F-FDG Uptake in Reactive Neck Lymph Nodes of …jnm.snmjournals.org/content/49/7/1053.full.pdf18F-FDG Uptake in Reactive Neck Lymph Nodes of Oral Cancer: Relationship to Lymphoid Follicles

18F-FDG Uptake in Reactive Neck Lymph Nodesof Oral Cancer: Relationship to LymphoidFollicles

Tassei Nakagawa1,2, Masatoshi Yamada3, and Yoshio Suzuki3

1Department of Radiology, Asahi General Hospital, Chiba, Japan; 2Department of Radiology, Faculty of Medicine, Asahi GeneralHospital, Tokyo Medical and Dental University, Tokyo, Japan; and 3Department of Pathology, Asahi General Hospital, Chiba, Japan

PET using 18F-FDG is acceptable as a preoperative diagnostictool for head and neck cancer. PET combined with CT providesprecise localization of neck lymph nodes. Reactive lymphade-nopathy is well known as a principal cause of false-positive find-ings on PET/CT for nodal staging. We investigated the reactivelymph nodes of oral cancer to elucidate the 18F-FDG–avid areain these nodes. Methods: Surgically dissected neck lymphnodes of oral cancer were retrospectively reviewed. Of the pa-tients without pathologic nodal metastasis who underwent pre-operative PET/CT, 11 patients with 31 enlarged lymph nodes at20 levels were enrolled. The maximum standardized uptakevalue (SUVmax) of each lymph node was recorded. The diame-ters of the long and short axes were measured by pathologic sec-tioning, and the sectional surface area was calculated in squaremillimeters. Besides being stained with hematoxylin and eosin,the sections were immunohistochemically stained by CD79afor B cells, CD3 for T cells, CD68 for macrophages, CD21 for fol-licular dendritic cells (FDCs), and ubiquitous glucose transportertype 1 (GLUT1). The expression of GLUT1 was compared withstaining of lymphoid cells. The numbers of total lymphoid folliclesand hyperplastic secondary follicles were counted on CD21 andhematoxylin and eosin sections, respectively. The follicular reac-tivity index was determined as the ratio of secondary folliclesrelative to total follicles on the corresponding section. These pa-rameters of reactive lymph nodes were analyzed on a level basis.Results: GLUT1 was expressed exclusively in lymphoid follicles,whose staining pattern was identical to that of FDCs. The calcu-lated sectional area correlated significantly with the number oftotal follicles (r 5 0.560; P 5 0.0101). SUVmax did not correlatewith the number of total follicles (P 5 0.8947) but correlatedsignificantly with the number of secondary follicles (r 5 0.535;P 5 0.0152). In addition, a strong positive correlation betweenSUVmax and the follicular reactivity index was demonstrated(r 5 0.829; P , 0.0001). Conclusion: GLUT1 was expressedon cytoplasmic protrusions of FDCs in lymphoid follicles. The18F-FDG accumulation in reactive lymphadenopathy dependedon secondary follicles. FDCs in germinal centers of secondaryfollicles are suggested to be avid for 18F-FDG and the principalcause of false-positive findings for nodal staging.

Key Words: follicular dendritic cell; germinal center; glucosetransporter; reactive lymphadenopathy; oncology; PET/CT

J Nucl Med 2008; 49:1053–1059DOI: 10.2967/jnumed.107.049718

PET is an imaging tool that provides biochemical andphysiologic information (1). The glucose analog 18F-FDGis transported into cells by facilitative glucose transporters(2). An overexpression of ubiquitous glucose transportertype 1 (GLUT1) in malignant tumors allows 18F-FDG PETto have a useful role in oncology (3). The use of PET/CTfor nodal staging is based on an increased 18F-FDG ac-cumulation in metastatic lymph nodes. In-line PET withCT, furthermore, enables precise localization of 18F-FDG–avid spots on the conventional image and increases diag-nostic accuracy for nodal staging in the head and neck(4–6). It is well known, however, that 18F-FDG accumu-lates in areas of inflammation and in reactive lymphade-nopathy (7,8). In previous articles, GLUT1 expression inlymphoid follicles was reported in mediastinal lymphade-nopathy of lung cancer patients, which the authors con-cluded was a major cause of false-positive findings on PET/CT for nodal staging of lung cancer (8,9). The semiquan-titative standardized uptake value (SUV) in lymph nodes,however, did not correlate with the area and grade of GLUT1expression (9). Lymphoid follicles are composed of lym-phocytes, macrophages, and follicular dendritic cells(FDCs). Networks of these cells in lymphoid follicles makeup germinal centers, which can easily be seen on histologicsections stained with hematoxylin and eosin (H&E) (10) andcan be differentiated by immunohistochemical methods; thatis, B lymphocytes by CD79a (11), T lymphocytes by CD3(12), macrophages by CD68 (13), and FDCs by CD21 (14).

