Dr. Lin is a PETCT Fellow and Dr. Iagaru is an Assistant Professor in the Division of Nuclear Medicine, Stanford University Medical Center, Stanford, CA.
Thyroid cancer is the sixth most common cancer in women in the United
States and accounts for approximately 1% of all cancer cases. According
to the National Cancer Institute, thyroid cancer had a prevalence of
>425,000 with an incidence of 37,200 in 2009, accounting for
approximately 1,600 deaths.1 Traditionally, ultrasonography
and radioiodine scintigraphy have been the imaging modalities most
commonly used to visualize thyroid cancer. However, interest is growing
in the utilization of whole-body positron emission tomography (PET) with
computed tomography (CT) to image thyroid malignancy. Currently,
whole-body PET-CT is approved for use in assessing suspected recurrence
of well-differentiated thyroid cancer (WDTC) in patients with
radioiodine-negative scans and detectable thyroglobulin (Tg) levels.
While PET-CT has proved itself in this clinical scenario, evidence is
emerging on the advantages of PET-CT imaging in other histological types
of thyroid malignancy, such as Hürthle cell, medullary, and the
anaplastic variants. Moreover, although current clinical PET-CT scans
are performed almost exclusively with 2-deoxy-2-(18F) fluoro-D-glucose
(FDG), recent advances in targeted molecular imaging are bringing new
possibilities to the imaging of thyroid cancer. The development of human
recombinant thyroid stimulating hormone (rhTSH), for example, is making
imaging under thyroid hormonal stimulation more feasible, and novel PET
radiotracers such as Iodine-124 (124I), 18F-DOPA, and 68Ga-DOTATOC
promise to change the way thyroid malignancies are imaged.
on histology, thyroid cancer can be broadly divided into
well-differentiated follicular and papillary, medullary, and anaplastic
variants. This classification is important because the histological type
impacts prognosis, treatment, and evaluation with imaging.
Well-differentiated thyroid cancer is by far the most common, accounting for approximately 80% of all cases.1 Histologically,
well-differentiated thyroid cancer can be further subdivided into
papillary, follicular, and Hürthlecell. Hürthlecell variants deserve
special consideration since they are poorly iodine-avid; they will be
discussed later in this article. Medullary thyroid cancer is a
malignancy of the parafollicular cells and is often seen in such
syndromes as multiple endocrine neoplasia (MEN). Anaplastic thyroid
cancer is characterized by poorly differentiated histology and is
associated with the worst prognosis, with a median survival time of 8.1
In a typical clinical scenario, the patient
with well-differentiated thyroid cancer undergoes total thyroidectomy,
followed in most cases by radioiodine ablation of the thyroid remnant.3 A
follow-up whole-body radioiodine scan is performed every 6 months to 12
months. Since thyroid cancer cells have a lower expression of
sodium-iodine symporters, and therefore have a decreased ability to
concentrate iodine compared with normal thyroid tissue,4
better diagnostic accuracy is obtained from the radioiodine scan when
the patient is administered thyroid-stimulating hormone (TSH).
can be achieved intrinsically via withdrawal of the patient’s thyroid
hormone replacement medications, or it can be done extrinsically by
administration of rhTSH. In addition to the radioiodine scan, standard
practice follow-up also usually involves obtaining serum Tg levels and a
neck ultrasound scan.3 Thyroglobulin is a dimeric protein
found exclusively within the thyroid gland unless thyroid pathology such
as thyroiditis or malignancy is present. Its detection in the serum in a
post-thyroidectomy patient indicates the existence of residual thyroid
Iodine-negative, thyroglobulin-positive, WDTC
the most common indication for a PET-CT scan is to evaluate thyroid
cancer. Numerous studies have shown the usefulness of a whole-body PETCT
scan in the detection of recurrent disease in patients with negative
radioiodine scans.5–10 WDTCs are generally slow growing and
retain some capacity to concentrate iodine. However, if the cancer
becomes more poorly differentiated, it gradually loses this
capacity—mainly due to decreased expression of the sodiumiodine
symporters—and becomes undetectable by the radioiodine scan. By virtue
of their increased growth rate and subsequent increased utilization of
glucose, these lesions then become detectable by FDG PETCT imaging
(Figures 1 and 2). The radioiodine and the PETCT scans are, therefore,
complementary in this clinical scenario. Most often, a lesion will take
up either only radioiodine or only FDG, although a patient can have both
radioiodine and FDG-avid lesions due to varying differentiation grades
of different lesions.8
In a metaanalysis of 17 studies
comprising 571 patients, the pooled sensitivity and specificity of FDG
PET-CT in patients with recurrent cancer but negative radioiodine scans
were shown to be 0.835 and 0.843, respectively.11 When
analyzed on a per lesion basis, the pooled sensitivity and specificity
were 0.916 and 0.775, respectively, and this increased to 0.935 and
0.839 when considering only those patients with elevated thyroglobulin.
