Correlation between Calcitonin Levels and [F]FDG-PET/CT in the Detection of Recurrence in Patients with Sporadic and Hereditary Medullary Thyroid Cancer

Abstract

Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy of combined [(18)F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and February 2011, 59 [(18)F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the 59 [(18)F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient sensitivity of [(18)F]FDG-PET/CT was 44.1%. Using as cut-off point the calcitonin value of 1000 pg/ml, in patients with calcitonin exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [(18)F]FDG-PET/CT was lower (23%) in patients with MEN IIA syndrome. Conclusion. The findings of this paper show that [(18)F]FDG-PET/CT is valuable for the detection of recurrence in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is questionable. Also, there is evidence that the sensitivity of [(18)F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA syndrome.

Full text

International Scholarly Research Network
ISRN Endocrinology
Volume 2012, Article ID 375231, 9pages
doi:10.5402/2012/375231
Clinical Study
Correlation between Calcitonin Levels and [18F]FDG-PET/CT in
the Detection of Recurrence in Patients with Sporadic and
Hereditary Medullary Thyroid Cancer
Evangelia Skoura,1Ioannis E. Datseris,1Phivi Rondogianni,1Stylianos Tsagarakis,2, 3
Marinella Tzanela,2Maria Skilakaki,4Dimitrios Exarhos,4and Maria Alevizaki5
1Nuclear Medicine Department, Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece
2Department of Endocrinology, Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece
3Department of Endocrinology, Polikliniki General Hospital, Pireos 3, 10552 Athens, Greece
4Department of Radiology and CT Department, Evangelismos General Hospital, Ipsilantou 45-47, 10676 Athens, Greece
5Department of Endocrinology, Alexandra General Hospital, Vassilissis Sofias 80, 11528 Athens, Greece
Correspondence should be addressed to Evangelia Skoura, lskoura@yahoo.gr
Received 10 February 2012; Accepted 28 February 2012
Academic Editors: M. Krebs and S. La Rosa
Copyright © 2012 Evangelia Skoura et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Purpose. Measurement of serum calcitonin is important in the followup of patients with medullary thyroid carcinoma (MTC) and
reliably reflects the presence of the disease. This is the largest study so far in bibliography investigating the diagnostic accuracy
of combined [18F]FDG-PET/CT in patients with MTC and elevated calcitonin levels. Methods. Between February 2007 and
February 2011, 59 [18F]FDG-PET/CT were performed on 51 patients with MTC and elevated calcitonin levels for localization
of recurrent disease. Conventional morphologic imaging methods were negative or showed equivocal findings. Results. Among the
59 [18F]FDG-PET/CT, 29 were positive (26 had true-positive and 3 false-positive findings) and 30 negative. The overall per-patient
sensitivity of [18F]FDG-PET/CT was 44.1%. Using as cut-offpoint the calcitonin value of 1000 pg/ml, in patients with calcitonin
exceeding this value, sensitivity raised to 86.7%. The overall sensitivity of [18F]FDG-PET/CT was lower (23%) in patients with
MEN IIA syndrome. Conclusion. The findings of this paper show that [18F]FDG-PET/CT is valuable for the detection of recurrence
in patients with highly elevated calcitonin levels, >1000 pg/mL, but in patients with lower calcitonin levels, its contribution is
questionable. Also, there is evidence that the sensitivity of [18F]FDG-PET/CT is lower in patients with MTC as part of MEN IIA
syndrome.
1. Introduction
Inherited and sporadic medullary thyroid cancer (MTC) is
an uncommon and challenging malignancy. Its low incidence
has limited both widespread clinical expertise and definitive
randomized clinical trials [1]. It originates from the parafol-
licular calcitonin-secreting cells of the thyroid, explaining the
key role of calcitonin as a specific and sensitive marker of
this cancer [2]. MTC may occur in sporadic (75% of cases)
or hereditary (25% of cases) forms that include multiple
endocrine neoplasia (MEN) types IIA and IIB and isolated
familial MTC [3,4].
When no distant metastasis is present, the curative
treatment for MTC is total thyroidectomy and lymph node
dissection [1,5,6]. Measurements of the serum calcitonin
and CEA are important in the followup of patients with MTC
and reliably reflect the presence and volume of disease in the
vast majority of them [1,7].Thesetumormarkerstypically
require several months after surgery to achieve their nadir
[1,7]. At 2-3 months after surgery, a basal calcitonin level is
undetectable in 60%–90% of patients without initial lymph
node involvement and in less than 20% of patients with
lymph node metastases. If calcitonin is then undetectable, a
pentagastrin stimulation test may be performed to exclude

2ISRN Endocrinology
any residual disease [1,8]. When both the basal and the
stimulated serum calcitonin are undetectable, the patient
is in complete biochemical remission and has about a 3%
chance of biochemical recurrent disease during followup [9].
It is reported that biochemical cure predicted a survival rate
of 97.7% at 10 years [10].
