Hematological OncologyHematol Oncol 2006; 24: 146–150Published online 26 May 2006 in Wiley InterScience(www.interscience.wiley.com) DOI: 10.1002/hon.782

Research Article

Different histopathological subtypes of Hodgkinlymphoma show significantly different levelsof FDG uptake

Martin Hutchings1,4*, Annika Loft1, Mads Hansen2, Elisabeth Ralfkiaer3 and Lena Specht4,5

1Department of Clinical Physiology and Nuclear Medicine, PET and Cyclotron Unit2Department of Haematology3Department of Pathology4Department of Oncology5Department of Radiotherapy, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Abstract

Positron emission tomography using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) enablesquantitative analysis of metabolic activity. This study investigated standardized uptakevalue (SUV) levels in the different histopathological subtypes of Hodgkin lymphoma(HL). Sixty patients with newly diagnosedHLunderwent staging FDG-PET/CTafter lymphnode biopsy. Maximum SUV in each patient (SUVmax/total) and in each affected region ororgan (SUVmax)were recorded.MeanSUVmax/total was 9.3 g/ml in seven nodular lymphocytepredominance (NLP) patients, 16.3 g/ml in 38 nodular sclerosis (NS) patients, 20.8 g/ml in 11mixed cellularity (MC) patients, and 19.5 g/ml in four patients with unclassified classical HL(CHL-NOS), (ANOVA,p¼ 0.011).Out of 780 sites (600 lymphnode regions plus 180 organs),208 sites were found to be affected with HL. Mean SUVmax was 8.3 g/ml in the 12 siteswith NLP, 11.2 g/ml in the 147 sites affected with NS, 14.6 g/ml in the 36 sites with MC,and 13.1 g/ml in the 13 sites with CHL-NOS (ANOVA, p¼ 0.002). There is a significant dif-ference in FDG/glucose uptake between the different histopathological subtypes of HL.Copyright# 2006 John Wiley & Sons, Ltd.

Keywords: Hodgkin lymphoma; PET/CT; FDG; histopathology

Introduction

Functional imaging with positron emission tomography

using 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) has

gained widespread use in the management of Hogdkin

lymphoma (HL) [1]. Along with histological subtyping,

the choice of initial HL therapy strategy is primarily based

on clinical staging. FDG-PET and FDG-PET/CT add

important additional information to the existing conven-

tional staging techniques such as clinical examination,

computerized tomography (CT), and ultrasound [2–11].

After treatment induction, the most important determinant

for changes of therapy is the response to treatment.

FDG-PET has been proven superior to conventional tech-

niques in the early detection of individuals who respond

poorly to the treatment [12,13].

FDG-PETenables quantitative analysis of tumour meta-

bolism, commonly measured as the semiquantitative stan-

dardized uptake value (SUV) [14]. Although SUV

analyses can be used to assist the qualitative evaluation of

an FDG-PET scan, this is not particularly common and

SUVanalyses are rarely used routinely for diagnostic pur-

poses. However, with the introduction of FDG-PET/CT

guided radiotherapy planning, this could change. In order

to minimize the adverse late effects of treatment, HL radio-

therapy is moving from the involved-field technique

towards techniques with more precise targeting (intensity-

modulated radiotherapy, IMRT, and involved-node radio-

therapy, INRT) [15–17]. For those purposes, an accurate

determination of the extent of disease is crucial and FDG-

PET/CT, beingmore accurate for staging than conventional

methods, is likely to be of importance. A number of studies

suggest a role for SUVanalysis in the definition of the PET-

positive tumour volume [18–22]. For this purpose, more

knowledge is required about the FDG metabolism in HL

masses. The aim of this study was to investigate the levels

of FDG uptake and its variation between the different sub-

types of HL.

