99mtc-edda/hynic-toc and 18f-fdg in thyroid cancer patients with negative 131i whole-body scans

European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 3, March 2004

Abstract. Several studies have reported on the expres-sion of somatostatin receptors in patients with differenti-ated thyroid cancer (DTC). The aim of this study was toevaluate the imaging abilities of a recently developedtechnetium-99m labelled somatostatin analogue, 99mTc-EDDA/HYNIC-TOC (99mTc-TOC), in terms of preciselocalisation of disease. The study population comprised54 patients (24 men, 30 women; age range 22–90 years)with histologically confirmed DTC who presented withrecurrent or persistent disease as indicated by elevatedTg levels after initial treatment. All patients were nega-tive on the iodine-131 post-therapy whole-body scans.Fluorine-18 fluorodeoxyglucose positron emission to-mography (18F-FDG PET) was performed in a subgroupof 36 patients. The study population consisted of twogroups: Group A (n=22) comprised patients with diseaserecurrence as shown by elevated Tg levels but withoutdetectable pathology. In group B (n=32), pre-existing le-sions were known. Among the 54 cases, SSTR scintigra-phy was true positive in 33 (61.1%), true negative in 4(7.4%) and false negative in 17 (31.5%) cases, which re-sulted in a sensitivity of 66%. A total of 138 tumour fociwere localised in 33 patients. The fraction of true posi-tive 99mTc-TOC findings was positively correlated(P<0.01) with elevated Tg levels (higher than 30 ng/ml).Despite two false positive findings, analysis on a lesionbasis demonstrated better diagnostic efficacy with 18F-FDG PET (P<0.001); however, it also revealed substan-tial agreement between the imaging techniques [Cohen’skappa of 0.62 (0.47–0.78)]. In conclusion, scintigraphywith 99mTc-TOC might be a promising tool for treatmentplanning; it is easy to perform and showed sufficient ac-

curacy for localisation diagnostics in thyroid cancer pa-tients with recurrent or metastatic disease.

Keywords: Technetium-99m – Somatostatin – Tyrosine-octreotide – Scintigraphy – FDG-PET – Thyroid carci-noma

Eur J Nucl Med Mol Imaging (2004) 31:330–341DOI 10.1007/s00259-003-1376-x

Introduction

The overall prognosis of differentiated thyroid carcino-ma (DTC) is generally rather good, with low metastaticpotential and a high chance of definitive cure [1]; how-ever, carcinoma type, stage and histological grading in-fluence the individual outcome. Therefore, clinical sur-veillance after surgery and radio-ablation is very impor-tant for early detection of residual disease or recurrence.For this purpose, thyroglobulin (Tg) measurement hasbecome a very important clinical tool. Tg determinationis considered the most sensitive and specific marker ofDTC [2, 3, 4]. If laboratory monitoring shows increasingTg levels or other conventional imaging modalities aresuspicious for tumour recurrence, iodine-131 (131I) stud-ies under TSH stimulation (either after withdrawal of L-thyroxine therapy or after recombinant human TSH stim-ulation) are required. In the event of pathological uptake,patients may undergo administration of high-dose radio-iodine therapy. Importantly, detectable serum Tg levelsnot infrequently occur in association with negative 131Iwhole-body scans in patients with DTC. If malignant le-sions are no longer taking up radioiodine, many othertechniques are used for precise localisation of malignantfoci, since the treatment regimen of thyroid carcinomapatients especially depends on the size and extent of tu-mour when detected [5]. For localisation diagnostics atan early stage, especially if radioiodine scanning is nega-

Michael Gabriel (✉)Department of Nuclear Medicine, University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austriae-mail: [email protected].: +43-512-5042677, Fax: +43-512-5042683

Original article

99mTc-EDDA/HYNIC-TOC and 18F-FDG in thyroid cancer patientswith negative 131I whole-body scansMichael Gabriel1, Franz Froehlich1, Clemens Decristoforo1, Christian Ensinger2, Eveline Donnemiller1, Elisabeth von Guggenberg1, Dirk Heute1, Roy Moncayo1

1 Department of Nuclear Medicine, University of Innsbruck, Innsbruck, Austria2 Department of Pathology, University of Innsbruck, Austria

Received: 9 August 2003 / Accepted: 1 October 2003 / Published online: 19 November 2003© Springer-Verlag 2003

331


tive, fluorine-18 fluorodeoxyglucose positron emissiontomography (18F-FDG PET) has already proven of value[6, 7, 8], even when other diagnostic procedures [ultra-sound, computed tomography (CT), magnetic resonanceimaging (MRI)] are normal. Therefore, 18F-FDG PET,which characterises hypermetabolic tumour tissue, hasgained widespread acceptance as a very sensitive methodin the follow-up of thyroid cancer patients, although itremains an expensive procedure which is not easilyavailable and needs adequate preparation of patients, i.e.a fasting period of at least 6 h before PET scanning. Be-sides 18F-FDG, other unspecific oncotropic radiopharma-ceuticals, e.g. 99mTc-sestamibi or 99mTc-tetrofosmin, areused for the diagnosis of recurrent and metastatic disease[9, 10, 11]. The uptake mechanism of these lipophiliccationic agents is different from that of 18F-FDG, in thataccumulation occurs within the mitochondria. These99mTc-labelled tracers are advantageous in terms of avail-ability and performance, i.e. results are independent ofthe blood glucose level, preparation is simple and the ra-diation dose is lower. However, sensitivity and specifici-ty are moderate compared with other imaging techniquesused for the follow-up of thyroid cancer [12, 13].

Another approach for localisation diagnostics is basedon specific binding of radiopharmaceuticals on somato-statin receptor (SSTR)-expressing tumour lesions. SSTRscintigraphy has become a reliable, non-invasive andhighly sensitive procedure for detection of a variety ofendocrine and non-endocrine tumours [14, 15, 16, 17,18].