Within the past decade the prognosis has improved
mainly because of earlier diagnosis and improvement in
surgical procedures [10,11]. Nevertheless, more than 50%
of thyroidectomized patients are not cured after surgery, as
persistent elevation of basal serum calcitonin levels, which
implies residual tumor, is frequently observed after primary
surgery [5,10]. In these cases, additional surgery is a treat-
ment option to achieve biochemical remission only when
specific, resectable lesions are evident by imaging studies
[5]. Recent ongoing trials with some novel compounds,
directed against angiogenesis and molecular targets in tumor
cells, have been shown promising [1]. However, the most
important prognostic factor in patients with recurrent MTC
remains the early diagnosis that facilitates early surgical
intervention before metastatic spread outside the thyroid
bed [12]. Until now, there is no single sensitive diagnostic
imaging method to reveal all MTC recurrence or metastasis.
Conventional morphologic imaging methods (U/S, CT,
MRI) and several methods of nuclear medicine have been
used for this purpose with variable accuracy [13]. [18 F]FDG-
PET has an established role in the restaging of various cancers
[14]. However, controversy exists regarding its ability to
assess reliably recurrent or persistent MTC.
In this paper we studied the diagnostic accuracy of
[18F]FDG-PET/CT, in patients with MTC and elevated cal-
citonin levels. Although there are published studies dealing
with the same subject, this study constitutes the one with
the largest cohort of patients with MTC examined with
combined [18F]FDG-PET/CT scans.
2. Materials and Methods
This is a prospective study of [18F]FDG-PET/CT scans per-
formed for localization of recurrent disease on patients with
histologically proven MTC, elevated calcitonin levels, and
negative or equivocal conventional imaging findings. From
February 2007 to February 2011, 59 [18 F]FDG-PET/CT
scans were performed on 51 patients with MTC. The group
included 15 men and 36 women, 12–79 years old (mean: 53±
15.17 years). 18 patients had hereditary MTC (7 familial
MTC and 11 as part of MEN IIA syndrome) and 33 sporadic
MTC. All patients underwent total thyroidectomy as initial
treatment. 36 among them had neck lymph node dissection
as well, while 5 patients had mediastinal node dissection. In
all 11 patients, with MEN IIA-related MTC, adrenalectomy
had been performed for pheochromocytoma, and in 4 of
them subtotal parathyroidectomy had been performed for
glandular parathyroid hyperplasia. Median followup after
initial surgery until performing [18 F]FDG-PET/CT was 8.4
years (range, 4 months–38 years). Characteristics of the study
population are listed in Tabl e 1 .
All patients were asymptomatic and all had elevated
serum calcitonin levels (19.3–21000 pg/mL, normal value:
<10 pg/mL). 22 patients also had elevated CEA levels (7.2–
130 ng/mL, normal value: <5ng/mL).
Asecond[
18F]FDG-PET/CT scan was performed in 8
patients when there was an increase by at least 20% in
calcitonin levels and the prior scan was negative or when
the prior scan was positive, and although the patient had
undergone surgical resection of the MTC recurrence, the
calcitonin level still had not normalized.
As previous studies have shown, [18F]FDG-PET/CT scan
has the greatest sensitivity in patients with calcitonin levels of
at least 1,000 pg/mL, and there is no significant difference in
sensitivities in cases with any value below this value [15,16].
We calculated the sensitivity in patients with calcitonin levels
exceeding 1000 pg/mL (15 cases).
All patients underwent additional examinations with at
least one other imaging method, depending on the local
preferences of the different centres, the previous 4 weeks
(5–28days), that had shown negative or equivocal findings.
They were either negative or showed equivocal findings: 25
patients underwent standard dose CT scan, 28 MRI, 32 U/S
of the neck, 14 111In-pentetreotide, 13 123/131IMIBG,9bone
scan and 1 99 mTc-(V)DMSA.
The study was approved by the institutional ethical
committee, and all patients gave written informed consent.
2.1. Image Acquisition
2.1.1. PET/CT. A standard whole-body protocol and an
additional dedicated neck [18F]FDG-PET/CT protocol were
used in all patients. The patients were asked to fast for
6 hours before the study. The serum glucose concen-
tration, before the injection of [18F]FDG, was less than
150 mg/dL. The image acquisition started about 60 min after
the intravenous administration of a dose of 5 MBq/Kgr
[18F]Fluorodeoxyglucose—[18F]FDG. All acquisitions were
performed by using an integrated PET/CT scanner (Dis-
covery ST; GE Medical Systems). The average total PET/CT
examination time was 35 minutes.
Whole-body image from the mid femur to the base of the
brain was obtained, divided usually in 6 bed positions. The
PET emission images were acquired for a 4-minute acqui-
sition period at each bed position. Imaging system enabled
the simultaneous acquisition of 47 transverse PET images
per field of view with intersection spacing of 3.27 mm, for
a total transverse field of view of 15.7 cm. PET resolution is
approximately 6.1mm full width at half maximum near the
centre of the field of view. The PET/CT system also includes
a 4-detector row helical CT scanner (140 kV and 80 mA).
The CT images were used not only for image fusion but
also for generation of the attenuation map for attenuation
correction. PET scan was acquired in the two-dimensional
mode (2D). The field of view and pixel size of the recon-
structed images were 50 cm and 3.91 mm, respectively, with
a matrix size of 128 ×128. The reconstruction method used
was filtered back projection with Hanning filter.
In neck dedicated protocol, the acquisition started imme-
diately after the whole-body scan, and the field of view
and pixel size of the reconstructed image were 30cm and
2.34 mm respectively, with a matrix size of 128 ×128. The

ISRN Endocrinology 3
Tab l e 1: Patients’ characteristics and [18F]FDG-PET/CT findings.
