PET/CT in thyroid nodule and differentiated thyroid cancer patients. The evidence-based state of the art

Abstract

A more conservative approach to the clinical management of thyroid nodules and differentiated thyroid cancer has recently been proposed by the 2015 ATA guidelines. In this context, fine-needle aspiration biopsy has been reserved for nodules with particular ultrasound features or dimensions that exclude low-risk thyroid lesions. Accordingly, a less aggressive surgical approach (i.e. lobectomy) has been recommended as the first-choice treatment in nodules with indeterminate cytology or in small cytologically confirmed malignant nodules. At the same time, radioactive remnant ablation has been considered only for DTC patients with concrete risks of disease persistence/relapse after thyroidectomy. In addition, further radioactive iodine therapies (RAI) have been proposed only for patients presenting unresectable and iodine-avid structural relapse. In this complex scenario, which requires attention to each clinical aspect of the patient, the introduction of accurate diagnostic tools is highly warranted. PET/CT is a very sensitive and specific diagnostic procedure that can better characterize the risk of thyroid nodules, identify DTC relapse early and predict the response to RAI. Thus, it seems essential to customize a more conservative approach to thyroid nodules and DTC patients. The aim of this review is to report the principal clinical context in which PET/CT has been used and to evaluate the evidence-based support for each diagnostic indication.

Full text

PET/CT in thyroid nodule and differentiated thyroid cancer patients.
The evidence-based state of the art
Arnoldo Piccardo
1
&Pierpaolo Trimboli
2
&Luca Foppiani
3
&Giorgio Treglia
2,4,5
&Giulia Ferrarazzo
1
&
Michela Massollo
1
&Gianluca Bottoni
1
&Luca Giovanella
2
#Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
A more conservative approach to the clinical management of thyroid nodules and differentiated thyroid cancer has recently been
proposed by the 2015 ATA guidelines. In this context, fine-needle aspiration biopsy has been reserved for nodules with particular
ultrasound features or dimensions that exclude low-risk thyroid lesions. Accordingly, a less aggressive surgical approach (i.e.
lobectomy) has been recommended as the first-choice treatment in nodules with indeterminate cytology or in small cytologically
confirmed malignant nodules. At the same time, radioactive remnant ablation has been considered only for DTC patients with
concrete risks of disease persistence/relapse after thyroidectomy. In addition, further radioactive iodine therapies (RAI) have been
proposed only for patients presenting unresectable and iodine-avid structural relapse. In this complex scenario, which requires
attention to each clinical aspect of the patient, the introduction of accurate diagnostic tools is highly warranted. PET/CT is a very
sensitive and specific diagnostic procedure that can better characterize the risk of thyroid nodules, identify DTC relapse early and
predict the response to RAI. Thus, it seems essential to customize a more conservative approach to thyroid nodules and DTC
patients. The aim of this review is to report the principal clinical context in which PET/CT has been used and to evaluate the
evidence-based support for each diagnostic indication.
Keywords PET/CT .Diagnosis .Thyroid nodules .Differentiated thyroid Cancer
Abbreviations
DTC differentiated thyroid cancer
131
I 131-iodine
124
I Iodine-124
NPV negative predictive value
WBS whole-body scan
Tg thyroglobulin
TgAb anti-thyroglobulin autoantibodies
RAI radioactive iodine therapy
TKI tyrosine kinase inhibitor
PSMA 68Ga-Prostate-specific membrane antigen
rhTSH recombinant human TSH
1 Introduction
Growing evidence has shown that PET imaging is an important
diagnostic cornerstone and is able to influence the clinical man-
agement of differentiated thyroid cancer (DTC) patients [1].
Indeed, nuclear medicine physicians are particularly involved
in DTC management in terms of both diagnosis and therapy;
131-iodine (
131
I) has been the main diagnostic and therapeutic
tool since the beginning of this discipline and still maintains a
major role in this setting [2]. Since
18
F-FDG PET/CT was intro-
duced into clinical practice, a possible role of this technique in
DTC management has been considered; to date, its main appli-
cation concerns patients with high thyroglobulin (Tg) serum
levels and negative post-therapeutic
131
I -whole body scan [1].
*Arnoldo Piccardo
arnoldo.piccardo@galliera.it
1
Department of Nuclear Medicine, Galliera Hospital, E.O. Ospedali
Galliera, Mura delle Cappuccine 14, 16128 Genoa, Italy
2
Clinic of Nuclear Medicine and Molecular Imaging, Imaging
Institute of Southern Switzerland, Lugano, Bellinzona, Switzerland
3
Department of Internal Medicine, Galliera Hospital, Genoa, Italy
4
Health Technology Assessment Unit, General Directorate, Ente
Ospedaliero Cantonale, Bellinzona, Switzerland
5
Department of Nuclear Medicine and Molecular Imaging, Lausanne
University Hospital, Lausanne, Switzerland
Reviews in Endocrine and Metabolic Disorders
https://doi.org/10.1007/s11154-019-09491-2

Other issues of growing interest are the role of
18
F-FDG PET/CT
in characterizing thyroid nodules suspicious for malignancy and
staging aggressive DTC subtypes at the time of diagnosis.
Specifically, the emerging role of
18
F-FDG PET/CT in thy-
roid nodules is rooted in extensive clinical experience of FDG
focal thyroid uptake incidentally detected on PET/CT per-
formed for unrelated, non-thyroid purposes [3,4]. In this field,
several meta-analyses [5–10] have revealed that thyroid nod-
ules with this feature have a high risk of malignancy, ranging
from 20 to 35% (Table 1and Fig. 1).
However, beyond FDG, other PET tracers evaluating dif-
ferent metabolic pathways or receptor status have been used in
DTC. Iodine-124 (
124
I), which assesses NIS expression, has
been introduced in recent years for both diagnostic and dosi-
metric purposes. More recently, receptor tracers, such as
radiolabelled somatostatin analogues and radio-conjugated
anti-PSMA monoclonal antibodies, have been proposed for
possible theragnostic applications.
We reviewed the literature on the use of PET in
thyroid nodules and DTC in order to outline pre- and
post-surgical conditions in which indications for PET in
clinical practice are supported by evidence-based
studies.
2 Materials and methods
We sought studies evaluating the use of PET in thyroid nod-
ules and DTC in online databases: PubMed/MEDLINE,
Embase, and Scopus. The search was updated until January
2019. No language restriction was used. To identify additional
studies and expand our search, references of the retrieved ar-
ticles were also screened.
The role of PET/CT in a specific clinical setting was de-
fined as Bsupported by high-quality evidence^only if studies
providing evidence-based results were available (Table 2). For
each diagnostic context, the indication was evaluated accord-
ing to the impact on clinical management. The indication was
supported in the case of accurate testing and demonstrable
benefits. Support for the indication was classified as weak in
the case of accurate testing and only partially recognized ben-
efits. The indication was not supported in the case of inaccu-
rate testing or, in the case of accurate testing, if the benefits
were not yet recognized.
3 Results
3.1 Preoperative
18
F-FDG PET/CT
3.1.1 Thyroid nodules with indeterminate cytology
or suspicious neck ultrasonography
The management of nodules with indeterminate cytology re-
sults is challenging, and still under debate. On the one hand,
the risk of malignancy reaches 15–30% [5], and a conservative
approach may not be completely safe. On the other, more ag-
gressive clinical management leads to over-treatment (i.e. total
thyroidectomy or lobectomy) in more than 70% of patients.
In this field, imaging procedures with high sensitivity and
high negative predictive value (NPV) are required in order to
reduce the number of inappropriate thyroidectomies.
Ultrasonography alone is not recommended in the clinical
management of indeterminate thyroid lesions [11–13]. In ad-
dition, although elastography has recently been reported to
increase the sensitivity of ultrasound, it has suboptimal accu-
racy in diagnosing thyroid nodules previously classified as
indeterminate [14,15].
18
F-FDG PET/CT seems to be helpful in defining the na-
ture of indeterminate thyroid nodules and is reported to have
high sensitivity and NPV [16–22].
In one recent clinical review, which considered all previous
studies in this field, Bertagna and colleagues confirmed the
accuracy of
18
F-FDG PET/CT in detecting thyroid malignan-
cy and found sensitivity and NPV values ranging from 77 to
100% and from 81 to 100%, respectively [5]. Two meta-
analyses have addressed this issue; the main findings are re-
ported in Table 3. Vriens and colleagues showed that the
pooled sensitivity, specificity, NPV and positive predictive
value were 95%, 48%, 96% and 39%, respectively [25].
Specifically, in patients with thyroid nodules who had indeter-
minate fine-needle aspiration biopsy results, a negative
18
F-
FDG PET scan improved diagnostic accuracy, particularly in
patients with lesions >15 mm [25]. A more recent meta-
analysis by Wang and colleagues [23], which included 7 pa-
pers published before 2012, reported a very high pooled sen-
sitivity (about 90%) of
18
F-FDG-PET, but lower than that
found by Vriens et al. However, Wang’s meta-analysis includ-
ed a paper by De-Andreis et al., who observed relatively low
sensitivity and NPV values of
18
F-FDG PET/CT (77% and
Table 1 Grade of evidence
assigned to each PET/CT
indication
Grade of evidence Supported By
High Quality Meta-analysis or RCT*, or overwhelming evidence from observational studies
Intermediate Quality Strong evidence from observational studies
Low Quality Observational studies/case studies
*Randomized clinical trials
Rev Endocr Metab Disord