The purpose of this study was to elucidate 18F-FDG–avidcells in reactive lymphadenopathy. First, an immunohisto-chemical method was used on reactive neck lymphadenop-athy of oral cancer to assess GLUT1 expression. Then,18F-FDG uptake in lymphadenopathy was evaluated bycomparison with the lymphoid follicles.

Received Dec. 9, 2007; revision accepted Mar. 7, 2008.For correspondence or reprints contact: Tassei Nakagawa, I-1326 Asahi-

city, Chiba 289-2511, Japan.E-mail: [email protected] ª 2008 by the Society of Nuclear Medicine, Inc.

18F-FDG UPTAKE IN REACTIVE LYMPH NODES • Nakagawa et al. 1053

by on March 31, 2020. For personal use only. jnm.snmjournals.org Downloaded from

http://jnm.snmjournals.org/

MATERIALS AND METHODS

PatientsThis retrospective research was approved by an institutional

review board and did not require the informed consent of thepatients. The cases of patients with oral cancer who underwentneck dissection with or without primary excision from March 2005to May 2007 were reviewed. Twenty patients underwent PET/CTfor clinically indicated nodal staging of newly diagnosed oralcancer and for the evaluation of clinically suspected recurrentlymphadenopathy in the neck. Patients with previous radiotherapyin the neck area or with pathologically proven neck metastaseswere excluded. With this exclusion, 14 patients with pathologicallynegative necks remained, and 11 patients (6 men and 5 women;average age, 62.6 y; range, 26–83 y) had lymphadenopathy at oneor more levels. Thirty-one enlarged nodes exceeding 10 mm inmaximal diameter (average, 13.5 mm; range, 10–19 mm) at 20levels were included. PET/CT was performed within 1 mo beforesurgery (average, 21 d; range, 13–30 d). The pathologic finding forthe enrolled patients was squamous cell carcinoma, except for1 case of adenoid cystic carcinoma. The primary lesion wasresected at this research in all patients except one, who had alreadyundergone surgery for the primary excision. Two of the enrolledpatients received oral chemotherapy before surgery. The otherpatients had no previous therapy for the neck lesion.

PET/CTThe patients received an intravenous injection of 3 MBq of

18F-FDG per kilogram. The 18F-FDG was produced in-houseusing a 10-MeV cyclotron (Cyclone 10/5; IBA) and an automatedsynthesis module (TRACERlab; GE Healthcare). All patientsfasted for at least 6 h before tracer injection, and plasma glucosewas in the acceptable range in all patients (mean, 84.8 mg/dL;range, 65–104 mg/dL). A PET/CT (Biograph LSO Duo; Siemens)study of the torso in arms-up position was started 110 min afterthe 18F-FDG administration, took approximately 20 min, and wasfollowed by imaging of the head and neck with the patient’s armsdown. Thus, a tracer uptake period of 130 min was allowed for thededicated head and neck scan. The CT (2-detector system) datawere used for attenuation correction of the PET emission images.

The CT parameters of the dedicated head and neck scan were asfollows: 3-mm slice width; 2.5-mm collimation; 1.5-s gantry rota-tion; 5-mm gantry feed per rotation; 130-kVp tube voltage; 67-mAtube current; and 500-mm field of view. PET emission data were

acquired in 3-dimensional mode with a spatial resolution of 6 mm infull width at half maximum. The dedicated head and neck PETparameters were as follows: 2 bed positions at 3 min per position;162-mm axial field of view; and 585-mm transaxial field of view.The reconstruction zoom factor was 2, and the reconstructed imageshad 1.3-mm pixels displayed in a 256 · 256 matrix.

