Download Thyroid Cancer Indications and

Thyroid Cancer—Indications and
Opportunities for Positron Emission
Tomography/Computed Tomography Imaging
Tony Abraham, DO,* and Heiko Schöder, MD†
Although thyroid cancer is a comparatively rare malignancy, it represents the vast majority
of endocrine cancers and its incidence is increasing. Most differentiated thyroid cancers
have an excellent prognosis if diagnosed early and treated appropriately. Aggressive
histologic subtypes and variants carry a worse prognosis. During the last 2 decades
positron emission tomography (PET) and PET/computed tomography (CT), mostly with
fluorodeoxyglucose (FDG), has been used increasingly in patients with thyroid cancers.
Currently, the most valuable role FDG-PET/CT exists in the work-up of patients with
differentiated thyroid cancer status post thyroidectomy who present with increasing thyroglobulin levels and a negative 131I whole-body scan. FDG-PET/CT is also useful in the
initial (post thyroidectomy) staging of high-risk patients with less differentiated (and thus
less iodine-avid and clinically more aggressive) subtypes, such as tall cell variant and
Hürthle cell carcinoma, but in particular poorly differentiated and anaplastic carcinoma.
FDG-PET/CT may help in defining the extent of disease in some patients with medullary
thyroid carcinoma and rising postoperative calcitonin levels. However, FDOPA has
emerged as an alternate and more promising radiotracer in this setting. In aggressive
cancers that are less amenable to treatment with 131iodine, FDG-PET/CT may help in
radiotherapy planning, and in assessing the response to radiotherapy, embolization, or
experimental systemic treatments. 124Iodine PET/CT may serve a role in obtaining lesional
dosimetry for better and more rationale planning of treatment with 131iodine. Thyroid cancer
is not a monolithic disease, and different stages and histologic entities require different
approaches in imaging and individualized therapy.
Semin Nucl Med 41:121-138 © 2011 Elsevier Inc. All rights reserved.
Clinical Background
T
hyroid cancer is the most common cancer of the endocrine system. Approximately 37,000 new cases of thyroid cancer are diagnosed in the United States each year.1
Papillary cancer is the most common type in the United
States and Europe; women are approximately 3 times more
likely to be diagnosed with thyroid cancer in the most recent
cancer statistics. The incidence of this disease has been increasing during the past several decades, at least in part be*Department of Nuclear Medicine, Montefiore Medical Center and Albert
Einstein College of Medicine, New York, NY.
†Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY.
Current address of Tony Abraham: Montefiore Medical Park, 1695A Eastchester Road, Bronx, NY 10461.
Address reprint requests to Heiko Schöder, MD, Memorial Sloan-Kettering
Cancer Center, Department Radiology/Nuclear Medicine, 1275 York
Avenue, Box 77, New York, NY 10065. E-mail: [email protected]
0001-2998/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1053/j.semnuclmed.2010.10.006
cause of better clinical surveillance and improved imaging
modalities. For instance, analysis of the Surveillance, Epidemiology and End Results Program (SEER) database from
1988 to 2005 showed that the incidence of differentiated
thyroid cancers has increased across sexes, ages, and for all
tumor sizes, although the greatest rate of increase was seen
for primary tumors ⬍ 1.0 cm. The increased incidence is
largely caused by increased detection of papillary thyroid
cancers. Of note, despite increasing incidence, the mortality
did not change significantly during the same period.2
Classification
Thyroid cancer comprises a group of tumors with very different histopathological and clinical features. We distinguish
broadly between malignant tumors of follicular cell origin
(papillary, follicular, Hürthle cell, poorly differentiated, and
anaplastic carcinomas) and cancers in which the parafollicular C-cell is the cell of origin (medullary thyroid carcinoma).
121
122
Papillary thyroid carcinoma (85% of all thyroid cancers;
PTC), follicular thyroid carcinoma (10% of all thyroid cancers; FTC), and Hürthle cell carcinoma are often referred to
as “differentiated thyroid carcinoma.” Variants of PTC include the follicular variant (10% of PTC, similar prognosis),
tall cell variant (worse prognosis, often with local invasion
and distant metastasis; the prevalence is traditionally quoted
as 1% of all PTC, but in most current series about 10% of
carefully reviewed PTC are indeed tall cell variants), as well as
other, rare entities, such as columnar or oxyphilic variant.