81%, respectively) [26]. Indeed, these authors reported that
18
F-FDG PET/CT did not add any diagnostic benefit to con-
ventional ultrasound. This is probable the only study to deny
the diagnostic efficacy of
18
F-FDG PET/CT in thyroid nod-
ules with undetermined cytology.
A recent paper from our group prospectively compared the
accuracy of
18
F-FDG PET/CT with that of multiparametric
neck ultrasonography and
99m
Tc-MIBI scintigraphy and
showed that PET imaging had very high sensitivity and
NPV (94% and 98%, respectively) (Fig. 2) - significantly
higher than that of the other two diagnostic modalities [15].
On the basis of all these favourable data, Vriens et al. [24]
evaluated the cost-effectiveness of
18
F-FDG -PET/CT in pa-
tients with inconclusive fine-needle aspiration biopsy who
were scheduled for thyroid surgery. They found that full im-
plementation of
18
F-FDG -PET/CT may reduce costs in com-
parison with diagnostic surgery and molecular tests.
Only one recent study by Rulhman et al. [27]report-
ed the ability of
18
F-FDG-PET/CT to exclude malignan-
cy in sonographically suspicious and scintigraphically
hypofunctional thyroid nodules. Regardless of fine-needle as-
piration biopsy results, they retrospectively analysed 65 pa-
tients with Bcold^thyroid nodules on thyroid scan and suspi-
cious Ultrasound characteristics and found that
18
F-FDG PET/
CT had very high sensitivity and NPV in detecting malignan-
cy (100%). Notably, they ascertained, in this well selected
population, that
18
F-FDG PET/CT had relatively high speci-
ficity and positive predictive values (87% and 61%,
respectively).
In conclusion, the authors claimed that
18
F-FDG PET/CT
was a very useful diagnostic modality for evaluating the risk
of thyroid nodules, and that a negative result could correctly
predict benign histopathology findings.
In sum, the role of
18
F-FDG PET/CT in predicting the risk
of malignancy in thyroid nodules with indeterminate cytology
is supported by high-quality evidence. This indication should
be considered in clinical practice. The use of
18
F-FDG PET/
CT to rule out malignancy in thyroid nodules with suspicious
ultrasound features is supported by low-quality evidence, and
further studies are warranted.
Table 2 Prevalence and risk of malignancy of
18
F-FDG PET and PET/CT thyroid incidentalomas according to published meta-analyses
Authors (publication year) Number of studies Number of patients Pooled prevalence (95%CI) Pooled risk of malignancy (95%CI)
Nayan et al. (2014) [10] 31 197,296 1.9% 20% (15.3–25)
Qu et al. (2014) [9] 29 196,298 2.9% NR
Treglia et al. (2013) [6] 34 215,057 1.92% (1.87–1.99) 36.2% (33.8–38.6)
Bertagna et al. (2012) [5] 27 147,505 2.46% (1.68–3.39) 34.6% (29.3–40.2)
Soelberg et al. (2012) [8] 22 125,754 1.6% 34.8%
Shie et al. (2009) [7] 18 55,160 1% 33.2%
CI confidence interval; NR not reported
Fig. 1 Focal and intense FDG
uptake (SUVmax 7) of the thyroid
isthmus incidentally detected by
PET/CT performed for oncologi-
cal purposes (a,b). This finding
corresponded to a small high-risk
nodule (EUTIRADS 5) on neck
US (c). Patient underwent surgery
and a papillary thyroid cancer was
confirmed
Rev Endocr Metab Disord

3.1.2 Assessment of biological behaviour of primary DTC
In thyroid nodules with positive fine-needle aspiration biopsy
results, it is difficult to predict the aggressiveness of thyroid
cancer pre-surgically. The principal risk factors related to the
biological activity of the tumour are revealed by neck ultraso-
nography. Indeed, the size and position of the nodule, together
with the presence of lymph-node enlargement, may identify
which patients are likely to develop disease persistence/
recurrence after initial treatment, i.e. thyroidectomy plus ra-
dioactive iodine therapy (RAI) [28,29]. In this field, some
molecular tests have recently been proposed, and BRAF mu-
tation has been identified as the most reliable [30]. However,
other molecular markers, such as TERT mutation, have
yielded promising results [31]. In particular, concomitant
BRAF and TERT promoter mutations identify the most aggres-
sive subgroup of papillary thyroid carcinomas (PTC) [32].
However, the relatively low accessibility and high costs of
these molecular analyses prevent their large-scale use. A sim-
ple and reproducible imaging biomarker, such as
18
F-FDG
PET/CT, that could provide information on the aggressiveness
of DTC would therefore be welcome.
In this context, little can be said about the prognostic sig-
nificance of
18
F-FDG uptakein primary DTC. However, some
studies support the hypothesis that
18
F-FDG avidity of prima-
ry DTCs might be associated with their prognosis, as reported
for other tumours [33–35] and for DTC metastases [36].
Indeed, Are and colleagues [37] reported that thyroid
malignancies incidentally detected on
18
F-FDG scan har-
bour a high rate of unfavourable prognostic features and may
constitute a more aggressive variant of primary thyroid carci-
noma. Specifically, in a very high percentage of patients
(54%), they found a very high rate of extra-thyroid extension
(63%), which was much higher (90%) in patients with the tall-
cell variant.
Another tangible clue that
18
F-FDG uptake may be associ-
ated to DTC aggressiveness was reported by Kim and col-
leagues [38]. They retrospectively analysed 60 patients affect-
ed by DTC for whom a pre- thyroidectomy
18
F-FDG PET/CT
was available. They found 17 patients with negative and 43
Fig. 2 A 25 mm hypoechoic solid nodule of the left thyroid lobe,
characterized on neck US by undefined margins and multiple
microcalcifications (a).
18
F-FDG PET/CT did not show any uptake cor-
responding to the thyroid nodule (b). Histopathology revealed a hyper-
plastic nodule characterized by micro- and macrocalcifications
(haematoxylin-eosin stain, 4×) (c). A 35 mm hypoechoic solid nodule
of the isthmus, characterized on neck US by defined margins and without
microcalcifications (d).
18
F-FDG PET/CT (e) showed focal uptake corre-
sponding to the thyroid nodule. Histopathology (haematoxylin-eosin
stain, 4X) revealed a follicular carcinoma (f)
Table 3 Ability of
18
F-FDG PET/CT to detect thyroid malignancy in patients with indeterminate thyroid nodules
Authors (publication year) Number
of studies
Number
of patients
Prevalence of
malignancy
Sensitivity
(95%CI)
Specificity
(95%CI)
NPV
(95%CI)
PPV
(95%CI)
Wang et al. (2013) [23] 7 267 26.2% (19.6–40) 89% (79–95) 55% (48–62) NR NR
Vriens et al. (2014) [24] 6 225 25.8% (13.6–41.7) 95% (86–99) 48% (40–56) 96% (90–99) 39% (31–47)
CI confidence interval; NR not reported. NPV negative predictive value; PPV positive predictive value
Rev Endocr Metab Disord