Detection of recurrence on the PETCT scan has been shown to correlate
positively with thyroglobulin levels,12 suggesting that
small lesion volume may be a cause of false negative studies. In fact,
prior studies have shown that FDG-PET imaging is inadequate for
assessing lung metastases <6 mm.13
variants of WDTC deserve special attention because they, as a group,
have low iodineconcentration functions and are more likely to be falsely
negative on a radioiodine scan.14 Suspicion for recurrence
should be especially high, and further imaging with PET-CT warranted, in
a Hürthle cell patient with elevated serum thyroglobulin levels despite
a negative radioiodine scan.
rhTSH and FDG PET-CT
retains the ability to concentrate iodine, but at a much lower level
compared with normal thyroid tissue. Stimulating thyroid cancer cells
with TSH increases their radioiodine uptake, thereby improving scan
sensitivity. Recombinant human TSH has been used successfully as an
alternative to traditional hormone withdrawal in preparing patients for a
radioiodine scan, and numerous studies have documented equivalent
imaging results with rhTSH.15–19 However, it is less clear
whether stimulation with intrinsic TSH or rhTSH improves the sensitivity
of FDG PETCT in thyroid cancer. While some early papers suggest
improved detection rates with rhTSH stimulation,20–21 more recent studies are more equivocal.22 For
instance, a 2009 study found that PETCT scans performed before and 24
hours to 48 hours after administration of rhTSH demonstrated per lesion
sensitivities of 81% and 95%, respectively, with a p value of 0.001.23
However, when the data were analyzed on a per-patient basis, the
sensitivity between the 2 groups became equivalent (54% vs. 49%) and
resulted in management changes in only 6% of patients. Another study,
published in 2010, placed the sensitivity of rhTSH-stimulated PET-CTs at
only 41%.24 Although it is logical to accept that rhTSH can
be used to improve the sensitivity of FDG PET-CT for thyroid
malignancy, more data are needed to determine the true usefulness of
rhTSH in this indication.
Incidental thyroid uptake
Incidental FDG uptake seen in the thyroid gland is not an uncommon finding on PET-CT scans performed for other indications.25–30
Diffuse, symmetric, bilateral uptake (Figure 3) can usually be
explained by noncancerous processes such as Grave’s disease or
thyroiditis and is associated with a low risk for malignancy of 1.4%.31
When FDG uptake is unilateral, focal, and/or corresponds to a nodule on
the CT portion of the exam, more follow-up is needed to exclude
malignancy. In a recent meta-analysis of 18 studies covering >55,000
patients, approximately 1% of patients were found to have such
scintigraphic incidentalomas in the thyroid gland.32 Of the
lesions that received diagnostic confirmation, 62.1% were benign, 33.2%
were malignant, and 4.7% were indeterminate. The risk of malignancy in
these lesions can be further stratified noninvasively by a follow-up
ultrasound. In one study, the probability of malignancy was found to be
only 13.2% when sonographic findings appear benign compared with 75.5%
when they do not.29
Of the malignant lesions, the vast
majority (82.2%) were papillary thyroid cancer. Remaining malignancies
included: follicular thyroid cancer (1.9%), Hürthle cell cancer (2.8%),
medullary thyroid cancer (1.9%), lymphoma (2.8%), and metastatic disease
(6.5%). One study suggests that primary thyroid cancers detectable by
FDG-PET tend to have more aggressive histological features and denote a
poorer prognosis,33 although more data are needed to confirm this finding.