Patient
no.
[18F]FDG-
PET/CT
scan no.
Age
(years)/sex
Time from
initial
surgery to
PET/CT
(months)
TNM initial
staging
Type of
MTC
Calcitonin-
CEA
(pg/mL-
ng/mL)
[18F]FDG-PET/CT
findings
(SUVmax)
[18F]FDG-
PET/CT
classification
Biopsy-
surgical
excision
1A 32/F 192 T1N1aM0 MENIIA 688–21.16 — FN —
B 216 821-NA — FN —
2 57/F 216 T2N1aM0 Fam 21000-NA
Neck (3),
mediastinum (2.8),
abdominal (3)
TP —
3A 44/F 21 T4aNIbMo S 809–17.4 — FN —
B 30 1601-NA Thyroid bed (2) TP —
4 71/M 83 T3N1bM0 S 3604–54.2 Neck (2.7) TP —
5A 63/F 4 T3N0M0 S 205–7.2 — FN —
B 13 352-NA Liver (4.7) TP —
6A 49/M 156 T2N1aM0 MENIIA 1001–39.8 — FN —
B 164 1203-NA — FN —
7 39/F 24 T3N1bM0 S 77–0.63 — FN Ex =(−)for
MTC
8 43/F 11 T1N1aM0 S 52.2–3.4 — FN —
9 40/M 84 T2N1bM0 S 2259–22.7 Neck (4) TP Ex =(+) for
MTC
10 A 63/M 240 T3N0M0 S 705-NA Neck (2.5) TP —
B 252 860-NA Neck (3.7) TP Ex =(+) for
MTC
11 21/F 60 T3N1bM0 S 1470-NA Neck (2.1),
mediastinum (2.2) TP —
12 A 40/M 48 T3N1bM0 Fam 3601–1.3 Thyroid bed (3.9),
mediastinum (3.7) TP Ex =(+) for
MTC
B 63 6000-NA Thyroid bed (4.6),
mediastinum (4.2) TP Ex =(+) for
MTC
13 52/F 36 T3N1bM0 S 850–114.7 — FN —
14 49/F 84 T1N1bM0 S 936–84.4 — FN —
15 35/F 216 T1N0M0 MENIIA 79.1–2.1 — FN —
16 46/F 120 T31bM0 MENIIA 230–10.4 — FN —
17 56/F 4 T2N1bM0 S 63–12.4 — FN —
18 60/F 48 T1NIbMo S 98.8-NA Mediastinum (2.5) TP —
19 61/M 36 T1N1bM0 S 57–7 — FN —
20 68/F 30 T3N1aM0 S 145–7.1 — FN —
21 67/M 120 T3N0M0 MENIIA 200–11 — FN —
22 70/M 36 T1N1aM0 MENIIA 28.3–1.4 — FN —
23 55/F 84 T1N1aM0 S 95.1-NA — FN —
24 53/F 108 T3N1aM0 Fam 10704–72,9 Neck (5.5) TP —
25 60/F 9 T2N0M0 S 35-NA Neck (3) FP Ex =(−)for
MTC
26 A 47/F 60 T1N1bM0 S 883–34.5 — FN —
B 70 1360–40.2 Thyroid bed (3.2),
Neck (3.5) TP Ex =(+) for
MTC
27 55/F 72 T1N0M0 Fam 100-NA Neck (2.2) TP —
28 28/F 84 T1N1bM0 S 622–13.4 Neck (6.3) TP Ex =(+) for
MTC

4ISRN Endocrinology
Tab l e 1: Continued.
Patient
no.
[18F]FDG-
PET/CT
scan no.
Age
(years)/sex
Time from
initial
surgery to
PET/CT
(months)
TNM initial
staging
Type of
MTC
Calcitonin-
CEA
(pg/mL-
ng/mL)
[18F]FDG-PET/CT
findings
(SUVmax)
[18F]FDG-
PET/CT
classification
Biopsy-
surgical
excision
29 66/F 228 T1N1bM0 S 17641-NA
Neck (2.5),
mediastinum (4),
Bones (5)
TP —
30 A 73/M 84 T3N1bM0 S 450–130 Mediastinum (4.3) TP Ex =(+) for
MTC
B 96 500-NA Neck (7),
mediastinum (3) TP —
31 42/F 72 T1N0M0 S 33,4-NA Neck (6.7) FP Ex =(−)for
MTC
32 72/M 132 T1N1bM0 S 36.6–4.1 — FN —
33 38/F 132 T1N1aM0 Fam 26.4–1 Neck (4.4) FP Ex =(−)for
MTC
34 43/F 204 T1N0M0 MENIIA 26.2–2.2 — FN —
35 64/F 84 T4N1bM0 S 410–7.2 Neck (3.9) TP —
36 70/F 456 T1N0M0 S 295–1.2 Neck (5) TP —
37 40/M 108 T1N1aM0 MENIIA 2096–22.3 Neck (5) TP Ex =(+) for
MTC
38 60/F 180 T1N0M0 S 330-NA — FN —
39 79/M 8 T1N0M0 S 137–5 — FN —
40 69/F 48 T3N0M0 S 453–10.2 — FN —
41 44/F 300 T1N0M0 MENIIA 5500-NA
Thyroid bed (3.5),
Neck (2.6),
Liver (5)
TP —
42 62/M 120 T1N1bM0 MENIIA 101–1.9 — FN —
43 59/M 21 T1N0M0 MENIIA 4800–67
Liver(6),
mediastinum(2.9),
bones (6.1)
TP —
44 45/F 7 T3N1bM0 S 650-NA Mediastinum (2.7) TP —
45 29/F 228 T1N0M0 S 986-NA — FN —
46 42/F 144 T1N1bM0 Fam 893–34.9 — FN —
47 52/F 8 T2N0M0 S 291–1.2 Neck (3.5) TP Ex =(+) for
MTC
48 12/M 7 T3N1aM0 Fam 92.4–4.5 — FN —
49 74/F 120 T1N0M0 S 48.6–4.6 Neck (2.4) TP —
50 65/F 39 T1N0M0 S 45-NA — FN —
51 79/F 28 T2N0M0 S 19.3–2.72 — FN —
Ex: surgical excision; [18F]FDG-PET/CT: 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography; F: female; M: male; S:
sporadic; Fam: familial; FN: false negative, TP: true positive; FP: false positive; MTC: medullary thyroid cancer; NA: not available.