Several studies have also reported on the expressionof somatostatin receptors in DTC [19, 20, 21, 22, 23, 24,25, 26, 27] using 111In-DTPA-octreotide (Octreoscan) asthe gold standard in SSTR scintigraphy. However, someresults of these studies were not clearly convincing, sothere is still no consensus concerning the clinical valueof this technique. Taking into consideration that smalland heterogeneous patient groups were investigated, i.e.several tumour types and grades showing different io-dine avidity were included, the differences might havebeen largely related to variable and sometimes decreaseddensity of somatostatin receptors in these tumours [28].For our study a new 99mTc-labelled compound, 99mTc-EDDA/HYNIC-TOC (99mTc-TOC), with high SSTR-af-finity, was used [29, 30]. The favourable imaging prop-erties of 99mTc-TOC as compared with 111In-DTPA-oct-reotide [31] makes this radiopharmaceutical a good can-didate for visualisation of SSTR-expressing tumours, es-pecially those with variable and lower receptor expres-sion. 99mTc-TOC combines advantages of improvedpharmacokinetics with higher spatial resolution due tothe use of the 99mTc label. The purpose of this study wasto evaluate the efficacy of the new 99mTc-labelled com-pound for detection of SSTR-positive lesions in a largerseries of patients with recurrent or metastatic disease asshown by elevated Tg levels. All patients were negativein the post-therapy whole-body radioiodine scans. In a

subset of patients we prospectively compared the SSTRprofile with the metabolic pattern using 18F-FDG PET inorder to obtain a more complete biochemical understand-ing of the disease.

Materials and methods

Patient eligibility criteria. Fifty-four patients (24 men, 30 women;age range 22–90 years; mean age ± SD, 63.9±15.9 years) with his-tologically confirmed DTC were included for localisation diagnos-tics. The patients had undergone near-total thyroidectomy and ra-dioactive ablation of the remnants and presented with either recur-rent or persistent disease as indicated by elevated Tg levels. Allpatients showed negative results of 131I post-therapy whole-bodyscans performed within 3 months prior to scintigraphy with 99mTc-TOC. The study population was subdivided into two groups:Group A (n=22) comprised patients with disease recurrence asshown by elevated Tg levels in serum for a minimum of two ob-servations but without detectable pathology. Group B (n=32) con-sisted of patients with pre-existing lesions. Out of the 54 patients,32 suffered from follicular, 16 from papillary and 6 from Hürthlecell carcinoma. The TNM classification according to Union Inter-nationale Contre Cancer (UICC) [32], edition 1997, was used toclassify the primary tumour. Initial pathologic tumour stages wereas follows: T2 in 11 patients, T3 in 22 patients and T4 in 21 pa-tients. The lymph node status was as follows: 21 patients werenode negative (N0), 12 patients were node positive (N1a=3, andN1b=9), and 21 patients had no information concerning lymphnode metastasis (Nx). Among the 54 patients, 13 initially had dis-tant metastases (M1). The clinical staging represented the higheststage achieved during the patient’s course and was determined ac-cording to the American Joint Committee on Cancer (AJCC) clas-sification [33]; stage I was present in 5 patients, stage II in 3 pa-tients, stage III in 4 patients to stage IV in 42 patients. Patientcharacteristics are given in Tables 1 and 2. The study was ap-proved by the local ethical committee and was performed in accor-dance with the Declaration of Helsinki. All patients gave theirwritten informed consent to participation.

Pretreatment evaluation and post-therapy scanning. Because ofincreasing serum Tg levels during TSH suppression, patients werereferred to our department for administration of high-dose radioio-dine therapy under TSH stimulation (in 41 patients 4 weeks afterL-thyroxine withdrawal and in 13 patients after recombinant hu-man TSH stimulation). X-ray of the chest and ultrasound of theneck were regularly performed in all patients, and CT of the chest(without contrast medium) was obtained in 24 patients. It was thesecond therapy for 15 patients, the third for 9, the fourth for 7, thefifth for 7, the sixth for 10, the seventh for 3 and the eighth for 3.Whole-body scans were carried out with a double-headed camera(Elscint HELIX, Haifa, Israel) 4–6 days after the therapeutic doseusing a high-energy collimator. Whole-body scan results werenegative.

Radiopharmaceutical. 99mTc-EDDA/HYNIC-TOC was preparedas recently described [29]. Briefly, 20 µg HYNIC-TOC was heatedwith 10 mg EDDA, 20 mg tricine, 15 µg stannous chloride dihy-drate and 1 GBq 99mTc-pertechnetate in 2 ml 0.05 M phosphatebuffer pH 6 at 100°C for 10 min. The solution was purified usinga SepPak mini cartridge (Waters, Milford, Mass., USA) elutedwith 80% ethanol and diluted with 5 ml saline. The purified radio-

332


Tab

le1.

Pat

ient

cha

ract

eris

tics

and

res

ults

in g

roup

A (

pati

ents

wit

hout

det

ecta

ble

path

olog

y pr

ior

to 9

9mTc

-TO

C)

No.

Sex

Age

H

isto

logy

TN

M s

tage

Sta

geT

CD

(cy

cles

)T

SH

on

T4

Tg

on T

4T

g-A

bF

indi

ngs

99m

Tc-T

OC

18F

-FD

GC

onfi

rmat

ion

(yrs

)(m

U/l

)(n

g/m

l)

1F

77F

olli

cula

rpT

3N0M

xIV

22,7

47 (

4)0.

340

1.2

Neg

.L

ung

FN

TP

CT

2F

70P

apil

lary

pT3a

NxM

xIV

19,7

50 (

4)<

0.1

32.8

Neg

.M

edia

stin

umF

NT

PB

iops

y3

M22

Pap

illa

rypT

2NxM

xI

29,8

44 (

6)0.

580

.5N

eg.

Lym

ph n

ode

FN

0U

S, s

urge

ry4

F66

Fol

licu

lar

pT2N

xMx

IV24

,536

(5)

0.3

1,95

0N

eg.