Methods

Sixty consecutive patients with newly diagnosed HL were

prospectively included in the protocol from November

2001 until June 2004. Exclusion criteria were diabetes,

pregnancy and age under 18 years. Written, informed con-

sentwas obtained fromall patients. The studywas approved

by the local human investigations ethical committee of

Copenhagen and performed in accordance with the revised

Helsinki Declaration. At least one lymph node biopsy was

Copyright � 2006 John Wiley & Sons, Ltd.

*Correspondence to:Dr Martin Hutchings, PET andCyclotron Unit, Department ofClinical Physiology and NuclearMedicine, The Diagnostic Centre—Copenhagen University Hospital, 9,Blegdamsvej, DK-2100 CopenhagenØ—Denmark.E-mail: martin.hutchings@rh.hosp.dk;hutchings@dadlnet.dk

Received: 31 December 2005

Revised: 13 March 2006

Accepted: 30 March 2006

obtained per patient. All specimens were reviewed by the

same expert haematopathologist at our institution, and sub-

typing was carried out according to the WHO classification

[23]. Along with other staging procedures, all patients were

scanned in a GE LS Discovery PET/CT scanner (General

Electric Medical Systems, Milwaukee, Wisconsin). 18F-

FDG was produced from an onsite cyclotron and chemistry

facility. All scans were performed as half-body scans (mid-

brain to upper thigh) after a 6-h fast. Emission data were

acquired for 5min per bed position starting 60–120min after

intravenous injection of approximately 400MBq 18F-FDG.

Intravenous CT contrast was given immediately before the

CT scanning procedure. Diazepam was given orally to

some patients before FDG-administration to avoid muscular

tracer uptake.

SUV analysis was performed for all patients [14].

Regions of interest (ROI) were drawn representing each

lymph node region and organ on all transaxial and coronal

slices. The following 10 nodal regions were investigated:

left and right side of the neck, left and right axillae, medias-

tinum incl. hilar regions, retroperitoneum incl. hila of the

spleen and liver, left and right iliac regions, left and right

inguinal/femoral regions. The organs considered were

lungs, liver and spleen. ROIs were normalized for injection

dose and body weight. SUVmax was recorded as the highest

SUV in each region or organ. For each patient, the highest

SUV in any site likely to represent disease and not physio-

logical uptake was recorded and labelled SUVmax/total.

Maximum values were used in order to minimize partial

volume effects and to enhance the reproducibility of the

measurements. FDG avidity regarded as a consequence of

a biopsy procedure was not included in the analysis.

Generally, a region or organ with involvement seen on

both PET and CT was regarded a true positive focus and a

sitewith no suspect signs on PETorCTwas regarded as truly

negative. Discrepant findings were assessed at a consensus

conference after minimum 1 year of follow-up. Later

scanning results and other clinical findings were considered,

allowing response to treatment and the clinical course

to eventually determine which sites were initially

affected and which sites were not affected (standard of

reference) [1].

Differences in SUVmax between groups were analysed

with independent-samples student’s t-test (two groups)

and one-way analysis of variance, ANOVA (more than

two groups). Stem-and-leaf plot were used to check for nor-

mality and Levene’s test was used to check homogeneity of

variances. Multiple linear regression analyses were

employed to test the independence of other factors on the

correlation between histopathological subtypes and SUV.

Since the histopathological subtypes represent a categorical

variable, dummy variables were defined (see results).

Durbin-Watson estimates were used to test the indepen-

dence assumption. Normal probability plots were used to

test the assumption of normality of residuals and

scatter plots were used to test the assumption of constant

variance. Tests were two-sided with 5% as the level of sig-

nificance.All data analyses were performed using the statis-

tical software package SPSS 13.0 (SPSS inc., Chicago,

Illinois).

Results

Fifty-three patients had classical HL and seven patients had

nodular lymphocyte predominance (NLP).Of the 53 patients

with classical HL, 38 patients had nodular sclerosis (NS), 11

patients had mixed cellularity (MC), and four patients had

classical HL, not otherwise specified (CHL-NOS). Out of

780 potential sites of disease (600 lymph node regions plus

180 organs), 208 sites were found to be involved with HL.