reconstruction method used was filtered back projection
with Hanning filter.
PET/CT scans were interpreted visually by both a
nuclear medicine physician and a radiologist. The evaluation
included calculation of the overall per-patient sensitivity of
[18F]FDG-PET/CT as well as calculation of this parameter
after division of the scans performed into two groups
according to calcitonin levels.
2.2. Interpretation. Standard whole-body PET/CT images
were reviewed on the Xeleris workstation in transverse, coro-
nal, and sagittal planes, along with maximum intensity pro-
jection images. For visual analysis, 18F-FDG PET uptake was
considered abnormal if located outside the normal anatomic
structures or if having intensity greater to the background
blood-pool activity or adjacent normal tissue. In addition,
standardized uptake value (SUV) of the lesions was measured
on the standard whole-body PET/CT in a semi-quantitative
factor. SUV was calculated using the following formula:
SUV =
Cdc
di/w ,(1)
where Cdc is the decay-corrected tracer tissue concentration
(in becquerels per gram), di is the injected dose (in
becquerels), and w is the patient’s body weight (in grams).
The maximum SUV (SUVmax) was recorded for each lesion

ISRN Endocrinology 5
after applying regions of interest (ROI) in the transaxial
attenuation corrected PET slices, around the pixels showing
the greatest accumulation of 18F-FDG.
2.3. Data Analysis. Imaging findings were classified as true-
positive for local recurrence or metastasis if confirmed by one
of the following criteria: (a) positive histopathology results
from biopsies or resections, (b) the presence of a detectable
lesion at the corresponding site on follow-up conventional
imaging studies, (c) an increase in the lesion size and/or
in [18F]FDG uptake on [18 F]FDG-PET/CT follow-up scans.
Because all patients presented with elevated calcitonin level,
any imaging study not showing a clear abnormality was
classified as false negative. The [18F]FDG-PET/CT scans that
had findings proved to be due to other reasons and not
to MTC, were also classified as false negative scans in the
calculation of the sensitivity of the method. The reason is
that they did not detect the real lesions of MTC recurrence
responsible for the elevation of calcitonin level.
3. Results
59 [18F]FDG-PET/CT scans performed in 51 patients were
included in this study. Among these, 8 scans from 8 patients
represented follow-up scans. Of these follow-up scans, 6 were
performed because there was an increase in calcitonin level
by at least 20% with a negative previous [18F]FDG-PET/CT.
The other 2 were performed in patients with a positive prior
scan who had undergone surgical resection of disease, but
the calcitonin level did not normalize. The median interval
between these scans was 12.38 ±5.21 months (range, 8–24
months).
There were 29 positive and 30 negative [18F]FDG-
PET/CT scans for detection of MTC recurrence. Two of the
negative (for MTC) scans had findings due to recurrence
of pheochromocytoma in two MEN IIA patients (patients
no. 6 and 34); two further scans (one negative and one
positive for MTC) of one patient had findings attributed
to adrenal cortical hyperplasia due to Cushing’s syndrome
caused by ectopic ACTH production (patient no. 5). The
latter was histologically proven as the patient underwent
bilateral adrenalectomy.
In 30 [18F]FDG-PET/CT scans, no abnormal [18F]FDG
uptake was identified, and therefore these were classified as
false negative because all patients had elevated calcitonin
levels. One patient of them (with calcitonin level: 77 pg/mL)
underwent surgical resection because of abnormal findings
in U/S of the neck, even though the [18F]FDG-PET/CT scan
was negative, but the biopsy was negative for MTC (patient
no. 7).
Of the 29 positive scans, in 12 surgery was obtained,
and there were biopsy results. Nine scans were proved true-
positive, with cervical lymph node metastases (patients no.
9, 10B, 26, 28, 37, and 47 (Figure 1)), recurrence in thyroid
bed (patients No. 12 and 26), or/and mediastinal lymph
node metastases (patients no. 12 and 30 (Figure 2)) of MTC.