Lymph Node Matching and Image AnalysesAll patients underwent unilateral or bilateral neck dissection, and

the surgeon assigned each lymph node to a neck level. The excisednodes were fixed in formalin, embedded in paraffin, sectioned, andstained with H&E separately for each neck level. Of the patientswith a pathologically negative neck, enlarged lymph nodes exceed-ing 10 mm on the section were included in the study. The maximumdiameters in the long and short axes were measured on the section.Then, size was calculated as the sectional area in square millimeters,approximately by the formula for an oval area; that is, 0.8· (theproduct of a long- and a short-axis diameter).

The included lymph nodes were identified on the CT image (15).Because it was difficult to discriminate each node if more than onenode was enlarged at the same level, the average value in that levelwas used in such cases. A workstation featuring PET and CT fusion(e.soft; Siemens) was used for image display and analysis. An ovalregion of interest was placed on the largest displayed lymph node.The SUVof the pixels in that region of interest was calculated usingthe formula SUV 5 Ctis/(dose/wt), where Ctis is the decay-correctedtracer tissue concentration (Bq/mL), assuming a tissue density of1 g/mL; dose is the injected total dose (Bq); and wt is the patient’sbody weight (g). The maximum SUV (SUVmax) in the region ofinterest was recorded as a semiquantitative evaluation of 18F-FDGuptake in the lymph nodes.

ImmunohistochemistryImmunohistochemistry by the biotin–avidin immunoenzymatic

method was performed on the included lymph nodes. Sections 4 mmthick were freed of paraffin (using xylene) and rehydrated in agraded ethanol series. Tissue antigens were retrieved by microwaveirradiation (CD79a, CD68) or by autoclaving (GLUT1, CD3, andCD21; 121�C for 15 min) with a 10 mmol/L concentration of citratebuffer (pH 6.0). An automated staining machine (Autostainer;DAKO) was used, and the sections were rinsed with phosphate-buffered saline (pH 7.6) between each step. After endogenous per-oxidase blocking by 3% hydrogen peroxide, the sections wereincubated with primary antibodies: rabbit anti-GLUT1 polyclonal

FIGURE 1. Secondary lymphoid folliclein neck node (in left level II of patient 7).(A) Hyperplastic germinal center com-posed of light zone (LZ) and dark zone(DZ) is asymmetrically surrounded bydarkly stained mantle zone (MZ) (H&E;bar, 250 mm). (B) On CD21 section,fingerprintlike configuration formed byprotrusions of FDCs is characteristicallydepicted, notably in light zone (bar, 250mm; ·100).

1054 THE JOURNAL OF NUCLEAR MEDICINE • Vol. 49 • No. 7 • July 2008



TA

BL

E1

Patients

and

Reactive

Neck

Lym

ph

No

des

Patient

no

.A

ge

(y)

Sex

Prim

ary

site

Tsta

ge

Path

olo

gy

Inte

rval*

(d)

Pre

vio

us

thera

py

Leve

lo

fLN

s

Dia

mete

r

of

LN

s(m

m)

SU

Vm

ax

of

LN

s

No

.o

f

tota

lfo

llicle

s

No

.o

f

seco

nd

ary

folli

cle

s

Fo

llicula

r

reactivity

ind

ex

(%)