Poorly differentiated carcinoma likely represents a step in the
spectrum of increasing de-differentiation of the cancer cell,
which uncommonly leads to anaplastic (undifferentiated)
carcinoma.
Prognostic Factors
Factors affecting the prognosis of patients with differentiated
thyroid cancer include patient age (worse if ⬎40 years), gender (worse for men), tumor histology (excellent for papillary,
worst for anaplastic), tumor size (best for ⬍1 cm, worse for
⬎4 cm), gross extrathyroidal extension, the presence of metastases, and iodine avidity. The presence of nodal metastasis
at the time of diagnosis and surgery does not appear to affect
prognosis in general,3 although risk for recurrence and possibly even death may be slightly elevated in older patients.
Accordingly, although clinically suspicious or biopsy positive lymph nodes should be removed during thyroidectomy
in a compartment-oriented approach, routine lateral neck
dissection is not generally advocated in patients with differentiated thyroid cancer. The role of routine central compartment neck dissection also remains controversial; however,
clinically suspicious nodes detected intraoperatively should
be removed. In contrast to classical papillary carcinoma, in
widely invasive Hürthle cell carcinoma, nodal metastases do
confer a worse prognosis (in addition to extrathyroidal extension and solid growth pattern).4
Over the years, various prognostic indexes have been proposed, including the ages, (age, tumor grade, extent and
size),5 age, metastasis, extent and size,6 MACIS (ie, metastasis, age, completeness of resection, invasion, and size),7 and
the Sloan-Kettering system.3 According to the aforementioned factors, patients can then be classified as high, intermediate, or low risk. It is important to note that all these
systems listed in the sentence before predict risk of death (not
risk of recurrence), whereas the American Thyroid Association (ATA) risk system, described in the following paragraph,
was specifically designed to predict risk of recurrence.
The recent guidelines of the ATA8 suggest the following
classification of differentiated thyroid cancers. Low-risk patients have the following characteristics: no local or distant
metastases, resection of all macroscopic tumor, no tumor
invasion into locoregional tissues, tumor that is not an aggressive histologic variant, no vascular invasion, and no uptake outside the thyroid bed on the post-treatment wholebody scan (WBS; if 131I is given). Intermediate-risk patients
show any of the following criteria: microscopic tumor invasion into the perithyroidal tissues at initial surgery, cervical
T. Abraham and H. Schöder
lymph node metastases or 131I uptake outside the thyroid bed
on the initial post-treatment scan, or tumor with aggressive
histology or vascular invasion. Finally, high-risk patients
show macroscopic tumor invasion or distant metastases, underwent incomplete tumor resection, and exhibit elevated
thyroglobulin levels out of proportion to the extent of disease
noted on post-treatment iodine scan. A more extensive discussion of this new risk classification and risk-adjusted patient management can be found in Tuttle.9
Molecular
Pathology—the Role of Oncogenes
Many thyroid cancers are characterized by oncogene expression and mutation. Awareness of these genetic changes,
which vary among the various subtypes of thyroid cancer, is
important as part of this review because they may provide
prognostic information and may present targets for novel
drug therapies that can be imaged with PET.