Three positive scans for cervical lymph node metastases
proved to be false-positive, as the biopsy showed only reactive
lymphadenitis in these lymph nodes (patients no. 25, 31, and
33). Five of the patients with positive scans could not have
resection of the lesions, as there was widespread dissemina-
tion of the disease (patients no. 2, 4, 11, 29, 41, and 43
(Figure 3)). The 12 remaining scans deemed true-positive
due to the presence of a detectable lesion at the corre-
sponding site on follow-up conventional imaging studies
or the increase in lesion size and/or in [18F]FDG uptake
on [18F]FDG-PET follow-up scans. In cooperation with the
referral endocrinologists and after all the appropriate clinical
and laboratory examinations, other possible pathologies in
these patients were ruled out.
In positive [18F]FDG-PET/CT scans the lesions were
located in the cervical lymph nodes (20), mediastinal lymph
nodes (10), thyroid bed (5), liver (3), bones (2), lungs (1),
and abdominal lymph nodes (1). In two patients the CT
componentofPET/CT(lowdoseCT)showedmultiplesmall
pulmonary nodules with no 18 FDG uptake, probably because
of their small size (<1 cm) (patients no. 2 and 4) and in
another patient the CT component showed a pulmonary
nodule 8 mm with no 18 FDGuptake(patient39).
Among the 8 follow-up scans, in the 8 patients that
underwent a second scan, six were true-positive for detection
of MTC recurrence and two negative.
Overall, [18F]FDG-PET/CT scans were positive, indicat-
ing the detection of possible MTC lesions, in 49.2% (29/59)
of patients with increased serum calcitonin levels and either
negative or equivocal conventional imaging. According to
the criteria we set for characterization of findings as true
positive or false negative, the overall per-patient sensitivity
of [18F]FDG-PET/CT was 44.1% (26/59) in detecting MTC
lesions in patients with increased serum calcitonin levels and
either negative or equivocal conventional imaging. After divi-
sion of the scans performed according to calcitonin levels, in
cases with calcitonin level of up to 1000 pg/mL we found a
sensitivity of 29.5% (13/44), and in cases with calcitonin level
>1000 pg/mL sensitivity was as high as 86.7% (13/15).
In the group with calcitonin level greater than
1000 pg/mL, there were two negative scans for MTC, both
from the same patient with MEN IIA syndrome (patient
no.6). In his second scan there were findings only due to local
recurrence of pheochromocytoma, as already mentioned.
Thirteen [18F]FDG-PET/CT scans were performed in
11 patients with MEN IIA syndrome, and 3 of them were
positive while 10 were negative (sensitivity 23%). Positive
were the [18F]FDG-PET/CT scans from 3 patients with very
high calcitonin levels 5500, 2096, and 4800 pg/mL, respec-
tively. Therefore, all patients with calcitonin levels <1000 pg/
mL had negative [18F]FDG-PET/CT scans while only cases
with calcitonin levels >1000 pg/mL had positive results (3 of
5 cases). When we excluded these patients with MEN IIA syn-
drome, then the overall per-patient sensitivity of [18F]FDG-
PET/CT in detecting MTC lesions increased to 50% and in
cases with calcitonin levels >1000 pg/mL increased to 100%.
The calcitonin levels ranged from 48.6 to 21000 pg/
mL (average 3347 pg/mL) in patients with true-positive
[18F]FDG-PET/CT scans and from 19.3 to 1203 pg/mL (aver-
age 361 pg/mL) in these with negative studies, while the CEA
levels ranged from 1.2 to 130 ng/mL (average 33.71 ng/mL)

6ISRN Endocrinology
(a) (b)
(c) (d)
Figure 1: [18 F]FDG-PET/CT images in a 40-year-old man with known MTC, as part of MEN IIA syndrome and calcitonin levels of
2096 pg/mL, about 9 years after the initial treatment. Images show increased uptake of 18FDGinleftcervicallymphnodes(SUVmax:5).The
scan was proved true positive as there was histological confirmation.
and from 0.63 to 114.7 mg/mL (average 17.77), respec-
tively. The mean value of SUVmax of all lesions showing
[18F]FDG uptake in true-positive [18F]FDG-PET/CT scans
was 3.76 ±1.29 (range, 2–7) (Tab l e 1). The 3 patients with
the false-positive [18F]FDG-PET/CT had calcitonin levels of
35 pg/mL, 33.4 pg/mL, and 26.4 pg/mL, and SUVmax 3, 6.7,
and 4.4, respectively.
The overall median followup of the patients after
[18F]FDG-PET/CT was 25 ±11 months (range, 2–47
months).
4. Discussion
As MTC secretes calcitonin, it is a highly sensitive and the
most specific marker for this tumor [17]. Despite aggressive
surgery, there is a significant group of patients who will
have persistently elevated calcitonin levels postoperatively
[13]. Postsurgically elevated or increasing calcitonin levels
strongly suggest the presence of residual or recurrent MTC,
and its elevated serum concentration can be observed much
earlier than a metastatic focus can be visualized by imaging
[18]. It has been estimated that the calcitonin serum level
of 1000 pg/mL, which is 100 times the upper normal value
limit, indicates on 1 cm3of tumor tissue, although this ratio
is variable [19]. Nevertheless, calcitonin estimation is a good
measure of tumor volume as the higher the calcitonin level,
the greater the chance that the patient has demonstrable
distant metastases [18,20].