Lun

gT

PT

PC

T, b

iops

y5

F75

Fol

licu

lar

pT2N

xMx

IV27

,780

(6)

0.6

283.

3N

eg.

Med

iast

inum

FN

TP

Bio

psy

6M

42O

xyph

ilic

pT4N

xMx

II27

,280

(6)

<0.

19.

1N

eg.

Med

iast

inum

FN

TP

Bio

psy

7F

74F

olli

cula

rpT

3N0M

xIV

17,5

52 (

4)<

0.1

5.2

Neg

.L

ung

FN

FN

CT

8F

39P

apil

lary

pT3N

xMx

I5,

631

(2)

0.3

16N

eg.

Loc

al r

ecur

renc

eF

NT

PU

S, s

urge

ry9

F77

Oxy

phil

icpT

2NxM

xIV

22,2

00 (

4)0.

461

.8N

eg.

Med

iast

inum

TP

TP

Sur

gery

10M

44P

apil

lary

pT4N

1bM

xIV

14,8

00 (

3)1.

065

0N

eg.

Lym

ph n

ode

TP

0U

S, s

urge

ry11

M53

Pap

illa

rypT

3N0M

0IV

15,8

91 (

3)<

0.1

13.4

Neg

.L

ymph

nod

eT

PT

PU

S, s

urge

ry12

F85

Fol

licu

lar

pT3N

1bM

0IV

29,6

75 (

6)<

0.1

67N

eg.

Lym

ph n

ode

TP

0U

S, s

urge

ry13

F59

Fol

licu

lar

pT3N

0M0

IV10

,954

(2)

0.3

22.4

Neg

.L

ung,

med

iast

inum

FN

FN

CT

14F

24P

apil

lary

pT4N

0M0

I9,

749

(2)

<0.

110

.4N

eg.

Loc

al r

ecur

renc

eT

P0

Sur

gery

15F

72F

olli

cula

rpT

3N0M

0IV

28,1

73 (

6)0.

549

7.5

Neg

.B

one

TP

TP

MR

I, S

K16

F60

Fol

licu

lar

pT4N

0M0

III

11,6

00 (

2)0.

49.

4N

eg.

No

TN

FP

15-m

onth

FU

17F

52P

apil

lary

pT4N

1bM

xII

I10

,034

(2)

0.1

11.5

Neg

.N

oT

NT

N12

-mon

th F

U18

F90

Fol

licu

lar

pT3N

0M0

IV13

,657

(3)

<0.

136

.8N

eg.

Lun

gF

NF

NC

T19

F63

Fol

licu

lar

pT4N

0M0

III

33,9

06 (

6)<

0.1

24.8

Neg

.L

ocal

rec

urre

nce

FN

TP

Sur

gery

20F

34P

apil

lary

pT2N

xMx

I5,

343

(2)

<0.

17

Neg

.N

oT

NF

P13

-mon

th F

U21

M72

Oxy

phil

icpT

3NxM

xII

I5,

550

(2)

0.5

1,03

0N

eg.

Loc

al r

ecur

renc

e,

TP

TP

Bio

psy

lym

ph n

ode

22F

72F

olli

cula

rpT

3NxM

xII

12,6

43 (

3)<

0.1

13.2

Neg

.N

oT

NT

N15

-mon

th F

U

TN

M s

tage

, In

itia

l tu

mou

r st

age;

Sta

ge,

high

est

tum

our

stag

e in

the

cou

rse

of d

isea

se;

TC

D,

tota

l cu

mul

ativ

e do

se o

f 13

1 I (

MB

q);

cycl

es,

num

ber

of 1

31I

ther

apy

cycl

es;

Fin

d-in

gs,

all

mal

igna

nt i

nvol

ved

tiss

ue s

ites

; F

U,

foll

ow-u

p.F,

Fem

ale;

M,

mal

e; T

CD

, to

tal

cum

ulat

ive

dose

of

131 I

; T4,

thyr

oxin

e; T

g, th

yrog

lobu

lin;

TP,

true

pos

itiv

e; T

N, t

rue

neg-

ativ

e; F

P, f

alse

pos

itiv

e; F

N, f

alse

neg

ativ

e; F

U, f

ollo

w-u

p; S

K, b

one

scin

tigr

aphy

; ot

her

abbr

evia

tion

s as

def

ined

in th

e te

xt

333


Tab

le2.

Pat

ient

cha

ract

eris

tics

and

res

ults

in g

roup

B (

pati

ents

wit

h le

sion

s kn

own

befo

re 9

9mTc

-TO

C)

No.

Sex

Age

H

isto

logy

TN

M s

tage

Sta

geT

CD

T

SH

on

T4

Tg

Tg-

Ab

Fin

ding

s99

mTc

-TO

C18

F-F

DG

Con

firm

atio

n(y

rs)

(cyc

les)

(mU

/l)

(ng/

ml)

1M

51F

olli

cula

rpT

3pN

1bM

xIV

14,7

07 (

3)0.

379

4N

eg.

Lun

g, b

one

TP

TP

CT,

MR

I, S

K2

M68

Fol

licu

lar

pT3N

xMx

IV15

,299

(3)

0.5

25.5

Neg

.L

ung

FN

0C

T3

F70

Oxy

phil

icpT

4N1b

M1

IV6,

550

(2)

<0.

174

Neg

.L

ung,

med

iast

inum

, T

P0

US

, CT,

bio

psy

lym

ph n

odes

4M

41F

olli

cula

rpT

3N0M

xII

12,2

65 (

3)1.

21,

100

Pos

.B

one

TP

TP

MR

I, S

K5

F72

Fol

licu

lar

pT2N

0Mx

IV18

,870

(4)

0.8

170

Pos

.L

ung,

med

iast

inum

, T

PT

PU

S, C

T, b

iops

ylo

cal r

ecur

renc

e6

F77

Fol

licu

lar

pT2N

xMx

IV37

,261

(7)

<0.

111

6N

eg.

Lun

gT

P0

CT

7F

90F

olli

cula

rpT

4N1b

M0

IV32

,925

(6)

0.6

375.