Papillary Thyroid Cancer
During the past decade, RAS, p53, RET/PTC, and BRAF (activating mutation of the B isoform of the Raf kinase gene)
were found to be involved in the development and progression of papillary thyroid cancer. RET/PTC is a chimeric fusion
oncogene that is generated as the result of gene rearrangements, found in ⬃20%-40% of PTCs, more commonly in
response to ionizing radiation and in pediatric patients. RET/
PTC gene rearrangement seems to be an early event in the
pathogenesis of papillary thyroid cancer.10 The gene encodes
the RET/PTC receptor tyrosine kinase, which is constitutively
active, leading to activation of tumor signaling pathways,
including the ras/Raf/mitogen-activated protein/extracellular
signal-regulated kinase kinase/extracellular signal-regulated
kinase pathway11 and PI3-K/AKT pathway,12 which promote
cell-cycle progression and inhibition of apoptosis. RAS oncogene mutations are more commonly observed in follicular
thyroid cancer (see below), but can also be noted in papillary
cancer. Ras proteins are GTP-ases in the plasma membrane
that can be activated by growth factors and through other
mechanisms, again leading to consecutive activation of various tumor pathways. BRAF is the most commonly mutated
gene in papillary cancer (⬃45% of all PTC cases)11,13 and is
associated with more aggressive disease and poor prognosis.14,15 BRAF mutations occur either as point mutation or by
gene rearrangement. The BRAF gene encodes the Raf kinase,
an important signaling molecule in the mitogen-activated
protein (MAP) kinase pathway participating in the regulation
of cell proliferation, differentiation, migration, survival, and
death.16 Accordingly, Raf and other kinases in the MAP kinase pathway are now recognized as targets for novel drug
therapies in thyroid cancer17-20 as well as other malignancies.21-24 Of note, BRAF mutations are not found in any other
well-differentiated thyroid cancers.25 Papillary thyroid cancers with BRAF mutation show markedly decreased gene expression levels for genes encoding the thyroid stimulating hormone (TSH)-receptor, enzyme thyroid peroxidase (needed for
thyroid hormone synthesis), sodium iodine symporter (NIS,
needed for iodine uptake),26 and interestingly also increased
Thyroid cancer: indications and opportunities for PET/CT imaging
expression levels for glucose transporter 1 (GLUT-1).27 Experimentally, treatment with mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor restores the normal expression level of NIS and TSH receptor.28
On the basis of these observations from laboratory studies it
would be expected that thyroid cancers with BRAF mutation
are more commonly fluorodeoxyglucose (FDG)-avid, are less
susceptible to treatment with 131iodine, and that inhibition of
the MAP kinase pathway by targeted drugs might restore
their iodine uptake and inhibit cancer progression. These
hypotheses are now being tested in clinical studies using
positron-emission tomography (PET) imaging.
Follicular Thyroid Cancer
PAX8-PPAR␥ rearrangements are found in up to 50% of
FTC,29 but the exact functional consequences of this abnormality are still under investigation. Mutations of the RAS
oncogene are found in up to 50% of FTC30 and may be
involved in cancer development and progression.31 Recent
studies have also reported mutations in the phosphoinositide
(PI)3-kinase/Akt pathway in ⬃50% of patients with FTC.32
Poorly Differentiated and Anaplastic Carcinomas
RAS mutations are a common phenomenon in poorly differentiated thyroid carcinoma (PDTC) (20%-50%) and are associated with poor prognosis.33,34 BRAF mutations are more
commonly found in anaplastic thyroid carcinoma (ATC) than
in PDTC. In contrast to well-differentiated cancers, activation
of the PTEN/PI3-kinase/Akt/mammalian target of rapamycin
(mTOR) pathway is commonly observed in PDTC and
ATC,35-37 either as the result of mutations of the AKT or
PIK3CA genes. This pathway is involved in regulation of cell
survival, cell-cycle progression, proliferation, and cellular
metabolism and can be imaged with FDG-PET.38,39
Medullary thyroid cancer (MTC) can occur sporadically
(75%) or as part of an autosomal-dominant genetic disorder
(25%). The inherited diseases include familial MTC, multiple
endocrine neoplasia (MEN) 2 A, and MEN 2 B; they are
characterized by gain-of-function germline mutations of the
RET proto-oncogene,40 which is used for screening purposes.
Among the sporadic cases, 40%-50% show somatic RET mutations.41,42 The presence of somatic RET mutations correlates with greater risk for nodal metastases and shorter survival.42
Presentation and Management
PTC usually presents in the third to the fifth decades of life.
Lymph node metastases in the neck are common, and up to
10% can present with distant metastasis, most commonly in
lung and bone. Classical PTC has an excellent prognosis,
with an estimated 10-year survival of 80%-95%.43 However,
the prognosis is worse in older patients (greater than 45
years), with larger tumors (⬎4 cm) and distant metastasis, in
patients with tall cell variant and patients with BRAF mutations.