intensity of FDG uptake, as expressed by the standard uptake value
(SUV), does seem to be higher in malignant lesions vs. benign (6.8 ± 4.6
vs. 4.6 ± 2.1).32 However, significant SUV overlap exists
between the 2 groups; this could explain why some studies have not found
statistically significant differences in the SUV.26,29,34
Iodine-124 as a PET radiopharmaceutical
radioiodine imaging for thyroid cancer has typically been done with
gamma (Anger) cameras using either 123I or 131I. Both radiotracers have
their pros and cons. For instance, 131I is inexpensive and widely
available, but it has the disadvantages of poor image resolution and of
possibly causing “stunning.”35 On the other hand, 123I
produces superior image quality, but it is expensive, has a relatively
short half-life, and has limited availability. Because of the spatial
resolution limitations of these 2 radiotracers and the widespread
availability of PET-CT imaging, interest is growing in using 124I and
PET to image thyroid malignancies. 124I, a positron-emitting isotope
with a half-life of 4.2 days, combines the resolution and localization
advantages of PET-CT with the specificity of an iodine-based tracer in
imaging the thyroid (Figure 4). A head-to-head comparison found 124I to
have superior sensitivity and localization to both a pre-ablation and a
post-ablation 131I scan.36 Another study compared 124I
PET-CT with FDG PET-CT in patients with elevated thyroglobulin but
negative ultrasonography and found the sensitivities for WDTC detection
to be 80% and 70%, respectively.37 Other recent articles
have also pointed out the role of 124I in recurrence detection, as well
as in quantifying patient-specific radioiodine therapy radiation
dosimetry prior to ablation.38–39
Medullary and anaplastic thyroid cancer
Medullary thyroid cancer (MTC), which is rare, affects the
parafollicular C cells of the thyroid gland and cannot be imaged
effectively with radioiodine. Currently, FDG PET-CT in medullary thyroid
cancer is most commonly used in cases where conventional imaging
modalities are negative or inconclusive in the presence of elevating
tumor markers such as calcitonin and carcino-embryonic antigen (CEA).40 Some
studies show that FDG PET-CT is superior to conventional modalities,
such as ultrasound, contrast-enhanced CT, and 111In octreotide scans in
the detection of recurrent MTC.41-42 However, the diagnostic
accuracy of FDG PET-CT for MTC is limited compared with its use in
WDTC. Overall sensitivity has been reported to range from 47.4%43 to 80%;44 however, detection rates seem to improve in patients with higher serum calcitonin levels.
novel, experimental PET-CT radiotracers seem to show promise in the
imaging of MTC. For instance, PET-CT performed with
18F-dihydroxyphenylalanine (18F DOPA) was shown in a European trial to
have a sensitivity of 94% vs. 62% for FDG.45 A number of
68Ga-DOTA peptides that bind to somatostatin receptors, such as DOTA-TOC
and DOTA-NOC, are also being evaluated for this indication.46 However, more experimental data are needed before these new radiotracers will see clinical use in the United States.
thyroid cancer is an undifferentiated carcinoma that arises from
thyroid follicular cells. It is very aggressive and portends a poor
prognosis; it is capable of doubling its volume in 7 days.47 Due
to its aggressive growth and subsequent significantly elevated glucose
utilization, several case reports have shown FDG PET-CT’s ability to
detect both primary and metastatic anaplastic thyroid cancer.48–51 A
2007 study found that PET-CT imaging with FDG detected all primary
tumor and nodal metastases, as well as 5 out of 8 lung metastases.46 However, better characterization of FDG PET-CT’s diagnostic accuracy and more studies are needed.
conventional modalities such as ultrasonography and radioiodine
whole-body imaging are still important, FDG PET-CT is playing an
increasingly important role in the evaluation of thyroid cancer. In
addition to strong data already showing the utility of PET-CT imaging
with FDG, the advent of novel PET radiotracers such as 18F DOPA and
68Ga-somatostatin receptor binders may one day revolutionize imaging of
medullary and anaplastic thyroid cancers.
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