patients with positive
18
F-FDG findings and reported that the
positive and negative groups were similar in terms of age,
gender and presence of extra-thyroid extension of their papil-
lary thyroid carcinomas. In contrast, there were marked differ-
ences in tumour size (p= 0.02) and lymph-node involvement
(17.6% vs 62.7%, respectively; p=0.0034).
However, with regard to the clinical outcome of DTC pa-
tients, only two retrospective studies are available [39,40].
One study from our group [39] confirmed that tumour size
and aggressive histological subtype were related to intense
18
F-FDG uptake. In addition, on using the SUV ratio of 3.0
as a cut-off, patients with higher
18
F-FDG uptake had a higher
risk of disease persistence/progression than those with lower
uptake. Similarly, other risk factors included in this study (his-
tological subtype, tumour size, nodal status and distant metas-
tases) were all correlated with disease persistence/progression.
However, when a multivariate analysis was carried out, after
adjusting for all other factors considered, tumour size was the
only independent factor which remained associated with dis-
ease persistence/progression (Table 4).
In conclusion, these studies showed that an intense
18
F-
FDG uptake by the primary DTC may help to identify a sub-
group of patients with a high risk of disease progression.
Nevertheless, when all other prognostic factors are taken into
account,
18
F-FDG uptake itself does not add further prognos-
tic information [39,40].
In sum, the role of
18
F-FDG PET/CT in predicting the
biological aggressiveness of DTC is supported by low-
quality evidence. This indication should not be considered in
clinical practice.
3.1.3 Initial staging of DTC
Neck ultrasonography is the first-line imaging technique able
to properly stage DTC patients. This technique is recommend-
ed by recent 2015 ATA guidelines for all patients undergoing
thyroidectomy for malignant or suspicious nodules [41]. By
contrast, pre-thyroidectomy use of other imaging procedures,
such as contrast-enhanced computed tomography and
multiparametric magnetic resonance imaging, is reserved for
DTC patients at high risk of developing distant metastases or
those with suspicious involvement of mediastinal nodal re-
gions [41]. In thisfield, the ATA guidelines do not recommend
the pre-surgical use of
18
F-FDG PET/CT. Indeed, few papers
have investigated this issue. Specifically, Kim and colleagues
retrospectively analysed 60 patients with low- or intermediate-
risk DTC who underwent
18
F-FDG PET/CT before thyroid-
ectomy. They found very low sensitivity and NPVin detecting
lymph-node metastases (10% and 50%, respectively) but very
high specificity (90%) [38]. Other studies have evaluated the
diagnostic accuracy of
18
F-FDG PET in nodal staging [42,
43]. These compared the accuracy of PET with that of neck
ultrasound and contrast-enhanced CT. The sensitivity and
specificity of PET in evaluating the central neck compartment
were 5.0–22.7% and 93.6–98.8%, respectively; those of ultra-
sound were 25–63.6% and 74.9–97.6%, respectively; and
those of contrast-enhanced CT were 15.1–25.0% and 93.8–
98.8%, respectively. The sensitivity and specificity of PET in
evaluating lateral lymph nodes (LNs) were 30.6–50% and
90.4–97%, respectively; those of ultrasound were 41.3–
82.2% and 64.3–97.4%, respectively; and those of contrast-
enhanced CT were 33.3–42.3% and 53.6–96.6%, respectively.
The specificities of PET, ultrasonography, and contrast-
enhanced CT in evaluating both the central and lateral neck
regions were very high. However, the sensitivities were low
(≤50%) for all three modalities. The overall diagnostic accu-
racy of
18
F-FDG PET tended to be higher for lateral LNs than
for central LNs [42]. Neck ultrasound proved to be su-
perior to
18
F-FDG PET and contrast-enhanced CT and
was considered the best methodology for preoperative assess-
ment of nodal status [44].
In this regard, we agree with recent ATA guidelines about
the poor usefulness of
18
F-FDG PET/CT in detecting lymph-
node metastases before surgery. However, in high-risk DTC
patients affected by aggressive tumour subtypes or patients
with suspected distant metastases, the role of
18
F-FDG PET/
CT should be better evaluated and further prospective studies
should be conducted. Indeed,
18
F-FDG PET/CT might be very
useful in correctly addressing disease aggressiveness, in de-
tecting distant metastases (especially bone), and in predicting
response to
131
I first-line therapy.
Indeed, little can be said about the role of
18
F-FDG PET/
CT in the aggressive DTC subtypes (such as tall-cell, diffuse
sclerosing, solid/trabecular and insular variants) or high-risk
DTC patients at the time of first staging. Only one study, by
Rosenbaum-Krumme et al. [45], analysed 90 consecutive pa-
tients with either extensive or metastasised high-risk DTC
who underwent
18
F-FDG PET after the first
131
I treatment.
Table 4 Risk of relapse in FDG-
avid vs non-avid primary DTC Statistical analysis Piccardo et al.
(54 patients) [39]
95%CI p Kim et al. (412
patients) [40]
95%CI p
Univariate analysis OR 11.6 1.84–73.3 <0.001 HR 6.25 2.51–15.53 0.0049
Multivariate
Analysis*
HR 1.75 0.29–10.64 0.5 NR NR NS
OR odds ratio; HR hazard ratio; NR not reported; NS not significant
Rev Endocr Metab Disord