158

FR

tong

ue

T1

SC

C13

LII

y12.5

·7.5

2.1

0z

120

37.5

31.3

263

FL

buccalm

uco

sa

T2

SC

C23

Op

era

tio

n§

RII

y11.5

·5.5

2.9

182

21.5

26.2

355

MR

tong

ue

T1

SC

C17

RII

y15

·10.5

2.5

892.5

30

32.4

RIII

19

·8

1.3

467

34.5

478

MP

ala

teT

1A

deno

idcystic

carc

ino

ma

28

RII

y14

·7.5

1.8

3147

64.1

LII

y14

·8

2.0

8115.5

13

11.3

563

MR

tong

ue

T1

SC

C28

Chem

oth

era

pyk

RII

¶12

·9

3.7

370.3

29.8

42.3

672

FR

buccalm

uco

sa

T1

SC

C21

Chem

oth

era

pyk

RII

y10

·8

2.0

561.5

5.5

8.9

RIIIy

10

·8

1.8

595

44.2

764

ML

tong

ue

T1

SC

C16

LII

16

·10

2.1

7198

46

23.2

868

FR

tong

ue

T1

SC

C15

RII

15

·8

1.9

066

913.6

959

ML

gin

giv

aT

1S

CC

30

LII

19

·8

1.4

366

46.1

10

26

MR

tong

ue

T2

SC

C23

LI

12

·7

1.4

798

20

20.4

RII

14

·10

1.8

2128

13

10.2

LII

12

·7

2.9

157

20

35.1

RIII

14

·9

3.2

2115

41

35.7

LIII

16

·10

2.7

5162

55

34.0

RV

y13.5

·8.5

2.3

590

25.5

28.3

11

83

FR

gin

giv

aT

2S

CC

27

RI

10

·7

2.2

873

21

28.8

RII

18

·11

2.1

5188

49

26.1

*Days

betw

een

PE

T/C

Tstu

dy

and

surg

ery

.yA

vera

ge

valu

es

of

2ly

mp

hno

des.

zS

UV

was

estim

ate

do

nP

ET

imag

eo

fto

rso

.§P

rim

ary

lesi

on

and

ipsila

tera

lneck

LN

shad

been

resecte

d1

yand

8m

ob

efo

re.

k Chem

oth

era

py

by

teg

afu

rw

ith

gim

era

cil

(TS

-1;

Taih

o)

had

been

taken

ora

llyfo

r1

mo

befo

reo

pera

tio

n.

¶A

vera

ge

valu

es

of

4ly

mp

hno

des.

Level

I5

sub

menta

land

sub

mand

ibula

rno

des;

leve

lII

5up

per

deep

cerv

ical

no

des;

level

III

5m

idd

led

eep

cerv

ical

no

des;

leve

lIV

5lo

wer

deep

cerv

ical

no

des;

leve

lV

5sp

inal

accesso

ryand

transve

rse

cerv

icalno

des.

SC

C5

sq

uam

ous

cell

carc

ino

ma;

LN

s5

lym

ph

no

des.




antibody (1:100; DAKO), anti-CD79a (1:60, clone JCB 117;DAKO), anti-CD3 (clone PS1; Nichirei), anti-CD68 (1:60, cloneKP1; DAKO), and anti-CD21 (1:60, clone 1F8; DAKO). Thesections then were incubated with biotinylated secondary antibodyand peroxidase-labeled streptavidin–biotin complex (LSAB kit;DAKO). Finally, the sections were treated with diaminobenzidine aschromogen and counterstained with hematoxylin.

Lymphoid FolliclesFunctionally, there are 2 types of lymphoid follicles. Secondary

lymphoid follicles are considered functionally reactive to antigenicstimuli and are characterized by a germinal center and a surroundingasymmetric mantle zone. Primary follicles, in contrast, are typicallysmall, with or without a symmetric concentric mantle zone. Lym-phoid follicles containing FDCs are explicitly demonstrated onCD21 sections even if the follicles are too small to be recognized onH&E sections. On H&E sections, in contrast, the mantle zonesurrounding the germinal center is easily recognized as a darklystaining area.

At first, the total follicles on the section were counted by CD21staining. Secondary follicles were counted on the correspondingH&E section. Because secondary follicles are not necessarily seencompletely on histologic sections, we chose as the area to be countedeither a germinal center exceeding 0.25 mm in diameter with orwithout a mantle zone or a germinal center surrounded by a mantlezone with an asymmetric concentric configuration regardless of itssectional size (Fig. 1). The follicular reactivity index was thendetermined as the ratio of secondary follicles relative to totalfollicles in the section.

Statistical AnalysisThe correlation between the nodal SUVmax and other nodal

parameters was determined using the Pearson correlation coeffi-cient. A P value of less than 0.05 was considered statisticallysignificant.

RESULTS

SUVmax in Reactive Lymph Nodes

The included lymph nodes are summarized in Table 1.When more than one lymph node was present at the samelevel, the average values for SUVmax, diameter, number offollicles, and follicular reactivity index were used for theanalyses for that level. For lymphadenopathy with anSUVmax ranging from 1.34 to 4.53 (average, 2.24), 3 nodeson 2 levels were false-positive, with a cutoff of 3.5. SUVmaxwas not associated with nodal size calculated as area insquare millimeters (P 5 0.5281).