4N

eg.

Lun

g, m

edia

stin

um,

FN

0U

S, C

Tlo

cal r

ecur

renc

e8

M82

Fol

licu

lar

pT2N

0M1

IV38

,200

(6)

1.1

2,70

0N

eg.

Lun

g, b

one

TP

TP

CT,

SK

9M

79F

olli

cula

rpT

4N0M

xIV

16,7

42 (

4)0.

380

Neg

.L

ung,

loca

l rec

urre

nce,

T

P0

US

, CT,

bio

psy,

SK

cere

brum

10M

57F

olli

cula

rpT

4NxM

xIV

20,7

95 (

4)<

0.1

25.8

Neg

.L

ung,

med

iast

inum

, bon

eT

P0

CT,

MR

I, S

K11

M58

Oxy

phil

icpT

3N1a

M0

IV12

,778

(3)

0.8

1,06

0P

os.

Lun

g, m

edia

stin

umT

P0

CT

12M

75F

olli

cula

rpT

4NxM

1IV

29,9

12 (

5)1.

232

5N

eg.

Lun

g, b

one

TP

0C

T, S

K, b

iops

y13

M59

Pap

illa

rypT

4N1b

M1

IV8,

595

(2)

0.9

2,06

2N

eg.

Lun

gT

PT

PC

T14

M68

Fol

licu

lar

pT2N

0M1

IV51

,000

(8)

0.3

56.6

Neg

.L

ung,

med

iast

inum

, bon

eT

PT

PC

T, M

RI,

SK

15M

46O

xyph

ilic

pT4N

1bM

1IV

5,69

9 (2

)0.

34,

490

Pos

.L

ung,

med

iast

inum

TP

0C

T, s

urge

ry16

M74

Pap

illa

rypT

2NxM

xIV

41,3

14 (

7)<

0.1

209

Neg

.L

ung

FN

TP

CT

17M

64F

olli

cula

rpT

3NxM

0IV

7,10

4 (2

)0.

61,

300

Pos

.B

one

TP

0M

RI,

SK

, bio

psy

18F

74F

olli

cula

rpT

4N0M

1IV

11,9

55 (

3)1.

31,

020

Neg

.B

one

TP

TR

CT,

SK

, bio

psy

19F

87P

apil

lary

pT3N

0M1

IV27

,750

(5)

0.7

475.

4N

eg.

Lun

gT

PT

PC

T20

F81

Fol

licu

lar

pT4N

xM1

IV16

,873

(5)

<0.

174

Neg

.B

one,

live

rF

N0

CT,

MR

I, S

K21

F75

Fol

licu

lar

pT3N

0M1

IV44

,979

(8)

0.4

920

Pos

.B

one

TP

0M

RI,

SK

22M

66P

apil

lary

pT4N

1bM

1IV

26,8

30 (

5)1.

14,

910

Neg

.L

ung

TP

TP

CT,

bio

psy

23M

67F

olli

cula

rpT

3N1a

Mx

IV35

,672

(7)

<0.

181

.2N

eg.

Lun

g, m

edia

stin

umT

PT

PC

T24

M57

Fol

licu

lar

pT2N

xMx

IV20

,350

(5)

1.4

900

Neg

.L

ung,

med

iast

inum

, bon

eT

PT

PC

T, M

RI,

SK

, bi

opsy

25F

63P

apil

lary

pT3N

0Mx

IV9,

250

(2)

0.5

1,64

0P

os.

Bon

eT

PT

PC

T, M

RI,

SK

, su

rger

y26

F52

Fol

licu

lar

pT4N

0M1

IV44

,899

(8)

0.7

154

Neg

.B

one

TP

0C

T, M

RI,

sur

gery

27F

80F

olli

cula

rpT

4N0M

1IV

33,9

06 (

6)1.

018

5.1

Neg

.B

one

TP

TP

MR

I, S

K28

F76

Fol

licu

lar

pT3N

0Mx

IV26

,241

(5)

0.2

94.3

Neg

.L

ung,

med

iast

inum

FN

0C

T, b

iops

y29

M57

Pap

illa

rypT

4NxM

xIV

12,9

50 (

2)1.

042

9.4

Pos

.L

ung,

bon

eT

P0

CT,

MR

I, S

K,

biop

sy30

M38

Pap

illa

rypT

3N1a

Mx

I11

,100

(2)

<0.

142

.2N

eg.

Lym

ph n

ode

FN

TP

US

, CT,

sur

gery

31F

71F

olli

cula

rpT

4NxM

xIV

34,0

36 (

6)<

0.1

630

Pos

.L

ung,

bon

eT

PT

PC

T, S

K32

M51

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labelled peptide was sterilised by filtration and 350–400 MBq ofthe resulting solution was used for each patient study. Radiochem-ical purity was greater than 95% using analytical techniques basedon high-performance liquid chromatography and thin-layer chro-matography as described elsewhere [34].

99mTc-TOC imaging. Whole-body imaging was performed with adouble-headed camera (Elscint HELIX, Haifa, Israel). For the99mTc whole-body studies, the camera was equipped with a low-energy all-purpose parallel-hole collimator, window setting140 keV, width 10%. For tomographic acquisition, the same dou-ble-headed gamma camera was used. Acquisition parameterswere: 60 projections, 25 s/projection, matrix 64×64, zoom 1.99mTc-TOC studies were performed 4 h p.i. and additional 2-h p.i.images were acquired if the clinical interest was related to the ab-domen in order to avoid pitfalls due to unspecific bowel activity.Abdominal single-photon emission tomography (SPET) was per-formed in 22 patients 4 h p.i. SPET of the neck and chest was ob-tained in all patients and SPET of the head was obtained in 12 pa-tients. Since many SPET acquisitions were carried out, primarilyfor reasons of patient convenience, given the length of the proce-dure, complementary scintigraphic planar images were only ac-quired in a small group of patients (n=14). For SPET analysis rawdata were transferred to a HERMES system (Nuclear Diagnostics,London, UK) and filtered (Wiener filter) before reconstruction.