About one-third of patients (29%) had FDG-positive tumour
lesions, one-third (36%) had RAI-positive lesions, and 8%
had matching RAI-positive and FDG-positive lesions.
18
F-
FDG-PET/CT improved initial staging in 9% of patients and
changed patient management in 21% of cases, mainly those
with T3bN1 staging and those with distant metastases.
Other studies have shown very promising results of
18
F-
FDG PET/CT performed at the time of first postoperative
staging in patients with Hürthle cell thyroid cancer [46–48].
This aggressive thyroid cancer was initially included in the
DTC group, but is now considered to be a different disease
owing to both its histological features and clinical course [49].
Pryma et al. [46] conducted the largest study, which
enrolled 44 patients; they found that this technique
had diagnostic sensitivity and specificity of 95.8% and
95%, respectively, and provided more information than
conventional imaging. In addition, the intensity of FDG
uptake in metastatic lesions provided important prognos-
tic information. The authors suggested using
18
F-FDG
PET/CT at the time of postoperative staging, and periodically
to detect occult relapse, particularly in patients with elevated
serum Tg levels (Fig. 3).
In sum, the role of
18
F-FDG PET/CT in staging DTC is
supported by evidence of moderate quality. This indication
should be not considered in clinical practice. By contrast,
the use of
18
F-FDG PET/CT in the initial staging of more
aggressive subtypes (e.g. Hürthle cell carcinoma) should be
considered in clinical practice, this indication being support-
ed by moderate-quality evidence.
3.2 Suspicious DTC relapse
The main indication for
18
F-FDG PET/CT in DTC is during
follow-up in the case of high or increasing Tg levels but
negative or doubtful ultrasound and negative diagnostic (D)
and post-therapeutic
131
I whole-body scan (WBS).
Incomplete biochemical response after thyroidectomy and
radioactive remnant ablation, defined as suppressed Tg ≥
1 ng/ml or stimulated Tg ≥10 ng/ml without structural evi-
dence of disease on conventional imaging (neck ultrasound
and
131
IWBS)[41], may occur in 15–20% of patients [50].
In this context, at least 30% of patients evolve spontaneously
to an excellent response characterized by negative suppressed
and stimulated Tg and negative neck ultrasonography [41].
However, persistently elevated or increasing Tg levels under
TSH suppression or TSH stimulation may identify patients
with structural residual or recurrent disease.
The first meta-analysis on the diagnostic accuracy of
18
F-
FDG PET or PET/CT in DTC patients with elevated post-
thyroidectomy serum Tg levels and negative
131
IWBS
reported high accuracy of these diagnostic methods,
with pooled sensitivity and specificity values of 88.5% and
84.7%, respectively [51].
Another meta-analysis focused on re-staging of PTC pa-
tients confirmed that
18
F-FDG PET and PET/CT were accu-
rate methods in this setting, and pooled sensitivity and speci-
ficity were 82% and 84%, respectively [52].
Further recent evidence-based documents have confirmed
the high diagnostic performance of
18
F-FDG PET and PET/
CT in this setting [53–56](Table5).
In addition, the diagnostic performance of
18
F-FDG PET/
CT may improve after TSH stimulation [57]; however, the
sensitivity of
18
F-FDG PET/CT can be only marginally im-
proved by TSH stimulation (especially in patients with low Tg
values), and the clinical benefit of identifying these additional
small foci has yet to be proven [41].
The current ATA guidelines suggest that
18
F-FDG PET/CT
should be performed when stimulated Tg levels are >10 ng/ml
Fig. 3 A 77-year-old woman who
underwent thyroidectomy for
thyroid Hurtle cell carcinoma
(pT4N1b).
18
F-FDG PET/CT,
performed in the presence of ele-
vated Tg levels, showed intense
focal uptake in the left femur,
corresponding to a lytic bone
metastasis on CT
Rev Endocr Metab Disord

[41]. However, although the positivity rate of
18
F-FDG PET/
CT increases as the Tg level rises, true-positive findings have
also been reported in 10–20% of DTC patients with Tg levels
<10 ng/ml [58,59]. Giovanella and colleagues suggested that
Tg doubling time independently predicted a positive
18
F-FDG
PET/CT scan in patients with biochemical recurrence [59,60].
The accuracy of
18
FDG PET/CT significantly improved when
the Tg doubling time was <1 year, irrespective of the absolute
Tg value [60].
Considering the low sensitivity of diagnostic
131
I WBS,
one of the most important issues is the comparison of post-
therapeutic
131
IWBSwith
18
F-FDG PET/CT. Leboulleux
et al. [61] evaluated the sensitivity of post-therapeutic
131
I
WBS vs
18
F-FDG PET/CT in patients with elevated serum
Tg levels. The sensitivity in detecting DTC relapse was 88%
for
18
F-FDG-PET/CT and 16% for post-therapeutic WBS
(p<0.01), respectively.
18
F-FDG-PET/CT was abnormal in
22 patients, five of whom also had an abnormal post-
therapeutic
131
I-WBS. The authors concluded that, in patients
with suspicion of recurrence based on Tg levels after a normal
post-ablation WBS,
18
F-FDG-PET/CT is better able to local-
ize disease than post-therapeutic
131
I-WBS. Similarly, Kim
et al. [62] reported that second empiric
131
I therapy and
post-therapeutic
131
I-WBS were neither diagnostically nor
therapeutically useful in 39 patients with elevated stimulated
Tg and negative
18
F-FDG-PET/CT after initial treatment.
These data suggest that the correct use of
18
F-FDG-PET/CT
may reduce the number of unnecessary second adminis-
trations of high
131
I activities [63]. In this setting, pos-
itive
18
F-FDG-PET/CT findings may also change the
clinical management in 20–40% of patients [63]. Indeed, sur-
gical procedures or external beam radiotherapy are important
options if
18
F-FDG-positive lesions are not suitable for
131
I therapy.
Another aspect regards the presence of anti-thyroglobulin
autoantibodies (TgAb), which can interfere with serum Tg
measurement and compromise the clinical utility of Tg mon-
itoring for recurrence [56]. Theoretically, TgAb may be pro-
duced as a result of the presence of thyroid tissue. Therefore,
increasing serum TgAb levels during the follow-up of DTC
patients appear to be a good biomarker of persistent or
recurrent DTC with undetectable serum Tg levels [56]. The
diagnostic performance of
18
F-FDG PET/CT in detecting re-
current and/or metastatic diseases in DTC patients with pro-
gressively and/or persistently elevated TgAb levels and nega-
tive
131
I-WBS was evaluated by a recent meta-analysis, which
reported pooled sensitivity and specificity of 84% and 78%,
respectively [56].
In sum, the role of
18
F-FDG PET/CT in evaluating DTC
relapse is supported by high-quality evidence. This indication
should be considered in clinical practice.
3.3 Prognostic role in DTC
An accelerated rate of glucose metabolism mediated by over-
expression of glucose transporters is among the most charac-
teristic biological signatures of malignant cells. In primary
thyroid neoplasms, as described above, more aggressive and
high-grade tumours show a higher FDG uptake than tumours
with favourable prognosis. Indeed, expression of glucose
transporters on the cell membrane is closely related to the
grade of malignancy of thyroid neoplasms [64]. Thus,
18
F-
FDG PET/CT has been described as a promising technique
in identifying DTC patients at higher risk of developing dis-
tant metastases or patients with distant metastases at higher
risk of disease progression.
The most important clinical paper in this field is that of
Robbins and colleagues [36], who retrospectively analysed
the initial
18
F-FDG PET/CT uptake behaviour in 400 DTC
patients. They examined the prognostic value of clinical pa-
rameters, namely gender, age, serum Tg levels, stage, histol-
ogy, radioiodine avidity,
18
F-FDG-PET positivity, number of
FDG-avid lesions, and the glycolytic rate of the most active
lesions. On multivariate analysis, they found that only age and
18
F-FDG PET/CT results were strongly associated with sur-
vival. Furthermore, there were significant inverse relation-
ships between survival and both the glycolytic rate of the most
active lesions and the number of FDG-avid lesions [36,65].
Considering patients with metastases, Deandreis et al.
showed that, in comparison with radioiodine uptake and his-
tological or immunohistochemical patterns, FDG uptake was
the only significant prognostic factor for survival. The
Table 5 Diagnostic performance
of
18
F-FDG PET/CT in DTC
restaging according to published
meta-analyses
Authors (publication year) Number of
studies
Number
of patients
Sensitivity
(95%CI)
Specificity
(95%CI)
Kim et al. (2018) [40] 9 515 84% (77–89) 78% (67–86))
Schütz et al. (2018) [55] 11 NR 94% (87–98) 78% (52–92)
Haslerud et al. (2016) [54]17 905 80%(73–86) 75% (63–85)
Caetano et al. (2016) [53] 7 260 93% (84–97) 81% (69–90)
Miller et al. (2011)* [52]11 498 82%(69–94) 84% (77–92)
Dong et al. (2009) [51] 6 165 93% (87–97) 84% (72–92)
CI confidence interval; NR not reported; *both PET and PET/CT
Rev Endocr Metab Disord