FIGURE 2. Secondary follicle stainedby GLUT1 (A), CD79a (B), CD3 (C), andCD68 (D) (same follicle as in Fig. 1). (A)Marked similarity of staining pattern be-tween GLUT1 and CD21 (Fig. 1B) ingerminal center is noted. Erythrocytesseen in extrafollicular area are positivecontrols. (B) B cells are numerous inlymphoid follicle and medullary cords(MC). (C) T cells predominate in paracor-tex (PC), and a few are also seen withingerminal center. (D) Macrophages aredispersed in germinal center and medul-lary cord (MC) and are rarely seen inparacortex (bar, 250 mm; ·100).

FIGURE 3. Nodal size calculated as cut surface area in squaremillimeters shows positive correlation with number of totallymphoid follicles. Solid line indicates linear best fit.




GLUT1 Expression in Lymphoid Follicles

Immunohistochemistry demonstrated that GLUT1 wasexpressed in lymphoid follicles other than the erythrocytesof positive controls in the extrafollicular area. The immuno-histochemistry for lymphoid cells showed a distributiondifferent from that of GLUT1, with the exception of CD21.The staining pattern in lymphoid follicles for GLUT1 wasmarkedly similar to that for CD21, which was characterizedby a fingerprintlike configuration (Fig. 2A). In secondaryfollicles, GLUT1 staining was relatively localized to thegerminal center whereas CD21 staining was beyond thegerminal center. In addition, the cortical side of the germinalcenter was predominantly stained by both GLUT1 and CD21,with areas of variation. B cells, on CD79a sections, wereobserved in cortical areas, including lymphoid follicles andthe medullary cord (Fig. 2B). T cells, on CD3 sections, wereobserved mainly in the paracortex and scattered in thegerminal centers of secondary follicles (Fig. 2C). Macro-phages, on CD68 sections, were observed in the medullarycords to a variable degree and dispersed within lymphoidfollicles (Fig. 2D).

18F-FDG Uptake and Follicular Reactivity

The number of total lymphoid follicles counted on CD21sections correlated significantly with nodal size (r 5 0.560;P 5 0.0101) (Fig. 3). No relationship between nodal SUVmaxand the number of total lymphoid follicles was noted (P 5

0.8947) (Fig. 4). However, nodal SUVmax correlated signif-icantly with the number of secondary follicles (r 5 0.535; P 5

0.0152) (Fig. 5A). In addition, the follicular reactivity index,ranging from 1.9% to 57.5% (average, 21.4%) on a nodalbasis, showed a strong positive correlation with SUVmax on alevel basis (r 5 0.829; P , 0.0001) (Fig. 5B).

DISCUSSION

In the routine clinical setting, we perform PET/CT with atracer uptake period of 110 min for whole-body imaging and130 min for head and neck imaging. We apply an uptakeperiod longer than the standard because of previous reportsabout the usefulness of delayed PET imaging for detectingmalignant lesions, including nodal metastases (16–18). Innodal staging, however, there is a trade-off of some false-positive findings against the false-negatives. The sensitivityand specificity for neck nodal staging in our study were75.0% and 94.4%, respectively, on whole-body imaging witha cutoff SUV of 3.5. With the same cutoff value, sensitivityand specificity on dedicated head and neck imaging were75.0% and 89.5%, respectively. This assessment, whosevalues are in line with other articles (5,19,20), was performedfor lymphadenopathy that could be detected on CT andcalculated on a level basis. Compared with whole-bodyimaging, dedicated head and neck scanning showed anincrease in SUVmax for most lymph nodes. There werereactive nodes, even a few with an SUVmax exceeding thecutoff value, only in head and neck imaging. Furthermore, asother investigators reported (21–23), there were occult met-astatic nodes showing an SUVmax of much less than thecutoff value. Thus, it is not surprising that the dedicated headand neck imaging had a higher false-positive rate (10.5%)than the whole-body scanning (5.6%) without having animproved sensitivity. In addition, false-positive nodes arelikely to be due to constant stimuli by carcinogenic andextrinsic antigens.