Follicular cancer occurs more commonly in the fourth to
sixth decades of life. In contrast to PTC, neck lymph node
metastases are less common, and distant (hematogenous)
123
metastases are more common (mostly in lungs or bones).
Because follicular cancer tends to have a greater rate of distant
metastasis and patients are generally older, the mortality is
higher than in PTC, although the 10-year survival is still in
the range of 70%-95%.43,44
Hürthle cell carcinoma was initially considered a variant of
FTC; however, it shows a different oncogenic expression profile than FTC and is therefore now recognized as distinct
clinicopathologic entity. It is an uncommon and occasionally
aggressive differentiated thyroid malignancy,45 particularly
when the primary tumor is widely invasive.4,46 Approximately 3.6% of thyroid cancers are of the Hürthle cell subtype.47 This tumor tends to be refractory to treatment with
131I, has a greater tendency to develop nodal metastases, and
is frequently FDG-avid (see “FDG-PET in Hürthle Cell Cancer” section). When clearly defined histopathologically as an
invasive tumor, Hürthle cell thyroid cancer has a higher incidence of distant metastasis (33%) than other differentiated
thyroid cancers (range, 10%-22% in papillary or follicular
thyroid cancers).48 It has a worse prognosis with a 10 year
disease free survival of 40% and mortality of 51%, compared
with a disease-free survival of 75% and mortality of 20% for
follicular carcinoma.49
Poorly differentiated thyroid carcinoma forms a distinct
subgroup of thyroid cancers with distinct clinicopathologic
features. Most likely, this tumor does not arise de novo, but
instead represents a distinct stage in the progression from
well differentiated to anaplastic carcinoma. Recent molecular
pathology studies now support this long-held clinical believe.50
Anaplastic thyroid carcinoma has a particularly poor prognosis. Most patients present with a readily enlarging neck
mass, although ATC is sometimes found incidentally during
careful histopathologic assessment of specimens from patients who underwent thyroidectomy for other indications.51
In the 1997 SEER database,52 ATC represented only 1.6% of
all thyroid cancers, but it was responsible for more than 50%
of all deaths from thyroid cancer. A review of studies from the
last 2 decades shows a median overall survival in the range of
4-6 months.53
MTC is a neuroendocrine cancer that secretes calcitonin
(primary serum tumor marker) and carcinoembryonic antigen (CEA). MTC accounts for approximately 4% of all thyroid cancers in the USA.54 About 25% of cases occur as part of
an autosomal dominant genetic disorder, and the other 75%
as sporadic cases.55 Inherited syndromes associated with
MTC include familial MTC, MEN 2 A and MEN 2 B. The
hereditary form is therefore typically discovered early, thanks
to screening of calcitonin levels and RET proto-oncogene. In
contrast, early detection of the approximately 75% of cases
that occur sporadically remains difficult. Lung, liver or bone
metastases are therefore found in up to 50% of patients at the
time of clinical presentation. The 10-year survival rates decrease significantly with advanced stage.56
For patients with differentiated thyroid cancers, the current guidelines of the ATA8 recommend total or near total
thyroidectomy for all primary thyroid cancers ⬎1.0-1.5 cm,
in the presence of contralateral thyroid nodules, with a his-
124
tory of prior radiotherapy to the neck and with first degree
family members with thyroid cancer; in addition, this operation also appears most appropriate for patients older than 45
years because of greater risk for recurrence. On the contrary,
thyroid lobectomy may be appropriate in selected individuals with small (⬍1.0 cm) tumors that are well encapsulated
and confined within that lobe. Central compartment neck
dissection (level VI) is suggested when nodes appear clinically involved, lateral neck dissection only when nodes are
clearly involved clinically or on preoperative ultrasound.
Surgery is also the mainstay of treatment of Hürthle cell carcinoma, MTC and poorly differentiated thyroid cancers, although control rate in the latter is limited due to the aggressive nature of the disease and presence of distant metastasis at
the time of diagnosis. In cases of distant metastasis, surgery is
still favored if technically feasible because it may prevent
tumor fungating and death from intratracheal hemorrhage
and asphyxiation. Most poorly differentiated cancers do not
concentrate iodine to a therapeutically meaningful degree;
therefore, additional external beam radiotherapy is oftentimes indicated.
