, our

study used a standardized procedure to draw a mean ROI

rate and mass influx estimations in the same study (9). No

to represent only the viable tumor area that could be taken from the CT and/or MRI image. The use of a strictly de
fined ROl may be a way to avoid nondetection caused by,

firm conclusions can be drawn as to whether the less re source demanding SUV method is sufficient for quantitat
ing tracer uptake in lymphomas or other tumors. In our

study, transport rate estimations appeared to be advanta

geous. In Patient 15, who had a low transport rate value

for example, necrosis in the tumor. We cannot further

explain the apparent discrepancies between the two studies partly because the level of description in the Leskinen Kallio study is not always sufficient for further compari

son. In our study, 8FDG could discriminate between low gradeand high-gradeNHL. This discriminationwas appar ently better when transport rate calculation was used in stead of SUV or mass influx estimations. In actuality, the transport rate value discriminated entirely between prog nostic groups without any overlapping values. Because our patient population is small; this result should be interpreted cautiously. On the other hand, C-methionine had no discriminative
ability. Although group differences may exist, we noted

(Figs. 2B, 3B) but a high SUV (Figs. 2A, 3A) despite a low-grade histology, the PET study was actually repeated after 6 mo with virtually identical results. During that time, no treatment was given and there was no lymph node
enlargement and a new biopsy showed the same histolog

ical subtype.

From a clinicalview, tumor detection and clearly distin

guishing in vivo between low-grade and high-grade NHL

with one tracer, 8FDG, is promising. There are, however, clinical considerations. For many reasons PET is not widely available. Therefore, for more readily available and
accessible methods are needed. Computed tomography

and 67Ga scintigraphy have been extensively used for tu mor staging, but neither method can distinguish between
grades. In this context, heterogeneity investigations using

overlappingvalues irrespective of the calculation method. Ourfindingsare also supportedby the results of Leskinen
Kallio et al. (11 ), who detected no discriminative ability of

1C-methionine.
DiChiro (23) studied patients with malignant glioma and

MRI have, shown promising results (25,26). Gallium-67 scintigraphy also reportedly has a lower sensitivity for detecting low-grade NHL (27,28). PET imagingwith nonspecific tracers may, however, be
of importance for other clinical purposes. For example, it

found a similar ability of 18FDGto discriminate between

malignancy grades. In studies of other tumor types, how

ever, in which the patient populations are usually small, overlapping values between different malignancy groups have been reported for C-methionine and 18FDGuptake
(11,24).

may illustrate important differences between low- and high-grade NHL that could direct future diagnostic, and possibly, therapeutic studies. The ability to reflect meta
bolic/proliferative activity, as also found by Okada et a!. (9), may provide helpful data in predicting early treatment response ofmalignant lymphomas. In a comparative study,

There have been few comparisons of SUV, transport

1794

The Journal of Nuclear Medicine Vol. 36 No. 10 October 1995

A
1,2

I.Methionine]

A
II

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41

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0
0

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Transport

rate

rate FiGURE4. Corralallons between1C-methionine (A)transport FiGURE5. Correlationbetween (A) 18@ (B)massinflux[@&mde/(100 ml min)]/SUV and(C) rate (mmn1)/SIN, (B) mass influx [nmoie/(mI . min)]/SUVand (C) (min1)/SUV,
transportrate (m1n1)/massInflux[nmole/(mI . mm)],respectively. transport rate (mirr1)/mass influx [@&moie/(100 ml mm)], respec

the correlation with metabolic state was superior for

8p-@G compared to 67Ga scintigraphy (10). Hoekstra et a!.

(29)found that these two methods reflectedfunctionalac

tivity equally well, but that 18@?TV@ imaging appeared supe

discriminate between remaining active tumor cells and fi brotic tissue in residual mass after treatmentmay be pos
sible. Gallium-67 imaging has been reported to be useful in assessing prognosis after therapy (30) and evaluating tu

nor to 67Gain predictingearly response. Also, the abilityto

PET in Non-Hodgkin's Lymphoma Rodriguez at al.

1795

mor viability in residual masses (31,32). In the study by

Hoekstra et al. (29), neither planar 8FDG nor 67Ga imag

and descriptionof a workingformulationfor clinicalusage. Cancer 1982;

49:21122135. 13. Carbone PP, Kaplan HS, MusshoffK, Smithers DW, Tubiana M. Report of the committee in Hodgkin's disease staging classification. CancerRes 1971; 31:18601861. 14. Kops ER, Herzog H, Schmid A, Holte S, Feinendegen LE. Performance characteristics of an eight-ring whole-body PET scanner. J Cotnput Assist Tomogr 1990;14:437445. 15. Ungstrom B, Haltdin C, Antoni G, et al. Synthesis of L- and D- [methyl C]-rnethionine. I Nuci Med 1987;28:10371040. 16. Hamacher K, Coenen HH, StOcklin0. Efficient stereospecific synthesis of no-carrier-added 22-('8F)-fluoro-2-deoxy-D-glucose using aminopolyether supported nucteophiic substitution. J NuciMed 1986;27:235238. 17. Toorogian SA, Mulholland GK, Jewett DM, et al. Routine production of 2-deoxy-2-('8F) fluoro-D-glucose by direct nucleophilic exchange on a quan temary4-aminopyridiunium resin. IntlRadAppllnstnsm 1990;17:273279. 18. Abumrad NN, Rabin D, Diamond MP, Lacy WW. Use of a heated super ficial hand vein as an alternative site for the the measurement of amino acid concentration and for the study of glucose and alanine kinetics in man. Metabolism 1981;30:936940. 19. Bergstrom M, Eriksson L, Bohrn C, Blomqvist 0, Litton J. Correction for scattered radiation in a ring detector positron camera by integral transfor mations of the projections. J ComputAssist Tomogr 1983;7:4250. 20. Patlak CS, Btasberg RG, Fenstermacher JD. Graphic evaluation of blood

ing could exclude remaining viable tumor. Hoekstra et a!.

postulate that PET may provide clinically relevant infor

mation due to its superior detection capacity in these pa tients. CONCLUSION Future PET research should focus on developing more
specific tracers as we!! as clinically important issues in

assessing patients with malignant lymphoma. For selected indications or sites where other imaging methods are insuf ficient for diagnostic and staging purposes, PET may have a limited but definitive role.
ACKNOWLEDGMENTS This work was supported by grants from the Swedish Cancer

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