maximum standardised uptake value and the number of FDG-
avid lesions were also related to prognosis [66].
Another important study to validate the prognostic role of
18
F-FDG PET/CT in DTC follow-up was conducted by Vural
et al. They showed that a negative
18
F-FDG PET/CT predicts a
favourable prognosis in DTC patients with Bsuppressible Tg
levels^under TSH suppressive therapy (<1 ng/ml) despite sig-
nificant elevation of Tg after TSH stimulation [67]. By contrast,
Marcus et al. found that DTC patients with a positive follow-up
FDG-PET/CT scan had shorter overall survival than those who
had a negative scan (p< 0.0001) [68]. In a multivariate Cox
regression model,
18
F-FDG PET/CT remained associated to
overall survival (p < 0.0001). Regarding the prognostic value
of
18
F-FDG PET in patients with DTC and circulating anti-Tg
antibodies, Bosgrud and colleagues reported that negative PET
results were associated with the absence of active disease and
the disappearance of antibodies over time. By contrast, residual
FDG-avid lesions were associated with more aggressive dis-
ease and persistently increased TgAb levels [69].
DTC harbouring a BRAF
V600E
gene mutation has been
shown to exhibit aggressive behaviour and carries higher risks
of recurrence and disease-specific death. A recent meta-
analysis of the accuracy of
18
F-FDG PET/CT in detecting
residual disease in patients with BRAF
V600E
mutated DTC
demonstrated that the presence of this mutation confers a
higher likelihood of
18
F-FDG avidity than the absence of
BRAF
V600E
mutation [70].
In sum, the prognosticrole of
18
F-FDG PET/CT is support-
ed by moderate-quality evidence. This indication should be
considered in clinical practice.
3.4
18
F-FDG-PET/CT to identify radioiodine refractory
disease
After thyroidectomy and radioactive remnant ablation, ap-
proximately 15% of DTC patients develop metastases, mostly
those with extensive disease and aggressive histologic sub-
types [71]. Only two-thirds of metastatic patients show sub-
stantial
131
I uptake, and complete remission is achieved after
radioactive iodine therapy (RAI) in only one-third of patients
with distant metastases. The remaining patients may be de-
fined as having RAI-refractory disease. Although a negative
post-therapeutic
131
I-WBS was for a long time the only pre-
dictor of lack of response to RAI, today
18
F-FDG-PET/CT is
probably the most reliable diagnostic method of identifying
patients at higher risk of disease progression after RAI.
Indeed, as first described by Feine and colleagues [71], the
more differentiated thyroid carcinoma cells retain their iodine-
trapping mechanism, and have a low glucose metabolism,
while the more undifferentiated thyroid carcinoma cells lose
their iodine-trapping mechanism and have a high glucose me-
tabolism. Thus, not only patients with metastatic disease un-
able to concentrate
131
I, but also those with FDG-avid
metastases still able to concentrate
131
I, could be regarded as
having RAI-refractory disease [72].
18
F-FDG-PET/CT may identify lymph-node or distant me-
tastases that are not detected or only partially detected by post-
therapeutic
131
I WBS. In such cases, any further RAI ap-
proach should be reconsidered or avoided [73]. Similarly,
18
F-FDG-PET/CT may detect new radioiodine-negative me-
tastases in advanced DTC patients with unchanged positive
post-therapeutic
131
I WBS and increasing Tg levels [74].
Also, in this case, more appropriate treatment than RAI should
be considered. In brief, a positive
18
F-FDG-PET/CT, together
with a negative
131
I WBS or evidence of metastatic disease
progression despite significant concentration of radioiodine,
is able to identify radioiodine-refractory DTC [75].
Moreover,
18
F-FDG-PET/CT has been claimed to be one
of the main procedures able to detect major sites of disease
requiring additional localized intervention, such as surgery,
external radiation therapy, radiofrequency ablation, cryother-
apy, cement injection, or embolization. These treatment mo-
dalities may help physicians to postpone the initiation of sys-
temic treatment.
In sum,
18
F-FDG-PET/CTcanbeveryusefulinidentifying
radioiodine-refractory disease (moderate quality of evi-
dence). However, it is not sufficient in order to definitely ex-
clude metastatic patients from RAI administration. This indi-
cation is supported by Bmoderate quality of evidence^,and
further studies are warranted.
3.4.1
18
F-FDG-PET/CT to predict the response to systemic
therapies in iodine-refractory DTC
Patients with metastatic RAI-refractory disease and posi-
tive
18
F-FDG-PET/CT scans are more likely to suffer pro-
gressive disease and have a median survival of <5 years
[36]. In the last few years, different multi-targeted tyro-
sine kinase inhibitors (TKIs) have been proposed in clin-
ical trials and, more recently, introduced into clinical prac-
tice. The use of TKIs, given their toxicities, should be
reserved for selected metastatic patients [76]. In this con-
text, by identifying metabolic changes within the tumour,
18
F-FDG-PET/CT can provide an early assessment of
treatment response and seems to be more sensitive in de-
tecting treatment-related changes than conventional imag-
ing based on tumour size (i.e. RECIST criteria) [77]
(Fig. 4). However, the available data are few and incon-
clusive, and larger randomized studies are needed to eval-
uate the ability of
18
F-FDG-PET/CT to distinguish pa-
tients who are more likely to achieve a morphological
response from those who are unlikely to respond to new
therapies.
Carr et al. [78] conducted a phase II trial to assess the
efficacy of Sunitinib (37.5 mg daily) in patients with metasta-
tic RAI-refractory DTC. They considered at least one FDG-
Rev Endocr Metab Disord

avid lesion to be the objective criterion for trial entry and
assessed the early response via
18
F-FDG-PET/CT after 7 days
of treatment. The authors observed a high rate of disease re-
sponse (78%) and a significant association between average
SUV percent change and the RECIST response criteria.
Patients with partial/complete response and stable disease
displayed a significantly greater decline in average SUVs than
patients with progressive disease. In other words, an early
18
F-
FDG-PET/CT in patients on TKI treatment could be an early
indicator of response and may identify patients unlikely to
respond to Sunitinib, thus anticipating suspension of the treat-
ment. By contrast, in a phase II clinical trial of sorafenib,
Kloos et al. [79] evaluated the functional response, as mea-
sured by
18
F-FDG-PET/CT, as a secondary endpoint of the
study. They found no correlation between
18
F-FDG-PET/CT
response (changes in SUVmax and metabolic volume) and
RECIST response. Interestingly, in their experience of the
off-label use of sorafenib, Marotta et al. [80] assessed the early
metabolic response by using
18
F-FDG-PET/CT at the baseline
and 15 days after treatment initiation. Baseline average
SUVmax was significantly higher in patients with disease
progression but showed no correlation with progression-free
survival. This means that FDG-PET assessment at the baseline
may predict radiological response but not clinical outcome.
In a randomised, double-blind, placebo-controlled phase 2
trial, adult patients with locally advanced or metastatic
radioiodine-resistant DTC were randomised to receive either
vandetanib 300 mg per day (vandetanib group) or matched
placebo (placebo group). In patients treated with vandetanib
(11.1 months) progression-free survival was significantly
higher (p= 0.008) than in the placebo group (5.9 months).
However, based on early (i.e. within 3 weeks of starting treat-
ment)
18
F-FDG PET scans, no correlation was found between
18
F-FDG uptake and disease control; i.e. this metabolic imag-
ing technique was not an early predictor of response to
thyrosine kinase inhibitors [81].
A Japanese non-randomised single-arm multicentre study
is currently ongoing in patients with radioiodine-refractory
DTC, the aim being to determine whether
18
F-FDG-PET/TC
performed soon (1 week) after commencing the TKI
lenvatinib can predict the treatment outcome. Since patient
recruitment will continue until the end of March 2019, and
considering the median progression-free survival of patients
receiving lenvatinib, the results will be available no earlier
than April 2020. If FDG PET/CT at an early time-point after
treatment initiation were able to predict outcomes in these
patients, adverse effects (very common with TKIs) and high
treatment costs could be avoided [82].
In sum, the role of
18
F-FDG PET/CT in predicting the
efficacy of TKI is supported by moderate quality of evidence
with conflicting results. This indication should not be consid-
ered in clinical practice.
3.4.2 Diagnostic role of
124
IPETinDTC
If serum Tg levels suggest persistence/recurrence of disease
after initial treatment (i.e. suppressed Tg > 5 ng/ml) [41]and
the principal diagnostic procedures, such as neck ultrasonog-
raphy, diagnostic
131
I-WBS/
123
I-WBS and
18
F-FDG-PET/CT
are unable to identify structural disease amenable to directed
Fig. 4 A 73-year-old man affected by multiple lung and bone metastases
from follicular thyroid cancer (a). The disease was considered radioiodine-
refractory after 2 ineffective cycles of RAI without evidence of disease on
post-therapeutic WBS (a). A full dose of Sunitinib was started and a partial
response was observed 3 months later on
18
F-FDG PET/CT (b). However,
after a further 8 months, rapid progression of disease was observed (C)
Rev Endocr Metab Disord