Figure 1 shows the SUVmax values depicted as box plots

with one box for each of the histological subtypes. The

mean SUVmax values varied significantly between the dif-

ferent histological groups (ANOVA, p¼ 0.002). Mean

SUVmax was significantly higher in the sites affected with

classical HL (CHL) than in the sites with NLP (t-test,

p¼ 0.013). Likewise, mean SUVmax in sites with NS was

significantly higher than in sites with NLP (t-test

p¼ 0.042) and significantly lower than in sites with MC

(t-test, p¼ 0.011). The distribution of SUVmax values

from sites with CHL-NOS resembled the distribution

from sites with MC.

Figure 2 shows the SUVmax/total values. The pattern of the

SUVmax values was repeated. Themean SUVmax/total values

varied significantly between the different histological

groups (ANOVA, p¼ 0.011) and mean SUVmax/total was

significantly higher in the patients with CHL than in the

patients with NLP (t-test, p¼ 0.006). SUVmax/total in sites

with NS was significantly higher than in patients with

NLP (t-test, p¼ 0.019) but not significantly lower than in

patients withMC (t-test, p¼ 0.078). SUVmax/total in patients

with CHL-NOS was indistinguishable from in SUVmax/total

patients with MC. In Table 1, the mean SUVmax and

SUVmax/total values and their corresponding 95%

Figure 1. Box-and-whiskers plots showing the distributions ofSUVmax according to histopathological subtype. Black horizontalbars represent the median value, grey boxes represent theinterquartile range (IQR), whiskers represent the range.Abbreviations: NLP¼ nodular lymphocyte predominance,CHL¼ classical Hodgkin lymphoma, NS¼ nodular sclerosis,MC¼mixed cellularity, CHL-NOS¼CHL—not otherwise spe-cified, ANOVA¼ analysis of variance

Copyright � 2006 John Wiley & Sons, Ltd. Hematol Oncol 2006; 24: 146–150

DOI 10.1002/hon

Different FDG uptake in histopathological subtypes of Hodgkin lymphoma 147

confidence intervals are displayed. Multiple linear regres-

sion analyses were performed in order to test the influence

of gender, age and body weight. For this purpose, three dif-

ferent dummy variables were defined, grouping the patients

into NLP or NS, NLP orMC, andNS orMC. All three dum-

my variables correlated strongly with both SUVmax and

SUVmax/total, independently of the other variables (data

not shown).

Figure 3 shows FDG-PET/CT coronal section images

displaying the sites with the most FDG uptake in three dif-

ferent patients with NLP, NS and MC.

Discussion

FDG-PET and FDG-PET/CT are important tools in the

management of HL. A number of studies have shown the

value of FDG-PET in the staging of HL and more recent

investigations have assessed the properties of FDG-PET/

CT [2,4–11]. Other studies have assessed the use of FDG-

PET for early treatment monitoring or evaluation of a resi-

dual mass after treatment [12,13]. Many studies have been

carried out onmixed lymphoma populations, often with HL

only comprising a small subgroup. A recent study by

Schoder et al of 97 newly diagnosed or relapsing

non-Hodgkin lymphoma (NHL) patients showed that

aggressive NHL had significantly higher FDG uptake than

indolent lymphoma [24]. In 2003, Dobert et al performed

SUVmax analyses on 22 HL patients, 16 of whom were

undergoing primary staging investigations and six of

Figure 2. Box-and-whiskers plots showing the distributions ofSUVmax/total according to histopathological subtype. Blackhorizontal bars represent the median value, grey boxes representthe interquartile range (IQR), whiskers represent the range.Abbreviations: NLP¼ nodular lymphocyte predominance,CHL¼ classical Hodgkin lymphoma, NS¼ nodular sclerosis,MC¼mixed cellularity, CHL-NOS¼CHL—not otherwise spe-cified, ANOVA¼ analysis of variance