Bone scintigraphy. The same doubled-headed gamma camera asmentioned before was used for planar bone scintigraphy. Data ac-quisition was started 2–3 h after intravenous injection of 740 MBq99mTc-DPD (Teceos, Schering). At least 1.5 million counts wererequired for each head.

18F-FDG PET. Thirty-six patients received 370 MBq (10 mCi)18F-FDG (FDG-TUM, Munich) after a fasting period of 6–12 hwhile still under thyroxine therapy. Between 50 and 60 min afterintravenous injection of the tracer, transaxial imaging was per-formed using an Advance PET scanner (General Electric MedicalSystem, Milwaukee, WI) with an axial field of view of 15.2 cm.The emission scan was acquired from the head to the upper legswith five to six bed positions, at 6 min per bed position. A trans-mission scan was acquired with a 68Ge/68Ga rod source for attenu-ation correction of the PET emission data, at 4 min per bed posi-tion. Iterative image reconstruction was performed with an or-dered subset-expectation maximisation (OSEM) algorithm (2 iter-ations, 28 subsets). A visually abnormal focus of 18F-FDG uptakewas rated as a positive finding when the focal uptake clearly ex-ceeded the activity profile of the surrounding tissue without con-nection to organs showing physiologically increased uptake andno similar activity was seen in the contralateral side of the body.

CT and MRI. Abdominal, chest and head CT scanning (Hi speedAdvantage CT scanner; GE Medical System, Milwaukee, WI) wasperformed with 5-mm contiguous sections using a 512×512 matrix,before and after rapid i.v. infusion of contrast medium. All MR ex-aminations were performed on a 1.5-T whole-body scanner (Mag-neton Vision; Siemens Medical Systems, Erlangen, Germany) byusing a phased-array surface coil. T1- and T2-weighted spin-echoimages were obtained with and without fat suppression. Lesionswithin parenchymatous organs were rated as organ metastases ifthey were not clearly identified as benign lesions according to stan-dard criteria (attenuation or signal intensity and enhancement pat-tern after administration of contrast medium). Lymph nodes werestaged morphologically according to the standard criterion of nodal

diameter, i.e. lymph nodes with a diameter of more than 1 cm inthe longest axis were rated as lymph node metastases. CT and/ orMRI were performed on a routine basis in all patients.

Sonography. High-resolution neck ultrasound was also performedon a routine basis using a real-time, high-frequency (7.5- to 10-MHz), small-part probe transducer. Ultrasound scanning coveredthe entire neck region to visualise the submandibular glands, thethyroid bed, the supra- and infraclavicular area, the superior medi-astinum as far as possible and areas lateral to the carotid arteryand jugular vein.

Thyroglobulin measurement. Blood samples for measuring serumTg and anti-Tg antibody were taken prior to scintigraphy duringsuppression therapy. The Tg levels were determined in duplicateby a sensitive, commercially available radio-immunoassay(Brahms Dynotest Tg-S, Brahms Diagnostics, Berlin, Germany).A reference recovery value for exclusion of unspecific interactionsin the serum (e.g. antibodies) was determined using the zero stan-dard and was classified as abnormal if values >1 ng/ml were foundduring TSH suppression.

Image and data analysis. Somatostatin receptor images were inter-preted by two nuclear medicine physicians (M.G., R.M.) blindedto the results of conventional or PET examinations. Any focaltracer accumulation exceeding normal regional tracer uptake wasrated as a pathological finding (tumour uptake). Linear, non-focallimited intestinal uptake was rated as non-specific, non-pathologi-cal uptake. In relevant areas, SPET images were available to theviewer. All data were analysed on a HERMES system (NuclearDiagnostics, London, UK). In both groups, readers of the scanswere blinded to the underlying pathology and to the results of thestandard staging procedures, including PET data. All images werevisually evaluated and abnormal scintigraphic findings were clas-sified according to the sites typical for recurrences or metastases(local recurrence, lymph node of the neck, mediastinum, lungs,bone structures) and other sites. The reference standard againstwhich the results of the 99mTc-TOC procedure were measured wasbased on the results of all of the imaging procedures, with inclu-sion of serial follow-up morphological imaging and histopatholo-gy of surgical specimens or biopsy in 28 patients. All patients un-derwent ultrasound of the neck and imaging with either CT (n=37)or MRI (n=14), or both (n=9). Bone scanning was performed in 19 patients.

18F-FDG PET was additionally performed in 18 patients ofgroup A and 18 patients of group B. The time interval between99mTc-TOC scintigraphy and 18F-FDG PET did not exceed 4 weeks and both techniques were prospectively compared. Theviewers of the studies were blinded to findings of other methods.Corresponding studies were compared for the final analysis lesionby lesion.

Statistical analysis. 99mTc-TOC images were classified as true pos-itive, true negative, false positive or false negative by consideringthe gold standard (histopathology or other imaging techniques), asdescribed above. The sensitivity, specificity and accuracy werecalculated using the standard method. The sensitivity was calculat-ed for the recognition of any lesion in the tissue belonging to fivecategories including local recurrence, lymph node of the neck, me-diastinum, lungs and bone structures in each patient. The χ2 testfor independence, or the Fisher exact test when appropriate, wasused to evaluate differences in lesion detectability with 99mTc-TOC when subgroups of the patients being investigated were sta-

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tistically compared. All P values below 0.05 were considered toindicate statistical significance. The McNemar test of correlatedproperties was used to assess the statistical significance of the dif-ference between the scintigraphic results of 99mTc-TOC and 18F-FDG PET. Analysis was performed both on a lesion and on a pa-tient basis. Two-sided P values less than 0.05 were considered sig-nificant. Cohen’s kappa with confidence intervals of 95% was cal-culated to show the degree of association between the two tech-niques. Statistical analysis was carried out with SPSS software.