Treatment options in ATC need to be tailored for each
patient. Total thyroidectomy should be performed if all disease can be resected and resection of vital structures avoided.
Airway management is of primary importance.131 Iodine
therapy has no role in ATC because it does not concentrate
iodine. Multimodality treatment with surgical resection or
maximal debulking, chemotherapy and radiotherapy has
only slightly improved the overall outcome for patients with
ATC.57-61 Novel therapies that overcome multidrug resistance secondary to expression of multidrug-resistance protein, overexpression of MUC1 oncoprotein, or presence of
cancer stem-like cells62-64 are therefore under development.
They include histone deacetylase inhibitors and proteasome
inhibitors,65 tyrosine kinase inhibitors, such as sorafenib or
sunitinib, angiogenesis inhibitor bevacizumab, and possibly
oncolytic virus therapy.66 Because ATC is exquisitely FDGavid, it would be important to integrate FDG-PET/CT in drug
trials for response assessment.
Patients with MTC and macroscopic residual disease after
surgery may benefit from additional radiotherapy. Treatment
options for recurrent and metastatic MTC are primarily
aimed at palliation and prevention of complications (eg, lytic
bone metastases); they include medical therapy with somatostatin inhibitors (cold or radiolabeled), interventional radiology procedures, and in selected cases also surgery or external beam radiotherapy. Drug trials with tyrosine kinase
inhibitors (eg, vandetanib, sorafenib) and proteasome inhibitors are ongoing.
PET Imaging in Thyroid Cancer
Molecular Basis, Patient
Preparation, and Indications for FDG Imaging
GLUTs are abundantly expressed on thyroid cells, and
GLUT-1 in particular on thyroid carcinoma cells.67 GLUT-1
overexpression is particularly prevalent in aggressive thyroid
T. Abraham and H. Schöder
cancers.68,69 In addition, a clinical study has shown that overexpression of hexokinase-1 promotes FDG uptake in thyroid
cancer cells.70 Another line of evidence implicates the hypoxia-inducible factor 1␣ (HIF-1␣) as signaling molecule in
glucose metabolism of thyroid cancer cells.71 HIF-1␣ is expressed in thyroid carcinomas with increasing frequency and
intensity (papillary ⬍ follicular ⬍ anaplastic carcinoma) and
regulated not only by hypoxia but in particular also by the
PI3-kinase pathway71 and/or BRAF-mediated signaling pathways.72 HIF-1␣ was previously shown to activate the transcription of genes encoding GLUTs and glycolytic enzymes.73,74
In clinical practice it is well known that the WBS with 131I
is more sensitive for localizing recurrent or metastatic disease
when TSH levels are elevated, either as the result of withdrawal of thyroid hormone-replacement therapy or the
administration of exogenous recombinant human TSH
(rhTSH). Experimental evidence suggests that glucose (resp.
FDG) uptake in thyroid cells should also be increased after
TSH stimulation. The expression of GLUTs and glucose uptake in (cultured) thyroid cells is increased with TSH stimulation.75,76 In vitro, TSH significantly increases FDG uptake
in a time- and concentration-dependent manner in cultured
thyroid cells. A TSH concentration of 50 ␮U/m L doubled the
FDG uptake compared with TSH-free conditions, and uptake
after 72 hours of TSH preincubation was approximately
300% of that without TSH preincubation.77 Prante et al78
demonstrated increased GLUT-1 concentrations in thyroid
cell membranes after TSH stimulation, which occurs because
of GLUT translocation from the cytoplasm to the plasma
membrane,79,80 likely through activation of the PI3-kinase
pathway.