The current study showed that GLUT1 was expressedexclusively in lymphoid follicles, as has been found by

FIGURE 5. (A) Maximum SUV of lymphnodes correlates significantly with num-ber of secondary follicles. (B) Strongpositive correlation is seen betweenSUVmax of lymph nodes and follicularreactivity index. Solid lines indicate linearbest fit.

FIGURE 4. No relationship is seen between number of totallymphoid follicles and SUVmax of lymph nodes. In contrast,SUVmax shows positive relationship with number of secondaryfollicles.




other investigators (8,9). The identical staining patternfound between GLUT1 and CD21 suggests that FDCs inlymphoid follicles express GLUT1 but does not indicate,however, that 18F-FDG accumulates in all lymphoid folli-cles harboring FDCs, because the number of total follicleswas not associated with nodal SUVmax. Rather, a signif-icant correlation between secondary follicles and nodalSUVmax increases the likelihood that 18F-FDG accumu-lates in secondary follicles.

Immunohistochemistry by lymphoid cells reflects thefunctions of lymph nodes, which comprise cortex, paracor-tex, medullary cord, and lymph-filled sinus. Lymphadenop-athy is recognized when any of these components becomeenlarged. B cells predominate in the cortex, where lymphoidfollicles generally exist, and plasma cells of B cell linkagepredominate in the medullary cords. T cells predominate inthe paracortex and are partially seen in the lymphoid folli-cles. Macrophages with phagocytized debris typically re-main in the sinus or medullary cord, and some macrophages(tangible body macrophages) are dispersed in the germinalcenter. Primary follicles housing B cells are stimulated tosecondary follicles when they encounter an antigenic pre-sentation in which the germinal center is formed in associ-ation with other lymphoid cells (24). T cells also encounter anantigen displayed on dendritic cells in the paracortex, andthe migration of T cells to lymphoid follicles is essential togerminal center formation (25,26). Secondary follicles withgerminal centers involute when this follicular-center cellreaction is over (27), resulting in the deposit of memory cellsand macrophages in the extrafollicular area. Local immuno-logic reactions, thus, remain in the extrafollicular area after

secondary follicles involute, contributing to extrafollicularenlargement (Fig. 6). Secondary follicles are sometimesfound deep in lymph nodes, especially with increased 18F-FDG accumulation (Fig. 7). Therefore, both small primaryand hyperplastic secondary follicles contribute to nodalenlargement, explaining the significant correlation betweennodal size and the number of total follicles.

In the germinal centers of secondary follicles, B cellmaturation from centroblasts to plasma cell precursorstakes place through processes such as proliferation, differ-entiation, and apoptosis. This follicular-center cell reactionoccurs in association with T cells, macrophages, and FDCs.Centroblasts on the deep side of follicles (dark zone) evolveto centrocytes on the cortical side (light zone), where theyundergo somatic hypermutation to make antigen receptorsthat perfectly fit the presented antigen. The polarity of thegerminal center shown by GLUT1, FDC, and T cells ex-plains that centrocytes were near the FDC network in as-sociation with T cells during this trial-and-error process(25,28,29). 18F-FDG appears to accumulate in FDCs withingerminal centers, where FDCs play an important role in Bcell maturation.

In the present study, the SUVmax of reactive lymph nodesranged up to 4.53, and the highest follicular reactivity indexof 57.4% was found at the same level. It was uncertain,however, if both highest values were estimated in the samenode and if the follicular reactivity index could be extrapo-lated to a higher value on a nodal basis. Moreover, this studywas performed solely on oral cancer patients. Further inves-tigations need to be performed on larger sample sizes and inother regional lymphadenopathies. We believe, however, that

FIGURE 7. Reactive lymphadenopathyof neck. (A) Enlarged lymph node withfalse-positive 18F-FDG uptake (in rightlevel II of patient 5) shows hyperplasticlymphoid follicles on H&E section. (B)Hyperplastic germinal centers located indeeper area and in cortex are demon-strated on CD21 section (bar, 500 mm;·20).

FIGURE 6. Lymphadenopathy of neck.(A) Enlarged lymph node with true-nega-tive 18F-FDG uptake (in right level III ofpatient 3) shows enlargement in extra-follicular area on H&E section. (B) Smallprimary follicles dispersed in lymph nodeare recognized on CD21 section (bar, 500mm; ·20).