therapy (surgical, thermal ablation or external beam radiother-
apy), a second empiric RAI can be considered, in order to
identify the site of disease and to provide therapeutic benefit.
However, this approach fails in over 50% of patients [83–85].
In this regard, imaging biomarkers able to predict which pat-
ents will respond to further RAI therapies are required, in
order to spare the patient any further fruitless exposure. This
is particularly important in paediatric patients.
Thediagnosticroleof
123
Iand
131
I in detecting DTC local-
izations is well established. These tracers are highly specific
for DTC and their bio-distribution provides a very high target-
to-background ratio. Attenuation correction and the proper
anatomical location of small findings are the main advantages
of dedicated SPECT/CT tomography. Thus, dedicated
SPECT/CT tomography significantly improves the diagnostic
sensitivity of these imaging modalities. However, the half-life
of
123
I is too short for adequate late imaging and of limited
value to dosimetry. On the other hand, while the half-life of
131
I is longer, the quality of imaging is poor, and the high dose
absorbed by the tumour might impair subsequent RAI (i.e.
risk of tumour stunning) [86].
The introduction of
124
I PET/CT may theoretically over-
come the intrinsic limits of the two other iodine isotopes.
Indeed, Iodine-124 is a positron-emitting isotope and there-
fore suitable for PET imaging; so far it has been used mostly
for dosimetry or thyroid volume measurements. However, be-
yond any dosimetric evaluation,
124
I PET/CT may be useful in
identifying persistence/recurrence of disease after initial DTC
treatment. Indeed, identifying iodine-avid DTC localizations
on
124
I PET/CT could allow us to select patients who will
benefit from RAI. Thus, any inappropriate and Bblind^addi-
tional RAI, based only on detectable Tg levels, negative neck
ultrasound and negative
18
F-FDG-PET/CT, could be avoided.
However, controversial results have been reported in the liter-
ature. In a pilot study conducted by Phan and colleagues [87]
on a small number of patients (n= 20) with advanced DTC
(including T4, extra-nodal tumour growth, or distant metasta-
ses),
124
I-PET was able to detect more abnormalities than di-
agnostic
131
I-WBS, but yielded comparable findings to post-
therapeutic
131
I-WBS; 11 patients had a positive
124
I-PET
scan, while only three had visible abnormalities on diagnostic
131
I WBS. These findings suggested that
124
I PET could better
predict the response to high-dose RAI and would constitute a
better diagnostic tool on which to base clinical decisions, such
as additional surgery. A negative
124
I PET scan could mean
that RAI should be avoided, and that further imaging should
be performed to detect (non-iodine-avid) metastatic disease
[87,88].
However, at least three important papers have reported low
sensitivity of
124
I in detectingiodine-avid metastases that were
subsequently identified by post-therapeutic
131
IWBS.
Freudenberg and colleagues [89] found that
124
I PET/CT, ac-
quired 24 h after the injection of
124
I at a very low activity
(24 MBq) during recombinant human TSH (rhTSH) stimula-
tion, did not identify small, disseminated lung metastases that
were well detected by post-therapeutic
131
I-WBS. Kist et al.
[90] and Khorjekar et al. [91] reported, albeit in a very limited
number of patients, that in cases of detectable Tg, negative
neck ultrasound, negative diagnostic and positive post-
therapeutic
131
IWBS,pre-RAI
124
I PET/CT, acquired 24 h
after the injection of low activity (about 74 MBq), did not
identify iodine-avid metastases. These latter authors [91]stat-
ed that the high false-negative rate of rhTSH stimulated
124
I
PET/CT, as implemented in their study, precluded its use as a
scouting procedure to prevent futile blind
131
Itherapy.
By contrast, others have reported that
124
I PET/CT has high
diagnostic accuracy [92,93]. Capoccetti et al. analysed 69
DTC patients (62 with papillary carcinomas and 7 with follic-
ular carcinomas) and ascertained that the findings of
124
I-PET/
CT and those of
131
I WBS matched in 58 (87%) of the 67
patients who underwent both examinations. In 12%,
124
I-
PET/CT revealed previously unknown lymph node metasta-
ses, resulting in a subsequent change of the N-stage from N0
to N1, and in a further 4%, unknown distant metastases [92].
In addition, a larger study by Ruhlmann et al., which involved
137 DTC patients with 277 metastases, showed a very high
sensitivity of
124
I PET/CT in detecting iodine-avid metastases
[93]. All but four patients had undergone 4-week thyroid hor-
mone withdrawal in preparation for imaging. In the lesion-
based analysis,
124
IPETand
131
I imaging detected 98%
(223/227) and 99% (225/227) of the iodine-positive metasta-
ses, respectively, the level of agreement between these imag-
ing modalities being 97% (221/227). In the patient-based anal-
ysis (61 of the 137 patients presented iodine-positive metasta-
ses)
124
I PET and
131
I imaging detected at least one iodine-
positive metastasis in 97% (59/61) and 98% (60/61) of the
patients, respectively, the level of agreement being 95% (58/
61). Both modalities concordantly identified 76 of 137 pa-
tients without pathologic iodine uptake. The authors conclud-
ed that
124
I PET/CTcould be used for individualized treatment
planning and staging in thyroid cancer patients [93].
One important observation arises from these authors’re-
sults. In this large study, all but four patients underwent
124
I
PET/CTafter thyroid hormone withdrawal. By contrast, in the
studies reporting low diagnostic sensitivity of
124
I PET/CT, all
patients underwent rhTSH stimulation. This difference might,
at least in part, explain these discrepant results. Indeed, Van
Nostrand and colleagues [94] reported a very high discrepan-
cy in
124
I PET/CT sensitivity between patients with endoge-
nous (n= 16) and exogenous (n=24)TSHstimulation. The
percentage of patients in whom foci were detected was signif-
icantly (p< 0.03) higher on thyroid hormone withdrawal
scans: 63% (10/16) than rhTSH scans: 29% (7/24). In addi-
tion, significantly more foci of metastases were identified after
thyroid hormone withdrawal than after rhTSH stimulation.
Rev Endocr Metab Disord