Results

Tables 1 and 2 contain a detailed summary of clinical in-formation for each patient. Among the 54 cases, SSTRscintigraphy was true positive (TP) in 33 (61.1%), truenegative (TN) in 4 (7.4%) and false negative (FN) in 17(31.5%) cases. No false positive (FP) scan result was ob-served. In group A (n=22), which comprised patientswithout detectable pathology, the scan result was TP ineight, TN in four and FN in ten cases. In group B, whichconsisted of patients with known lesions (n=32), the scanresult was TP in 25 patients and FN in seven patients. Inthree patients of this group, previously unknown lesions(two bone metastases and one pulmonary metastasis)were additionally detected with 99mTc-TOC, and laterconfirmed by other imaging modalities. No statisticallysignificant difference was observed in terms of positivefindings with 99mTc-TOC (P=0.12) when the two groupswere compared. Twenty patients with follicular thyroidcancer were positive with 99mTc-TOC, as were 8 of 15patients with papillary and five of six with Hürthle cellcarcinoma. Overall, the sensitivity of 99mTc-TOC foridentification of thyroid cancer was 66% on a patient ba-sis, with a specificity of 100% and an accuracy of68.5%. For higher stages (n=46), i.e. stages III and IV,sensitivity (70.4%) was higher than for stages I and II(n=8), in which there were only two positive scan re-sults. Site-related findings are listed in Table 3. When99mTc-TOC was correlated with other imaging modalitiesor histopathology for analysis on a lesion basis, 138 tu-mor foci were localised in 33 patients, affecting the fol-lowing five tissues: local recurrence (n=5 patients),lymph node metastases in the neck (n=5), mediastinum(n=10), pulmonary metastases (n=19) and bone (n=16).In addition to a pulmonary metastasis and local tumourrecurrence as assessed by biopsy, 99mTc-TOC identified asolitary brain metastasis in patient 9 of group B. In 17

patients, 46 lesions were not detected; an example waspatient 21 of group B, with multiple bone and also twoliver metastases of a follicular thyroid carcinoma. Only alarge osteolytic metastasis in the sternum was visible.Malignancy was assessed in 28 cases by histopathologyand in 38 cases by different imaging modalities: (repeat-ed) CT (n=33), MRI (n=13), ultrasound (n=10) and bonescintigraphy (n=17). Tumour foci were confirmed byhistopathology and the sum of imaging procedures in 16cases.

99mTc-TOC and thyroglobulin

Patients were categorised into two groups in order toevaluate the influence of the current Tg level on detect-ability with 99mTc-TOC: those with initial serum Tg lev-els of <30 ng/ml (n=14) and those with initial serum Tglevels of >30 ng/ml (n=40). None of the group with Tglevels below 30 ng/ml had anti-Tg antibodies above thenormal range, whereas anti-Tg antibodies were elevatedin nine patients of the second group. In the group withelevated Tg levels (n=40), the scan result was true posi-tive in 30 cases and false negative in seven. In the 14 pa-tients with Tg levels lower than 30 ng/ml, scanning wasnegative in 11 patients, including four true negative andseven false negative results. Three cases were true posi-tive. The fraction of true positive 99mTc-TOC findingswas positively correlated with elevated Tg levels, i.e.levels higher than 30 ng/ml, showing a significant differ-ence (P<0.01).

The lowest Tg level with unequivocal positive 99mTc-TOC findings was 10.4 ng/ml (patient 14 of group A, inwhom local tumour growth was revealed), and the high-est Tg level with false negative 99mTc-TOC scintigraphywas 401.1 ng/ml (patient 1 of group A). This patient pre-sented with multiple pulmonary metastases, all of whichwere smaller than 1 cm.

99mTc-TOC and 18F-FDG

True positive results were obtained in 20 patients out of36 with 99mTc-TOC (55.5%) and in 28 patients with 18F-FDG (77.7%). In 16 cases (44.4%), scintigraphy wasnegative with 99mTc-TOC, while 18F-FDG PET was neg-ative in six cases (16.6%). Of the 16 negative scinti-

Table 3. Scintigraphic findings: analysis per lesion

Local Neck Mediastinum Lung Bone Other Overallrecurrence (lymph node)

99mTc-TOC + 5 5 27 71 29 1 13899mTc-TOC − 2 2 5 25 10 2 46No. of lesions 7 7 32 96 39 3 184

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graphic studies using 99mTc-TOC in four patients (11.1%;patients 16, 17, 20 and 22 of group A), further clinicalexaminations did not reveal any pathological findingsand serum Tg levels also remained stable over a follow-up period of at least 1 year, so these cases were consid-ered true negative. Two of them showed suspicious up-take using 18F-FDG PET, leading to false positive re-sults. In patient 16, focal tracer accumulation was foundin the right neck due to an inflammatory reaction. Asym-metrical uptake was detected in the thyroid bed in patient20, mimicking recurrent local disease, but further cytodi-

agnosis confirmed granulomatous tissue. False negativescan results were obtained in 12 cases (33.3%) with99mTc-TOC and in four cases (11.1%) with 18F-FDGPET. Overall, 99mTc-TOC yielded a per-patient sensitivi-ty of 62.5%, a specificity of 100% and an accuracy66.7%, whereas 18F-FDG showed a sensitivity of 87.5%,a specificity of 50% and an accuracy of 83.3% (Table 4).An analysis per patient comparing the scan results of99mTc-TOC and 18F-FDG showed statistically significantbetter results for PET (P<0.004) using the McNemartest. This correlation was based on 36 observations.

In addition, a site-specific evaluation was performed.Tissue-related abnormal uptake is reported in Fig. 1. Outof 105 malignant foci, 18F-FDG PET revealed 77 tumoursites (73.3%) and 99mTc-TOC, 63 (60%). There were nofalse positive findings with 99mTc-TOC, whereas 18F-FDG showed two false positive findings, as mentionedabove. Analysis on a lesion basis also emphasised the im-proved diagnostic efficacy of 18F-FDG PET, with a P val-ue of <0.001. Cohen’s kappa of 0.62 (0.47–0.78), howev-er, revealed substantial agreement between the imagingtechniques. The difference in detection rate was mostpronounced for lung lesions: 32 of 55 lesions (58.1%)were positive with 99mTc-TOC, whereas 42 lesions werecorrectly identified with 18F-FDG (76.3%) (Fig. 2).