Clinical evidence is emerging that the performance of
FDG-PET is also improved after TSH stimulation in patients
with differentiated thyroid cancer. Whereas earlier studies
suggested that the state of TSH stimulation did not affect
findings on FDG-PET81 and one multicenter study even
showed lower sensitivity of FDG-PET when imaging was performed during TSH stimulation (67% compared with 91%
during thyroid hormone therapy),82 more recent studies
seem to suggest that the sensitivity of FDG-PET, or at least the
conspicuity of FDG-positive lesions, improves with TSH
stimulation. For instance, Moog et al studied 10 patients
prospectively with FDG-PET both under TSH suppression as
well as in the hypothyroid, TSH stimulated state.83 They
found an average increase of 63% in the tumor to background ratio after TSH stimulation for 15 of 17 lesions with
FDG uptake (secondary to decreased background activity
and increased tumor uptake). In one patient a lesion was seen
in the thyroid bed only under TSH stimulation. Petrich et al84
studied 30 patients with negative WBS and elevated or equivocal thyroglobulin levels. They found more “tumor-like lesions” (78 vs 22) in more patients (19 vs 9) when patients had
received rhTSH. Tumor to background ratios (5.51 vs 2.54)
and standardized uptake values (SUV; 2.77 vs 2.05) were
also greater with TSH stimulation. Chin et al85 randomized 7
patients with well-differentiated thyroid carcinoma, negative
131I WBS, and elevated thyroglobulin levels to undergo FDG-
Thyroid cancer: indications and opportunities for PET/CT imaging
PET both during TSH suppression and under rhTSH stimulation within 1 week. Some metastatic sites were only noted
on the rhTSH-stimulated scans, and the mean (2.54 ⫾ 0.72
vs 1.79 ⫾ 0.88) and maximum (2.49 ⫾ 0.95 vs 1.74 ⫾ 0.81)
lesion to background ratios were significantly greater with
rhTSH stimulation. In a multicenter study, including 63 patients (52 with papillary and 11 with follicular cancer), FDGPET/CT was performed at baseline (without stimulation) and
24-48 hours after rhTSH administration.86 A total of 108
lesions were detected in 48 organs in 30 patients. rhTSHstimulated PET showed more lesions than the nonstimulated
scan (102 vs 78 lesions, P ⬍ 0.01) and tended to be more
sensitive for the detection of involved organs (45 vs 38 of 48
organs assigned as involved by disease, P ⫽ 0.054). Surprisingly, in some instances, lesions were only detected on the
nonstimulated scan. Similarly, although SUV numbers for
lesions detected on both stimulated and nonstimulated scans
tended to be greater with rhTSH, they were significantly
lower in some cases. This finding appears counterintuitive
and has no clear biological rationale; instead, the better detection of some lesions and greater SUV in nonstimulated
scans may perhaps be related to the widely varying FDG
uptake times, which ranged from 41 to 152 minutes.
In comparison with nonstimulated scans, rhTSH-stimulated PET/CT changed the management of 6% of patients. A
recent meta-analysis of 7 prospective studies, including 168
patients also suggested that TSH stimulation (either by hormone withdrawal or rhTSH administration) slightly but significantly increased the diagnostic performance of FDG-PET
by showing more true positive lesions.87 Again, this metaanalysis did not find any differences in FDG SUV between
TSH-stimulated and nonstimulated scans, perhaps because
of the small sample size and study design. Our personal recommendation is to perform FDG-PET/CT after rhTSH stimulation (0.9 mg intramuscularly on 2 consecutive days, with
PET imaging late on day 2 or in the morning of day 3). For
practical purposes, the PET scan can be done just before
administration of 131I for diagnostic assessment or therapy.
The indications for FDG-PET/CT depend on the clinical
setting and thyroid cancer histology. In patients with differentiated carcinoma, an indication generally exists in patients
with elevated thyroglobulin levels but negative 131I WBS. The
initial workup for these patients includes neck ultrasound
and chest CT (the latter can be done as part of FDG-PET/CT).