Table 1. Standardized uptake values according to histological subtypes

NLP CHL NS MC CHL-NOS

SUVmax No. of affected sites 12 196 147 36 13Mean SUVmax 8.3 g/ml 11.9 g/ml 11.2 g/ml 14.6 g/ml 13.1 g/mlCI 5.7–10.9 11.1–12.8 10.3–12.0 12.1–17.0 8.8–17.3

SUVmax/total No. of patients 7 53 38 11 4Mean SUVmax/total 9.3 g/ml 17.4 g/ml 16.3 g/ml 20.8 g/ml 19.5 g/mlCI 4.2–14.4 15.4–19.4 13.9–18.6 15.3–26.2 14.5–24.4

Abbreviations: NLP¼ nodular lymphocyte predominance, CHL¼ classical Hodgkin lymphoma, NS¼ nodular sclerosis, MC¼mixedcellularity, CHL-NOS¼CHL—not otherwise specified.

Figure 3. FDG-PET/CT coronal section images displaying the sites with the highest FDG uptake in three different Hodgkin lymphomapatients with nodular lymphocyte predominance (NLP, panel A), nodular sclerosis (NS, panel B), and mixed cellularity (MC, panel C).The NLP patient had SUVmax/total of 9.0 g/ml, the NS patient had SUVmax/total of 16.8 g/ml, and the MC patient had SUVmax/total of21.0 g/ml, representing approximately average values for each of the histopathological subgroups

148 M Hutchings et al

Copyright � 2006 John Wiley & Sons, Ltd. Hematol Oncol 2006; 24: 146–150

DOI 10.1002/hon

whom had FDG-PET positive residual tumours after treat-

ment. The mean maximal SUV (corresponding to the

SUVmax/total value of the present study) was twice as high

in NS as in NLP, and a little higher in MC than in NLP

patients. Because of the low number of patients, the confi-

dence intervals were very large and the authors found a sig-

nificance test (ANOVA) obsolete. Still, it was concluded

that histopathological subtype does not influence the inten-

sity of glucose metabolism. It is questionable whether such

a conclusion should be drawn from a material which is too

small for statistical analysis and represents patients exam-

ined both before and after treatment [25]. The present study

points in the opposite direction, towards a difference in the

FDG uptake between classical HL and NLP as well as

between the subtypes of classical HL. This difference repre-

sents a difference in tumour glucose metabolism between

the different histological subtypes of HL.

It is not clear which cells are responsible for the high FDG

uptake in HL, but since the malignant cells in HL make up

only a very small proportion of the tumour volume, other

cells must account for the pathological uptake of FDG

[26]. Our finding may help future studies shedding light on

this issue. But what are the potential clinical implications

of this finding? On finding a difference in FDG uptake

between aggressive and indolent NHL, Schoder et al con-

cluded that SUV could be helpful in cases of discrepancy

between the histological subtype and the clinical behaviour

[24]. Since the difference in clinical behaviour between the

subtypes of HL is not as marked as in NHL, this is less likely

to be relevant for HL. Where the reading of an FDG-PET

scan is not straightforward, SUV can be used to guide the

diagnostic decision.When this is the case, it can be important

to realise the difference in FDGuptake between the subtypes.

FDG-PET is being introduced as a tool in the radiotherapy

planning of lymphoma [27–29]. SUV is used to define and

delineate the tumour volume in studies of FDG-PET in the

radiotherapy of solid tumours [19–21]. If SUV-aided radio-

therapy planning strategies are applied to lymphoma man-

agement, knowledge of the variation in SUV uptake might

be of interest. Most conclusions in the FDG-PET literature

regarding HL are drawn from studies of mixed HL popula-

tions, where different subtypes have not been considered

independently. This is probably due to the rather limited

number of patients in these studies. Knowing that FDG

uptake varies from subtype to subtype, it would be desirable

if histopathological groups were evaluated separately in

future studies of FDG-PET in HL.

In conclusion, this study shows significant differences in

FDG/glucose uptake between the different histopathologi-

cal subtypes of HL. The clinical implications of this finding

are not clear.

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