Clinical impact of 99mTc-TOC

Especially in group B, a high proportion of patientsshowed extended tumour disease that limited the thera-peutic options. Therefore, further therapeutic strategieswere not significantly influenced by 99mTc-TOC find-ings in many cases. However, scintigraphic findings af-fected the further treatment decision in ten patients.Three patients were referred to external beam radiationtherapy because their lesions were not amenable to surgical excision; such was the case in patient 15 of

Table 4. 99mTc-TOC and 18F-FDG results

Parameter 99mTc-TOC 18F-FDG

Sensitivity 62.5% (20/32) 87.5% (28/32)Specificity 100% (4/4) 50% (2/4)Accuracy 66.7% (24/36) 83.3% (30/36)

Number of patients is shown within parentheses

Fig 1. Number of abnormal findings revealed by 99mTc-TOC and18F-FDG PET in 36 patients and comparison with other imagingmodalities and histology, i.e. the gold standard

Fig 2a, b. A 77-year-old pa-tient with follicular thyroidcancer. A solitary pulmonarymetastasis, which was smallerthan 1 cm, was identified with18F-FDG FDG (a), while99mTc-TOC was negative (b)

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group A (Fig. 3). A bone metastasis in the thoracicspine was identified with 99mTc-TOC, and also con-firmed by 18F-FDG. Another bone metastasis, located inthe right humerus, was irradiated in patient 12 of groupB. This lesion was initially described with 99mTc-TOC,whereas the other pulmonary metastases were alreadyknown before the scan. In patient 26 of group B, the in-tention was to remove surgically a large lesion in thelateral orbital wall. Close to this known lesion, theSPET acquisition additionally showed a smaller bonemetastasis in the skull (Fig. 4), so this patient was

spared from further surgical intervention and externalradiotherapy was performed.

Patient 11 (Fig. 5) and patient 12 of group A showedtracer uptake in a cervical lymph node metastasis. Bothpatients were successfully treated by lymph node dissec-tion, which resulted in a decrease in Tg levels withoutdetectable pathology in the further follow-up. Only pa-tient 21 of group A showed another increase in Tg 6months after resection of malignant involved lymphnodes and recurrent local disease, which were initiallyvisualised with 99mTc-TOC.

Fig 3a–c. A 72-year-old patientwith follicular thyroid cancer.A matching scan result be-tween 99mTc-TOC (a) and 18F-FDG (b) was obtained for asmall bone lesion in the thorac-ic spine, which was not depict-ed on the post-therapy 131Iwhole-body scan (c)

Fig 4a–d. A 52-year-old pa-tient with follicular thyroidcancer presented with an osse-ous metastasis in the lateral or-bital wall on the right side. Thislesion was clearly delineatedwith SPET in the coronal (a),transverse (b) and sagittal (c)sections, and confirmed withCT (d). However, a smallerbone lesion (arrow) was addi-tionally detected close to thelarge metastasis in the skull onthe SPET acquisition (b),which affected further treat-ment planning. This patientwas subsequently treated byexternal beam radiation, andspared surgery

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Five patients (nos. 1, 5, 10, 13 and 25 of group B)were referred to receptor-mediated radionuclide therapyusing 90Y-DOTA-TOC. Intense uptake behaviour of the99mTc-labelled radiopharmaceutical was found in severaltumour lesions. All patients had extended disease withmore than one affected tissue site. Each of them respond-ed under this therapy regimen, and stable disease wasachieved for at least 5 months in all patients. Each pa-tient was well informed about this new treatment optionand each of them received three or four cycles with1,850 MBq per interval cycle. The therapy was well tol-erated. In the event of tumour progression under therapy,treatment with 90Y-DOTA-TOC was terminated.

Discussion

Several studies have reported on the high level of SSTRexpression on various tumour cells, which provides themolecular basis for successful somatostatin receptor im-aging. Despite the lack of SSTR subtype 2 in certain thy-roid tumours, relatively high tumour uptake of 111In-DTPA-octreotide has been observed [28]. However, thesensitivity of 111In-DTPA-octreotide varies markedlyamong studies, which might be especially related to thevariable and sometimes low expression of the receptorsin DTC. Our study was performed to investigate the clin-ical potential of 99mTc-TOC for tumour localisation in alarger series of patients. The study was initiated becauseof the more favourable imaging characteristics and thehigher sensitivity of this new compound as assessed byhigher tumour to organ ratios, which might be based onbetter pharmacokinetics and the higher spatial resolutionof the 99mTc label [31]. The results of the present study

reflect the favourable imaging abilities of the new tracerin patients with DTC, with an overall sensitivity of 66%for detection of tumour foci in the presence of elevatedTg levels and negative radioiodine scintigraphy. The re-sults indicate that although lesions had lost their abilityto take up radioiodine, a high percentage still showed ex-pression of SSTR. Comparing the results with those ofother studies using 111In-DTPA-octreotide in patientswith DTC, the overall sensitivity of the present study isgenerally comparable or even higher [19, 20, 23, 25, 26,27]. A limiting issue in all these studies has been thesmall number of patients included.

Many lesions in different body regions showed posi-tive tracer uptake, i.e. 138 of 184 lesions were detectedin 33 patients, with higher probability for a positive scanresult in patients with higher Tg levels exceeding30 ng/ml, which might be mainly attributed to the tu-mour load. However, the spatial resolution of the 99mTc-labelled compound is insufficient to detect smaller le-sions, e.g. in the presence of widespread pulmonary me-tastases. In our series of patients, 25 of 96 lung lesionsescaped detection, and in these cases the lesion diameterwas usually less than 1 cm. Although tumour load andTg levels were sometimes high in these cases, the scanresult was inconclusive, as exemplified in Fig. 6. The pa-tient with the highest Tg level with false negative 99mTc-TOC scintigraphy (patient 1 of group A) also presentedwith multiple pulmonary metastases, all of which weresmaller than 1 cm.