FDCs express glucose transporter in lymphoid follicles evenif they are located in other regions and are avid for glucosewhen they are functionally active.

To our knowledge, this is the first report of FDCs produc-ing false-positive findings on 18F-FDG PET for nodal stag-ing. Germinal centers harboring FDCs and other lymphoidcells are physiologically found in the extralymphoid organs,such as in the gastrointestinal tract. FDCs probably havean important role when the organs react to local antigenicstimuli in concert with the lymphoid cells. Despite muchresearch about 18F-FDG uptake in various inflammatoryprocesses, GLUT1 expression in FDCs never has been rec-ognized. Therefore, the present finding should be helpful inunderstanding the accumulation of 18F-FDG in inflammatoryprocesses and its physiologic mechanism.

CONCLUSION

The current study suggests that FDCs located in lym-phoid follicles express GLUT1. 18F-FDG uptake in reactivelymph nodes is associated with secondary follicles. There-fore, FDCs in the germinal centers of secondary folliclesmay be avid for 18F-FDG.

ACKNOWLEDGMENTS

We thank Tetsuya Uno for excellent technical assistance.We also thank Isao Umehara, Katsuya Yoshida, MasakazuAkiba, Yuji Murata, and Hitoshi Shibuya.

REFERENCES

1. Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET in

oncology. Radiology. 2004;231:305–332.

2. Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994;219:713–725.

3. Smith TA. Facilitative glucose transporter expression in human cancer tissue. Br

J Biomed Sci. 1999;56:285–292.

4. Adams S, Baum RP, Stuckensen T, Bitter K, Hor G. Prospective comparison of18F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph

node staging of head and neck cancer. Eur J Nucl Med. 1998;25:1255–1260.

5. Schoder H, Yeung HW, Gonen M, et al. Head and neck cancer: clinical

usefulness and accuracy of PET/CT image fusion. Radiology. 2004;231:65–72.

6. Jeong HS, Baek CH, Son YI, et al. Use of integrated 18F-FDG PET/CT to

improve the accuracy of initial cervical nodal evaluation in patients with head

and neck squamous cell carcinoma. Head Neck. 2007;29:203–210.

7. Kubota R, Yamada S, Kubota K, et al. Intratumoral distribution of fluorine-18-

fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation

tissues studied by microautoradiography. J Nucl Med. 1992;33:1972–1980.

8. Chung JH, Cho KJ, Lee SS, et al. Overexpression of glut1 in lymphoid follicles

correlates with false-positive 18F-FDG PET results in lung cancer staging. J Nucl

Med. 2004;45:999–1003.

9. Chung JH, Lee WW, Park SY, et al. FDG uptake and glucose transporter type

1 expression in lymph nodes of non-small cell lung cancer. Eur J Surg Oncol.

2006;32:989–995.

10. von der Walk P, Meijer CJLM. Lymph nodes. In: Mills SE, ed. Histology for

Pathologists. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:

763–780.

11. Mason DY, Cordell JL, Brown MH, et al. CD79a: a novel marker for B-cell

neoplasms in routinely processed tissue samples. Blood. 1995;86:1453–

1459.

12. Steward M, Bishop R, Piggott NH, et al. Production and characterization of a

new monoclonal antibody effective in recognizing the CD3 T-cell associated

antigen in formalin-fixed embedded tissue. Histopathology. 1997;30:16–22.

13. Pulford KA, Rigney EM, Micklem KJ, et al. KP1: a new monoclonal antibody

that detects a monocyte/macrophage associated antigen in routinely processed

tissue sections. J Clin Pathol. 1989;42:414–421.

14. Maeda K, Matsuda M, Suzuki H, et al. Immunohistochemical recognition of

human follicular dendritic cell (FDCs) in routinely processed paraffin sections.

J Histochem Cytochem. 2002;50:1475–1485.

15. Som PM, Curtin HD, Mancuson AA. Imaging-based nodal classification for

evaluation of neck metastatic adenopathy. AJR. 2000;174:837–845.