If no disease sites are identified or thyroglobulin levels are
elevated out of proportion to minor disease found on conventional imaging, FDG-PET should be performed. The current ATA guidelines suggest that this only be done when
thyroglobulin levels are ⬎10 ng/mL,8 but in reality, no clearcut-off can be established. Although the proportion of truepositive FDG-PET scans and findings increase with increasing thyroglobulin levels,88,89 true-positive findings have been
reported in 10%-20% of patients even when thyroglobulin
levels are ⬍10 ng/mL.88-90 Combined PET/CT is more accurate than PET alone.91 Depending on the clinical setting,
PET/CT findings may change patient management in up to
40% of cases.89,91 In daily practice, the decision regarding
when to perform FDG-PET/CT should therefore be individ-
125
ualized for each patient, considering not only thyroglobulin
levels and 131I WBS findings, but also individual risk on the
basis of clinical and histopathologic features.9
PET Thyroid Incidentalomas
PET/CT is now widely used for the staging and restaging of
various malignancies. With increasing clinical use of FDGPET/CT, incidental FDG uptake in the thyroid gland has
been reported with increasing frequency. Diffuse FDG uptake usually indicates chronic lymphocytic (Hashimoto’s)
thyroiditis, rarely acute thyroiditis or Grave’s disease. Of
note, the intensity of uptake (SUV) does not correlate with
disease activity (as reflected by TSH levels) or the titer of
thyroid peroxidase antibodies.92 In contrast, focal thyroid
uptake has been associated with malignancy, usually primary
thyroid carcinoma, in a significant fraction of patients. Data
are summarized in Table 1; some studies will be reviewed
briefly. We encourage readers to carefully examine the Methods and Results sections of publications on this subject. In
most studies, follow-up and verification of thyroidal FDG
uptake was only available for a fraction of these patients. It is
therefore likely that the true risk for malignancy in solitary
FDG-positive thyroid nodules is overstated in most publications.93-103
In a retrospective review of more than 4000 patients, Cohen et al93 found incidental diffuse thyroid FDG uptake in 31
patients (0.69%) and focal uptake in 71 patients (1.57%).
Fourteen of the 71 patients with focal uptake had thyroid
biopsy: 7 had thyroid cancer, and the other 7 had benign
pathology (nodular or lymphoid hyperplasia and atypical cell
of indeterminate origin). The one patient with diffuse uptake
and biopsy had Hashimoto’s thyroiditis. In a similar study of
1330 subjects (999 cancer patients, 331 healthy subjects undergoing cancer screening), Kang et al95 noted diffuse thyroid
FDG uptake in 8 (0.6%) and focal uptake in 21 individuals
(1.58%). Four of the 15 focal incidentalomas (27%) whose
histologic diagnoses were available showed papillary carcinoma. Hence, the risk of cancer was lower than in previous
studies, but still large enough to warrant further evaluation of
such finding. Of note, the prevalence of thyroid incidentaloma was similar for cancer patients and healthy individuals.
All 8 patients with diffuse FDG uptake in the thyroid glands
had clinical signs and symptoms of thyroiditis. Are et al96
reviewed PET reports of 8800 patients with a variety of primary extrathyroidal malignancies who had undergone
16,300 FDG-PET/CT scans. Two hundred sixty-three patients had incidental FDG uptake in the thyroid gland. Fiftyseven patients underwent fine-needle aspiration, and a thyroid malignancy was found in 24 of them (42%). Another 27
patients underwent total thyroidectomy or lobectomy, and
20 of them (74%) had a diagnosis of malignancy (19 papillary
carcinoma, 1 primary thyroid lymphoma). Focal unilateral
FDG uptake (as opposed to multifocal or diffuse uptake)
correlated with increased risk of malignancy. However, there
was one case in which diffuse thyroid FDG uptake (usually
associated with Hashimoto’s thyroiditis), represented diffuse
tumor infiltration from small cell lung cancer.
T. Abraham and H. Schöder
Some authors reported that SUV numbers were significantly lower in benign than malignant FDG-positive nodules;
this was not confirmed in other publications (Table 1). In any
event, there is considerable overlap in SUV numbers between
benign and malignant entities, and we caution against using
SUV numbers as the sole parameter on which to base management of thyroid nodules.
In summary, diffusely increased thyroid FDG uptake is
usually attributable to chronic thyroiditis (Fig. 1), whereas
focal FDG uptake in the thyroid gland has a significant risk of
being malignant (25%-50%; Fig. 2); histologic diagnosis
should therefore be obtained for focal lesions if the nature of
the thyroid disease has the potential to change patient management.
48
FDG-PET in Differentiated Thyroid Cancers
FNA, fine-needle aspiration, NR, not reported; SUV, standardized uptake value.