Clinical recurrences are often found at an early stage
because elevated calcitonin levels lead to their compulsive
search, and then disease will usually progress slowly with
time. Survival after recurrence may, thus, extend over de-
cades [4].Indeed, as for any tumor, prognosis is related to
both tumor burden and progression rate [19].Thus, it is
particularly important to identify metastases early, employ-
ing not only serologic markers such as calcitonin but also
imaging techniques as well [14]. Assessment of tumor bur-
den requires a combination of multiple imaging modalities
because metastases in the MTC patients often involve multi-
ple organs and tissues and are often multiple in each involved
organ, as recently reported on the present series of patients
[21].There is no single sensitive diagnostic imaging method
to reveal all MTC recurrences or metastases [13,17,22,23].
PET complements anatomic imaging by adding unique
metabolic information to the characterization of malignancy.
[18F]FDG-PET/CT has the great advantage of combining

ISRN Endocrinology 7
(a) (b)
(c) (d)
Figure 2: [18 F]FDG-PET/CT images in a 40-year-old man with known familial MTC and calcitonin level of 6000 pg/mL, about 4 years after
the initial treatment. Images show increased uptake of 18FDG in the right side of thyroid bed (SUVmax: 4.6) and in prevascular lymph nodes,
in the mediastinum. The scan was proved true-positive as there was histological confirmation.
Figure 3: [18 F]FDG-PET and [18 F]FDG-PET/CT images in a 59-year-old man with known MTC, as part of MEN IIA syndrome and
calcitonin levels of 4800 pg/mL, about 2 years after the initial treatment. Images show increased uptake of 18FDG in multiple hepatic lesions
(SUVmax: 6), a precarinal lymph node (SUVmax: 2.9) and in multiple bone lesions (SUVmax: 6.1).

8ISRN Endocrinology
functional and anatomic imaging at the same time, following
image fusion.
It seems that [18F]FDG-PET can play a major role in
the followup of patients with postoperative elevated plasma
calcitonin, and it leads to selection of patients for secondary
surgical intervention [23,24]. The sensitivity of [18F]FDG-
PET or [18F]FDG-PET/CT for recurrence and residual
disease detection per patient is reported to be 47.4%–85% [5,
12–17,21,25–29]. [18F]FDG-PET also provides additional
information in a significant fraction of cases (up to 54%)
[14]. Comparing [18F]FDG-PET with conventional morpho-
logic imaging methods (U/S, CT, MRI) and functional imag-
ing methods with single-photon emitters in several studies,
it can be noted that the [18F]FDG PET revealed metastatic
lesions in a higher percentage of patients [12,24–26]. Other
studies have suggested that [18F]FDG PET imaging is more
sensitive in patients with rapidly progressive disease than in
patients with slowly rising calcitonin levels [17].
Data from our previous study and that of other studies
indicate that [18F]FDG-PET or [18 F]FDG-PET/CT has its
greatest utility in patients with calcitonin level greater than
1000 pg/mL [15,16,25,26]. Using an arbitrary cut-offof
1000 pg/mL, the sensitivity for lesion detection in suspected
residual, recurrent, or metastatic MTC increased, in two dif-
ferent studies from 62% and 47.4% to 78% and 80%, respec-
tively [15,16]. These data also suggest that [18F]FDG-PET
and [18F]FDG-PET/CT have limited usefulness in patients
with low calcitonin levels (<1000 pg/mL), as the overall sen-
sitivity was only 20%–36.8% [15,16,26]. In one study, the
sensitivity had no significant difference when the calcitonin
levels were below 500pg/mL or 500–1000 pg/mL [16]. The
above results are in accordance with the present study.
This study showed an overall sensitivity of 44.1% for
[18F]FDG-PET/CT in patients with increased serum calci-
tonin levels and negative or equivocal conventional imaging.
Sensitivity was only 29.5% for patients with calcitonin levels
up to 1000 pg/mL. However, [18F]FDG-PET/CT detected
recurrence or metastasis in 86.7% of patients, when the
calcitonin level was greater than 1000 pg/mL.
In fact, the relatively low lesion detection rate in patients
with low calcitonin levels is likely a reflection of microscopic
disease or a smaller tumor burden. In general, a small
lesion size and slow growth rate are known limitations of
[18F]FDG-PET in several neuroendocrine tumors [30].
An interesting finding of the study was that among
the patients with MEN IIA syndrome the sensitivity of
[18F]FDG-PET/CT for MTC recurrence was significantly
lower (23%), and for patients with calcitonin levels
<2000 pg/mL this fell to zero (0%). When we excluded
the patients with MEN IIA syndrome, then the overall
per-patient sensitivity of [18F]FDG-PET/CT in detecting
MTC lesions increased from 44.1% to 50%, and in the
group with calcitonin level greater than 1000 pg/mL the
sensitivity increased from 86.7% to 100%. These findings are
in accordance with the results of other studies which support
that MEN IIA disease induce more indolent MTCs, and as
[18F]FDG uptake relies on the biological aggressiveness of
the tumor, the detection sensitivity of the method is low
[16,31,32].
In our study, in positive for MTC [18F]FDG-PET/CT
scans, the mean value of SUVmax of all lesions showing
[18F]FDG uptake in true-positive [18F]FDG-PET/CT scans
was 3.76 ±1.29 (range, 2–7), which is relatively low and may
reflect the more indolent nature of many MTC lesions, and it
is in agreement with literature data [15,20,21].