16. Hustinx R, Smith RJ, Benard F, et al. Dual time point fluorine-18 fluo-

rodeoxyglucose positron emission tomography: a potential method to differen-

tiate malignancy from inflammation and normal tissue in the head and neck. Eur

J Nucl Med. 1999;26:1345–1348.

17. Zhuang H, Pourdehnad M, Lambright ES, et al. Dual time point 18F-FDG PET

imaging for differentiating malignant from inflammatory processes. J Nucl Med.

2001;42:1412–1417.

18. Ma SY, See LC, Lai CH, et al. Delayed 18F-FDG PET for detection of paraaortic

lymph node metastases in cervical cancer patients. J Nucl Med. 2003;44:1775–

1783.

19. Vermeersch H, Loose D, Ham H, et al. Nuclear medicine imaging for the

assessment of primary and recurrent head and neck carcinoma using routinely

available tracers. Eur J Nucl Med Mol Imaging. 2003;30:1689–1700.

20. Schoder H, Yeung HW. Positron emission imaging of head and neck cancer,

including thyroid carcinoma. Semin Nucl Med. 2004;34:180–197.

21. Stoeckli SJ, Steinert H, Pfaltz M, et al. Is there a role for positron emission

tomography 18F-fluorodeoxyglucose in the initial staging of nodal negative

oral and oropharyngeal squamous cell carcinoma. Head Neck. 2002;24:345–

349.

22. Schoder H, Carlson DL, Kraus DH, et al. 18F-FDG PET/CT for detecting nodal

metastases in patients with oral cancer staged N0 by clinical examination and

CT/MRI. J Nucl Med. 2006;47:755–762.

23. Nahmias C, Carlson ER, Duncan LD, et al. Positron emission tomography/

computerized tomography (PET/CT) scanning for preoperative staging of pa-

tients with oral/head and neck cancer. J Oral Maxillofac Surg. 2007;65:2524–

2535.

24. Allen CD, Okada T, Cyster JG. Germinal-center organization and cellular

dynamics. Immunity. 2007;27:190–202.

25. Garside P, Ingulli E, Merica RR, et al. Visualization of specific B and T

lymphocyte interactions in the lymph node. Science. 1998;281:96–99.

26. Cyster JG, Ansel KM, Reif K, et al. Follicular stromal cells and lymphocyte

homing to follicles. Immunol Rev. 2000;176:181–193.

27. Vinuesa CG, Cook MC. The molecular basis of lymphoid architecture and B cell

responses: implications for immunodeficiency and immunopathology. Curr Mol

Med. 2001;1:689–725.

28. Li L, Choi YS. Follicular dendritic cell-signaling molecules required for

proliferation and differentiation of GC-B cells. Semin Immunol. 2002;14:259–

266.

29. Kosco-Vilbois MH. Are follicular dendritic cells really good for nothing? Nat

Rev Immunol. 2003;3:764–769.




Doi: 10.2967/jnumed.107.0497182008;49:1053-1059.J Nucl Med.

Tassei Nakagawa, Masatoshi Yamada and Yoshio Suzuki Lymphoid Follicles

F-FDG Uptake in Reactive Neck Lymph Nodes of Oral Cancer: Relationship to18

http://jnm.snmjournals.org/content/49/7/1053This article and updated information are available at:

http://jnm.snmjournals.org/site/subscriptions/online.xhtml

Information about subscriptions to JNM can be found at:

http://jnm.snmjournals.org/site/misc/permission.xhtmlInformation about reproducing figures, tables, or other portions of this article can be found online at:

(Print ISSN: 0161-5505, Online ISSN: 2159-662X)1850 Samuel Morse Drive, Reston, VA 20190.SNMMI | Society of Nuclear Medicine and Molecular Imaging

is published monthly.The Journal of Nuclear Medicine

© Copyright 2008 SNMMI; all rights reserved.


http://jnm.snmjournals.org/content/49/7/1053

http://jnm.snmjournals.org/site/misc/permission.xhtml

http://jnm.snmjournals.org/site/subscriptions/online.xhtml


Documents

F-FDG Uptake in Reactive Neck Lymph Nodes of …jnm.snmjournals.org/content/49/7/1053.full.pdf18F-FDG Uptake in Reactive Neck Lymph Nodes of Oral Cancer: Relationship to Lymphoid Follicles