This issue has been addressed by only one recent meta-
analysis [95] of five small studies [87–90,96,97], and the
authors reported a very high pooled sensitivity (Table 6).
However, to better clarify the clinical role of
124
I PET/CT,
further prospective studies are required. The principal indica-
tion for this imaging procedure remains for those cases in which
123
I SPECT/CT is likely to underestimate the disease burden
(e.g. children or patients with persistently high/detectable Tg
levels and history of RAI therapy), so as to avoid any empirical
RAI.
In sum, the diagnostic role of
124
I PET/CT may be pro-
posed as an alternative to conventional radioiodine scanning.
This indication is Bsupported by high-quality evidence^and
should be considered in clinical practice.
3.4.3 Somatostatin analogues in DTCs
The lack of concordance between negative imaging proce-
dures (both functional and morphological) and high or in-
creasing serum Tg levels in the case of suspicious DTC
persistence/relapse has prompted some authors to try other
PET tracers as alternatives to FDG or to iodine isotopes. In
this particular context, the use of radiolabelled somatostatin
analogues has been proposed in patients affected by DTC.
Somatostatin is a cyclic peptide hormone which regulates
the endocrine system and modulates neurotransmission and cell
proliferation. Specifically, somatostatin inhibits basal and TSH-
stimulated adenylate cyclase activity in normal and neoplastic
human thyroid tissue and thyroid hormone secretion and affects
the growth of human thyroid carcinoma cells. Normal thyroid
tissue and DTCs express different types of somatostatin recep-
tors. Specifically, DTC(s) express somatostatin receptors 2, 3
and 5 receptors [98]; consequently, the sensitivity of PET/CT
with radiolabelled somatostatin analogues in detecting DTC
localizations depends on the binding of these somatostatin an-
alogues to somatostatin receptors-expressing cells.
In 2010, Middendrorp and colleagues [98] first compared
the ability of
68
Ga-DOTATOC PET/CT with that of
18
F-FDG
PET/CT to detect DTC recurrence/metastases after thyroidec-
tomy and at least 2 cycles of RAI in 17 intermediate/high-risk
DTC patients. Their patient-based analysis did not show any
difference in terms of sensitivity; both PET/CTs identified
structural disease in 12 of the 17 patients. However, in the
lesion-based analysis (LBA)
18
F-FDG PET/CT proved more
sensitive, detecting 98 of the 104 DTC localizations con-
firmed on applying the multidisciplinary gold standard. In this
setting,
68
Ga-DOTATOC PET/CT identified only 54 DTC lo-
calizations. Interestingly, the authors reported that
18
F-FDG
PET/CT had a higher tumour/background ratio [98](Fig.5).
In 18 metastatic DTC patients with negative
131
IWBS,Traub-
Weidinger et al. [99] confirmed that
18
F-FDG PET/CT was sig-
nificantly more sensitive than
68
Ga-DOTATOC PET/CT in
Table 6 Lesion-based sensitivity of
124
I PET/CT in detecting DTC localizations
Authors (year) Study design Clinical context N° of pts Activity (MBq) PET or PET/CT Main TSH stimulation Mean/Median Tg Levels (ng/ml) Sensitivity (LB)
Phan et al. (2008) [87] Prospective Suspicious relapse 20 74 PET THW 265/49 82%
Freudenberg et al. (2008) [88] Retrospective Suspicious relapse 21 43 PET/CT THW 53.4/38.5 80%
Capoccetti et al. (2009) [92] Retrospective Ablation 69 37 PET/CT THW 5.5/NR 98%
de Pont et al.(2013) [96] Retrospective Ablation 20 22–27 PET/CT THW NR 91%
Kist et al. (2016) [90] Prospective Suspicious relapse 17 74 PET/CT rhTSH 99/28 57%
Gulec et al. (2016) [97] Prospective Ablation/Suspicious relapse 15 75 PET/CT THW NR 89%
Ruhlmann et al. (2016) [93] Retrospective Ablation/Suspicious relapse 137 27 PET/CT THW 528/16 98%
Santhanam et al. (2017) [95] Meta-analysis Ablation/Suspicious relapse 141 22–75 PET/PET/CT THW NR 94%*
LB lesion-based; NR not reported; NA not applicable; THW thyroid hormone withdrawal; rhTSH recombinant human TSH; *pooled sensitivity
Rev Endocr Metab Disord

detecting disease localization,
18
F-FDG PET proving positive in
88% of patients, and
68
Ga-DOTA-TOC in only 29% [99].
Kundu et al. provided further confirmation of the higher
sensitivity of
18
F-FDG PET-CT [100]. These authors were the
first to enrol an adequate number (n= 62) of DTC patients
with rising levels of Tg (stimulated Tg >10 ng/ml) and nega-
tive diagnostic
131
I WBS. Their patient-based analysis did not
reveal a significant difference in sensitivity and specificity
between
68
GaDOTANOC PET-CT (78.4% and 100%) and
18
F-FDG PET-CT (86.3%, 90.9%). However, in their LBA
of 186 lesions detected by both PET-CTs, only 121/186
(65%) lesions were seen on
68
Ga-DOTANOC PET-CT, versus
168/186 (90.3%) on
18
F-FDG PET-CT (p< 0.0001).
Moreover, the accuracy of
18
F-FDG PET-CT and
68
Ga-
DOTANOC PET-CT was not related to serum Tg levels and
no significant difference in accuracy was seen between high-
and low-Tg groups (cut-off: 127 ng/ml) [100].
More recently, and for the first time, one study [101]inves-
tigated the role of
68
Ga-DOTANOC PET-CT in 15 DTC pa-
tients with detectable or rising Tg levels, negative
18
F-FDG
PET-CT and negative diagnostic
131
IWBS.
68
Ga-DOTANOC
PET-CT was positive in five of patients (33%) and the rate of
positive findings was significantly higher in poorly
differentiated/oxyphilic carcinomas (4/4 patients) than in pap-
illary (1/5) or follicular (0/6) tumours. In addition, Tg levels
tended to be higher in patients whose tumours were detected by
68
Ga-DOTATOC PET/CT, but significance was not reached.
These data suggest that
68
Ga-DOTANOC PET-CT cannot
be regarded as a sensitive diagnostic procedure to identify
structural disease in DTC patients with negative
131
I WBS
and rising Tg levels (Table 7). It might, nevertheless, be a
second diagnostic option after a negative or inconclusive
18
F-FDG PET-CT. However, positive findings on
68
Ga-
DOTANOC PET-CT may pave the way to a different treat-
ment option, in the form of
177
Lu-DOTATATE therapy, when
other options have been exhausted. This option should be
reserved for patients with more aggressive DTC subtypes,
which are often characterized by intense radiolabelled somato-
statin analogue uptake (i.e. higher than surrounding normal
tissue) [102]. However, these patients account for less than
30% of radioiodine-refractory DTC patients, as PTC patients
often do not show somatostatin analogue uptake.
In sum, the diagnostic role of radiolabelled somatostatin
analogues is supported by moderate-quality evidence with
conflicting results. This indication should not be considered
in clinical practice.
3.4.4 Radiolabelled choline and DTC
The consolidation of radiolabelled choline PET/CTas a useful
tool for evaluating prostate cancer relapse has raised the level
of experience of this imaging procedure and increased the rate
of incidental detection of malignant lesions in several organs.
Some case-reports have suggested the need to rule out DTC in
the case of focal thyroid choline uptake incidentally detected
during PET/CT examinations of the prostate [103–107]. In a
very recent study involving a considerable number of patients,
Albano et al. retrospectively evaluated the prevalence of cho-
line thyroid Bincidentaloma^(2.4%) and its risk of malignan-
cy (25%) [106].
Other authors have reported that radiolabelled choline
PET/CT may be useful in patients with thyroid cancer and
metastases who prove negative on
18
F-FDG PET/CT. In this
regard, Wu et al. [108]studied
11
C-choline PET/CT in 4 pa-
tients (3 men, 1 woman, 24–59 years) with thyroid cancer (2
newly diagnosed and 2 with recurrence); previous
18
F-FDG
PET had shown no tracer uptake in 3 patients and only mild
uptake in one. In these patients, all the cancer lesions, except
for a few small lung metastases, were
11
C-choline-avid.
Similarly, our group described the case of a 77-year-old
Fig. 5 A 71-year-old woman af-
fected by radioiodine-refractory
multiple bone and lymph-node
metastases.
18
F-FDG PET/CT
showed intense uptake corre-
sponding to lymph node metasta-
sis of the upper mediastinum (a)
and to the left third rib (b). By
contrast,
68
Ga-DOTATOC PET/
CT showed very faint uptake by
these DTC metastases (c,d)
Rev Endocr Metab Disord