5. Conclusions
It seems that the sensitivity of [18F]FDG-PET/CT scan for
the detection of MTC recurrence, in patients with elevated
calcitonin levels and negative or equivocal conventional
imaging findings, is determined by the level of serum
calcitonin. The results from this cohort of patients suggest
that [18F]FDG-PET/CT provides additional information in
almost half of all cases (44.1%) detecting occult sites of calci-
tonin production or confirming equivocal findings of other
imaging modalities. However, when the calcitonin levels were
greater than 1000 pg/mL, this rate increased to 86.7%.
By inference, [18F]FDG-PET/CT appears a valuable tool
for the detection of recurrence in patients with highly
(>1000 pg/mL) elevated calcitonin levels. In patients with
lower calcitonin levels it cannot offer too much. It also seems
that the sensitivity of this method is better in patients with
sporadic or familial MTC than in those with MTC as part
of MEN IIA syndrome. Nevertheless, additional prospective
studies are necessary to confirm this conclusion.
References
[1] American Thyroid Association Guidelines Task Force, R. T.
Kloos, C. Eng et al., “Medullary thyroid cancer: management
guidelines of the American Thyroid Association,” Thyroid, vol.
19, no. 6, pp. 565–612, 2009.
[2] M. Schott, H. S. Willenerg, C. Sagert et al., “Identification of
occult metastases of medullary thyroid carcinoma by penta-
gastrin-stimulated intravenous calcitonin sampling followed
by targeted surgery,” Clinical Endocrinology, vol. 66, pp. 405–
409, 2007.
[3]D.J.Marsh,D.L.Learoyd,andB.G.Robinson,“Medullary
thyroid carcinoma: recent advances and management update,”
Thyroid, vol. 5, no. 5, pp. 407–424, 1995.
[4] S. Leboulleux, E. Baudin, J. P. Travagli, and M. Schlumberger,
“Medullary thyroid carcinoma,” Clinical Endocrinology, vol.
61, no. 3, pp. 299–310, 2004.
[5] W. H. Jang, J. Y. Choi, J. I. Lee et al., “Localization of medullary
thyroid carcinoma after surgery using 11C-methionine pet/ct:
comparison with 18F-FDG PET/CT,” Endocrine Journal, vol.
57, no. 12, pp. 1045–1054, 2010.
[6] M. Schlumberger, F. Carlomagno, E. Baudin, J. M. Bidart, and
M. Santoro, “New therapeutic approaches to treat medullary
thyroid carcinoma,” Nature Clinical Practice Endocrinology and
Metabolism, vol. 4, no. 1, pp. 22–32, 2008.
[7] L. Fugazzola, A. Pinchera, F. Luchetti et al., “Disappearance
rate of serum calcitonin after total thyroidectomy for medul-
lary thyroid carcinoma,” International Journal of Biological
Markers, vol. 9, no. 1, pp. 21–24, 1994.
[8] M. Schlumberger and F. Pacini, “Medullary thyroid carci-
noma,” in Thyroid Tumors, M. Schlumberger and F. Pacini,
Eds., pp. 305–332, Editions Nucleon, Paris, France, 2nd edi-
tion, 2003.

ISRN Endocrinology 9
[9] S. Franc, P. Niccoli-Sire, R. Cohen et al., “Complete surgical
lymph node resection does not prevent authentic recurrences
of medullary thyroid carcinoma,” Clinical Endocrinology, vol.
55, no. 3, pp. 403–409, 2001.
[10] E. Modigliani, R. Cohen, J. M. Campos et al., “Prognostic
factors for survival and for biochemical cure in medullary
thyroid carcinoma: results in 899 patients. The GETC Study
Group. Groupe d’´
etude des tumeurs `
a calcitonine,” Clinical
Endocrinology , vol. 48, pp. 265–273, 1998.
[11] A. Machens, P. Niccoli-Sire, J. Hoegel et al., “Early malignant
progression of hereditary medullary thyroid cancer,” The New
England Journal of Medicine, vol. 349, no. 16, pp. 1517–1525,
2003.
[12] D. Rubello, L. Rampin, C. Nanni et al., “The role of 18 F-
FDG PET/CT in detecting metastatic deposits of recurrent
medullary thyroid carcinoma: a prospective study,” European
Journal of Surgical Oncology, vol. 34, no. 5, pp. 581–586, 2008.
[13] S. Clarke, “Medullary thyroid cancer,” in Nuclear Medicine in
Clinical Diagnosis and Treatment,P.J.EllandS.S.Gambhir,
Eds., pp. 165–174, Churcill Livingstone, Philadelphia, Pa,
USA, 3rd edition, 2004.
[14] A. Iagaru, R. Masamed, P. A. Singer, and P. Conti, “Detection
of occult medullary thyroid cancer recurrence with 2-Deoxy-
2-[F-18]fluoro-d-glucose-PET and PET/CT,” Molecular Imag-
ing and Biology, vol. 9, no. 2, pp. 72–77, 2007.
[15] S. C. Ong, H. Sch¨
oder, S. G. Patel et al., “Diagnostic accuracy
of 18F-FDG PET in restaging patients with medullary thyroid
carcinoma and elevated calcitonin levels,” Journal of Nuclear
Medicine, vol. 48, no. 4, pp. 501–507, 2007.
[16] E. Skoura, P. Rondogianni, M. Alevizaki et al., “Role of
[18F]FDG-PET/CT in the detection of occult recurrent medu-
llary thyroid cancer,” Nuclear Medicine Communications, vol.