When comparing 99mTc-TOC and 18F-FDG, a pro-nounced difference was also found concerning the rate ofdetection of pulmonary metastases, which was 58.1%and 76.3% respectively. One explanation might be thehigher spatial resolution of PET. However, a biological

Fig. 5a–c. SSTR imagingshows a small cervical lymphnode metastasis (a) in a patientwith papillary thyroid cancer.This lesion was also intenselydelineated by 18F-FDG PET(b), but missed by post-therapy131I whole-body scan (c). This53-year-old patient was suc-cessfully treated by lymphnode dissection

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phenomenon cannot be excluded, which could imply thatsome hypermetabolic lesions do not express SSTR. Inparagangliomas and carcinoid tumours, Le Rest et al.showed that the different mechanism of uptake resultedin variation in tumour affinity for 111In-DTPA-octreotidecompared with 18F-FDG, i.e. Octreoscan identified somelesions which were negative with 18F-FDG PET and viceversa [35].

In the 36 patients of the present study who underwent18F-FDG PET, the diagnostic efficacy was statisticallysignificantly higher for 18F-FDG PET than for 99mTc-TOC, although two false positive findings on 18F-FDGPET were negative on 99mTc-TOC. However, there wassubstantial overlap in the lesions detected by each mo-dality, which implies high agreement between the meta-bolic pattern and the SSTR status in non-iodine-avid le-sions. From the clinical point of view, both techniquescan easily be performed without withdrawal of L-thyrox-ine, as long as some precautions are taken in the case ofPET, e.g. a 6-h fasting period before scanning. Althoughthere is no evidence that serum TSH levels influence therate of somatostatin receptor expression, higher glucoseconsumption in tumour foci can be observed under TSHstimulation, which could improve the accuracy of 18F-FDG PET [36]. In accordance with the prospective de-sign of the present study, all investigations were per-formed under TSH suppression.

High 18F-FDG uptake suggests more aggressive tu-mour cell growth in those types of lesion which have lostthe sodium-iodine symporter activity. In such cases, it ishighly doubtful whether high-dose radioiodine therapywill have an impact on the tumour growth [37]. If suchlesions are not accessible to surgical treatment, e.g. lo-calised disease, only a few non-invasive treatment op-tions are available, with a low impact on the individualprognosis. Recently, it was reported that the metabolicactivity as assessed by 18F-FDG PET decreased in tu-mour lesions after the use of a long-acting octreotide an-alogue in patients with metastatic thyroid cancer that ex-

hibited somatostatin receptors [38]. This new approach,with the aim of inhibiting the proliferation of neoplastictissue, seems very promising considering the benefit ofsomatostatin analogues in patients suffering from otherSSTR-expressing malignancies, e.g. neuro-endocrine tu-mours of the gastroenteropancreatic system [39]. Long-acting somatostatin analogues can also be used in multi-morbid patients, e.g. elderly patients with reduced kid-ney function.

High expression of somatostatin receptors in thyroidcarcinoma lesions also offers another treatment optionusing radionuclide targeted therapy, e.g. 90Y-DOTA-TOC[40]. We have followed this rationale in five patientswith advanced tumour stage who had a very high tumourload. These patients showed intense tumour uptake of99mTc-TOC. Prior to the use of either 90Y-labelled or un-labelled long-acting derivatives, the assessment of SSTRstatus in tumour lesions seems mandatory. In differentclinical settings, somatostatin receptor imaging with99mTc-TOC easily allows non-invasive selection of thesubset of patients who would benefit from such thera-pies.

In the case of DTC, 99mTc-sestamibi is currently apreferred radiopharmaceutical. 99mTc-sestamibi, howev-er, exhibits only a moderate detection rate with respect tolymph node metastases [41]. By contrast, we found that99mTc-TOC provided high spatial resolution in the neck,given that five of seven sites in the neck correspondingto lymph node metastases and also five of seven cases oflocal tumour recurrences were correctly identified. Be-side accurate anatomical localisation to permit adequatetreatment planning, 99mTc-TOC could help in the devel-opment of new surgical techniques, e.g. probes for mini-mally invasive radio-guided surgery, avoiding extensivesurgery in the neck. A similar approach has been takenwith 99mTc-sestamibi in a small series of patients with re-current thyroid cancer [42], but there is as yet no evi-dence whether this technique is accurate enough to de-tect malignant involved cervical lymph nodes. Since the

Fig. 6a, b. This 77-year-old patient with a serum Tg of116 ng/ml suffered from multi-ple pulmonary metastasis of afollicular thyroid carcinoma, asshown in the chest X-ray (a).Positive 99mTc-TOC uptake wasonly found in the two largestlesions in the right lung (b)

mechanism of uptake of the lipophilic cationic agent isdifferent from that of 99mTc-TOC, further investigationsare needed to evaluate which of the two 99mTc-labelledcompounds is better in terms of localisation diagnosticsand treatment stratification in patients with recurrent ormetastatic disease.

In conclusion, somatostatin receptor imaging using99mTc-TOC is a promising and easy-to-perform tech-nique for accurate anatomical localisation of malignantfoci in thyroid cancer patients with elevated Tg levelsand negative 131I scans. Although 18F-FDG showed ahigher sensitivity in our series of patients, with the ad-vent of new therapeutic approaches, e.g. minimally inva-sive radio-guided surgery or application of SST ana-logues, this new technique might be an effective tool toimprove treatment strategies in DTC.

Acknowledgements. We especially wish to thank Prof. G. Ricca-bona, Prof. Emeritus, University of Innsbruck, for his help andsupport in initiating this study.

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99mtc-edda/hynic-toc and 18f-fdg in thyroid cancer patients with negative 131i whole-body scans

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