woman who had undergone thyroidectomy and
131
Iremnant
ablation for tall-cell DTC of the left lobe [109]. Detectable Tg
levels (4.1 ng/ml) under TSH suppression, with undetectable
serum TgAb levels, prompted neck ultrasound, which revealed
a lymph node metastasis in the left laterocervical and right
retro-clavicular regions.
18
F-FDG PET/CT showed uptake by
the left lymph node, whereas
18
F-choline PET/CT showed in-
creased uptake by both lymph nodes. Histopathology revealed
DTC solid metastasis in the left lymph node and solid cystic
metastasis in the right one (Fig. 6). We concluded that
18
F-
choline PET/CT could detect virulent DTC recurrence, thereby
increasing
18
F-FDG PET/CT information [109].
In sum, the diagnostic role of radiolabelled choline in pa-
tients with suspected DTC persistence/relapse is not support-
ed by the evidence. This indication should not be considered
in clinical practice.
3.4.5
68
Ga-prostate-specific membrane antigen (PSMA)
68
Ga-PSMA PET/CT is an emerging diagnostic procedure
based on
68
Ga conjugated with anti-PSMA monoclonal anti-
body and is highly accurate in detecting prostate cancer. Case-
reports have described
68
Ga-PSMA-positive thyroid tumours,
including adenoma and carcinoma, incidentally detected dur-
ing PET/CT examination performed for suspected prostate
cancer relapse [110,111].
The uptake mechanism of this compound in DTC [112]is
related to PSMA expression in microvessels of tumour tissue.
The highest endothelial PSMA expression has been found in
RAI-resistant thyroid cancers, suggesting that it increases with
tumour progression. Indeed, its expression is also asso-
ciated with tumour size [113]. Moreover, high PSMA
expression in the tumour-associated neovasculature is
reported to be found mainly in poorly differentiated or
undifferentiated thyroid cancer [113]. These findings
might pave the way to further evaluation of PSMA-targeted
anti-neovascular or radioligand therapy in metastatic
dedifferentiated thyroid cancer.
However, one case-report confirmed that
68
GaPSMA PET/
CT was able to visualize a metastatic RAI-negative poorly
differentiated thyroid cancer [114]. In addition, Lütje et al.
used
68
Ga-HBED-CC-PSMA PET/CT to study six patients
with radioiodine-negative and
18
F-FDG-positive metastasised
DTC. In 5 out of 6 patients, sites of putative metastatic disease
were identified. All lesions detected were confirmed by
18
F-
FDG PET/CT or conventional CT imaging [115]. These pre-
liminary results indicate that
68
Ga-HBED-CC-PSMA PET/
CT might be appropriate to the staging of patients with
metastasised radioiodine-negative DTC.
In sum, the diagnostic role of radiolabelled anti-PSMA
monoclonal antibody in DTC patients with suspected DTC
persistence/relapse is not supported by the evidence. This in-
dication should not be considered in clinical practice.
Table 7 Lesion-based sensitivity of
68
Ga-DOTATOC PET/CT in detecting DTC localizations
Authors (year) Clinical context Comparison with
18
F-FDG
PET/CT(Y/N)
N° of pts Mean/Median
Tg Levels (ng/ml)
131
I WBS scan
68
Ga-DOTATOC PET/CT
Sensitivity PB/LB
18
F-FDG PET/CT
Sensitivity PB/LB
Middendrorp et al. (2010) [98] Suspicious relapse Y 17 6100/34.4 Positive in 7 pts 70%/52% 70%/94%
Negative in 10 pts
Traub-Weidinger et al. (2015) [99] Disease Progression Y 18 NR Negative in 18 pts 29%/NA 88%/NA
Kundu et al. (2015) [100] Suspicious relapse Y 62 275 /127 Negative in 62 pts 78.8/65% 86.3/90.3%
Binse et al. (2016) [101] Suspicious relapse N 15 134/1.6 Negative in 15 pts 33%/NA NA/NA
LB lesion-based, PB patient-based; NR not reported
Rev Endocr Metab Disord

Fig. 6 74-year-old woman affected by lymph node relapse of papillary
thyroid cancer (pT3mN1b). Neck US (not shown) detected an enlarged
lymph node with cystic and solid components in the right retroclavicular
region and one hypoechoic left laterocervical lymph node.
18
F-FCH PET/
CT showed focal uptake (a) corresponding to the 2 lymph nodes, one of
which was negative on
18
F-FDG PET/CT (b). Histopathology
(haematoxylin-eosin stain, 40X) revealed 2 DTC cystic metastases. In the
first (c), the solid portion of cystic lymph node metastasis displayed a solid/
trabecular structure with a tall cell component. In the second (d), lymph
node structure was completely substituted by papillary thyroid cancer with
a prevalent tall-cell component and nuclear grooves
Table 8 Clinical indication for PET/CT in thyroid nodules and DTC. Evidence-based support and recommendation
Indication Tracer Evidence-
based
data
Meta-
analysis
Randomized
clinical trials
Cohort
Studies
Cited by
Guidelines
*
Indication
in clinical
practice
Thyroid nodules with indeterminate cytology
18
FFDG Y Y N Y Y Y
Thyroid nodules with suspicious US features
18
F FDG N N N Y N Weak
Biological aggressiveness of primary DTC
18
FFDG N N N Y N N
Initial Staging of DTC
18
FFDG N N N Y Y N
Initial Staging of aggressive DTC subtypes
18
FFDG N N N Y Y Y
Suspicious DTC relapse and negative
diagnostic
131
I/
123
IWBS
18
FFDG Y Y N Y Y Y
Prognostic role
18
FFDG N N N Y Y Y
Identification of radiodine-refractory disease
18
F FDG N N N Y Y Weak
Prediction of response to TKI
18
FFDG Y N Y Y N N
Suspicious DTC relapse, negative diagnostic
131
I/
123
I WBS and negative
18
F FDG PET/CT
124
IYYYYNY
Suspicious DTC relapse, negative diagnostic
131
I/
123
I
WBS and negative
18
FFDG
PET/CT
68
Ga-somatostin
analogues
NNN YN N
Suspicious DTC relapse, negative diagnostic
131
I/
123
I WBS and negative
18
FFDG
PET/CT**
Radiolabelled
choline
NNN NN N
Suspicious DTC relapse, negative diagnostic
131
I/
123
I WBS and negative
18
FFDG
PET/CT**
68
Ga-PSMA N N N N N N
*ATA Guidelines [38]; **Indication supported only by case series and reports. Yyes; Nno.
Rev Endocr Metab Disord

4 Conclusions
18
F-FDG PET/CTis a very useful diagnostic procedure which
can solve different, and often complicated, clinical issues in
the management of thyroid nodules and DTCs. We recom-
mend its evidence-based use in clinical practice, as reported
in Table 8.
However, other PET tracers, which evaluate different met-
abolic pathways or receptor status, are being introduced into
clinical practice. Their use might add very specific and per-
sonalized information, enabling patients to be selected for
tailored surgical or radionuclide therapy.
Compliance with ethical standards
Conflict of interest The authors have nothing to disclose.
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