31, no. 6, pp. 567–575, 2010.
[17] K. Brandt-Mainz, S. P. M ¨
uller, R. G¨
orges, B. Saller, and A.
Bockisch, “The value of fluorine-18 fluorodeoxyglucose PET
in patients with medullary thyroid cancer,” European Journal
of Nuclear Medicine, vol. 27, no. 5, pp. 490–496, 2000.
[18] T. Gawlik, A. d’Amico, S. Szpak-Ulczok et al., “The prognostic
value of tumor markers doubling times in medullary thyroid
carcinoma—preliminary report,” Thyroid Research, vol. 3, ar-
ticle 10, 2010.
[19] S. A. Wells Jr., S. B. Baylin, D. S. Gann et al., “Medullary thy-
roid carcinoma: relationship of method of diagnosis to path-
ologic staging,” Annals of Surgery, vol. 188, pp. 377–383, 1978.
[20] A. L. Giraudet, A. Al Ghulzan, A. Auperin et al., “Progres-
sion of medullary thyroid carcinoma: assessment with calci-
tonin and carcinoembryonic antigen doubling times,” Euro-
pean Journal of Endocrinology, vol. 158, no. 2, pp. 239–246,
2008.
[21] A. L. Giraudet, D. Vanel, S. Leboulleux et al., “Imaging med-
ullary thyroid carcinoma with persistent elevated calcitonin
levels,” Journal of Clinical Endocrinology and Metabolism, vol.
92, no. 11, pp. 4185–4190, 2007.
[22] S. Hoegerle, C. Altehoefer, N. Ghanem, I. Brink, E. Moser,
andE.Nitzsche,“18F-DOPA positron emission tomography
for tumour detection in patients with medullary thyroid car-
cinoma and elevated calcitonin levels,” European Journal of
Nuclear Medicine, vol. 28, no. 1, pp. 64–71, 2001.
[23] S. Szak ´
all Jr., O. Esik, G. Bajzik et al., “ 18 F-FDG PET detection
of lymph node metastases in medullary thyroid carcinoma,”
Journal of Nuclear Medicine, vol. 43, no. 1, pp. 66–71, 2002.
[24] N. Khan, N. Oriuchi, T. Higuchi, and K. Endo, “Review
of fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission
tomography (FDG-PET) in the follow-up of medullary and
anaplastic thyroid carcinomas,” Cancer Control, vol. 12, no. 4,
pp. 254–260, 2005.
[25] M. Diehl, J. Risse, K. Brandt-Mainz et al., “Fluorine-18 fluo-
rodeoxyglucose positron emission tomography in medullary
thyroid cancer: results of a multicentre study,” European Jour-
nal of Nuclear Medicine, vol. 28, no. 11, pp. 1671–1676, 2001.
[26] J. W. de Groot, T. P. Links, P. L. Jager, T. Kahraman, and J.
T. Plukker, “Impact of 18F-fluoro-2-deoxy-D-glucose positron
emission tomography (FDG-PET) in patients with biochem-
ical evidence of recurrent or residual medullary thyroid can-
cer,” Annals of Surgical Oncology, vol. 11, no. 8, pp. 786–794,
2004.
[27] A. Bockisch, K. Brandt-Mainz, R. G ¨
orges, S. M¨
uller, J. Stattaus,
and G. Antoch, “Diagnosis in medullary thyroid cancer with
[18F]FDG-PET and improvement using a combined PET/CT
scanner,” Acta Medica Austriaca, vol. 30, no. 1, pp. 22–25, 2003.
[28] B. G. Conry, N. D. Papathanasiou, V. Prakash et al., “Compari-
son of 68Ga-DOTATATE and 18 F- fluorodeoxyglucose PET/CT
in the detection of recurrent medullary thyroid carcinoma,”
European Journal of Nuclear Medicine and Molecular Imaging,
vol. 37, no. 1, pp. 49–57, 2010.
[29] A. Oudoux, P. Y. Salaun, C. Bournaud et al., “Sensitivity and
prognostic value of positron emission tomography with F-18-
fluorodeoxyglucose and sensitivity of immunoscintigraphy in
patients with medullary thyroid carcinoma treated with anti-
carcinoembryonic antigen-targeted radioimmunotherapy,”
Journal of Clinical Endocrinology and Metabolism, vol. 92, no.
12, pp. 4590–4597, 2007.
[30]S.Adams,R.Baum,T.Rink,P.M.Schumm-Dr
¨
ager, K. H.
Usadel, and G. Hor, “Limited value of fluorine-18 fluoro-
deoxyglucose positron emission tomography for the imaging
of neuroendocrine tumours,” European Journal of Nuclear
Medicine, vol. 25, no. 1, pp. 79–83, 1998.
[31] F. Marini, A. Falchetti, F. Del Monte et al., “Multiple endocrine
neoplasia type 2,” Orphanet Journal of Rare Diseases, vol. 1, no.
1, article 45, 2006.
[32] C. Pestourie, B. Th´
ez´
e, B. Kuhnast et al., “PET imaging of
medullary thyroid carcinoma in MEN2A transgenic mice us-
ing 6-[18F]F-L-DOPA,” European Journal of Nuclear Medi- cine
and Molecular Imaging, vol. 37, no. 1, pp. 58–66, 2010.