96
3580
Zhai,102 2010
115 focal
NR
630 with cancer
Kwak et al,99 2008
Eloy et al,101 2009
30 focal
689 (head and neck cancer only)
7347 with cancer
Nam,97 2007
Bogsrud,100 2007
79 focal
19
NR
NR
18
NR
5
8.4 ⴞ 13.2
6.4 ⴞ 3.6
Range: 3.5-16.
7.6 ⴞ 8.09
3.4 ⴞ 2.6
Range: 1.1-7.4
6.7 ⴞ 3.1
Range 2.7-19.0
4.2 ⴞ 4.0
7.9 ⴞ 9.7
Range: 2.5-53
5.98 ⴞ 5.11
2.9 ⴞ 1.6
Range: 1.1-6.8
3.8 ⴞ 1.7
Range: 2.5-8.6
5
15
44/84 verified
84
FNA: 57 (42 focal, 15 diffuse)
Op: 27 (23 focal, 4 diffuse)
12
48
8800 with cancer
Are et al,96 2007
267 (101 focal, 162
diffuse)
1763 with cancer
Yi,98 2005
Choi et al,103
70 focal
44 (49 nodules)
17 (18 nodules)
5.4 ⴞ 0.8
Range: 4.6-6.2
10.7 ⴞ 7.8
Range: 2.2-32.9
9.2 ⴞ 6.9
Range: 4.1-21.3
6.92 ⴞ 1.54
16.5 ⴞ 4.7
13.7 ⴞ 13.2
Range: 3.0-32.9
6.7 ⴞ 5.5
Range: 2.3-33.1
8.2 ⴞ 7.0
Range: 2.9-27.0
4
4
6 focal
SUV Malignant
3.37 ⴞ 0.21
6.5 ⴞ 3.8
7
4
15
15 of 21 focal (8 Op, 7 core bx)
4525 with cancer
1330 (1014 with cancer
diagnosis, 331 for screening)
140 (Lung cancer staging only)
Cohen,93 2001
Kang et al,95 2003
102 (71 focal, 31 diffuse)
29 (21 focal, 8 diffuse)
Total Patients
Author, Year
Table 1 FDG-PET-Detected Thyroid Incidentalomas
FDG Uptake
No of Patients Verified
No. of Patients with
Thyroid Malignancy
SUV Benign
126
PET/CT is not recommended for preoperative assessment;
however, it can be useful in cases of larger tumors and aggressive histology or when distant metastases are suspected.
A study of 26 patients with newly diagnosed differentiated
thyroid cancer showed no added benefit of PET/CT in evaluation of cervical nodes compared with neck ultrasound.104
Some have proposed a role for FDG-PET in addressing
histologically inconclusive thyroid nodules.105 These authors
report a 100% negative predictive value for FDG-PET in this
setting, and suggest that this may help in avoiding unnecessary hemithyroidectomies. The positive predictive value was
35% (7 cancers detected, and 13 benign nodules with FDG
uptake). We do not believe that the 100% negative predictive
value will be reproducible in the long term and caution
against this approach.
The main application for FDG-PET/CT exists after thyroidectomy in patients with elevated thyroglobulin level (indicating the presence of persistent, recurrent or metastatic disease) but negative 131I WBS. The general understanding is
that differentiated carcinoma cells expressing the NIS will
take up radioiodine; as cells de-differentiate and disease becomes more aggressive, the capacity for iodine concentration
is lost and cellular glucose metabolism is activated. This pattern of differential radiotracer uptake was coined “flip-flop
phenomenon” by Feine in 1995.106 However, in contrast
with what the original name suggested, differential tracer
uptake (either, or) is not absolute107,108: Patients can have a
positive 131I scan with negative FDG-PET (Fig. 3), the opposite pattern (Fig. 4), a mixed pattern where some metastatic
lesions show 131I uptake and other lesions show FDG uptake,
and some lesions may show uptake of both iodine and FDG,
albeit to a different degree.
The utility of FDG PET scan in patients with elevated serum thyroglobulin and negative WBS was shown in several
studies; the reported sensitivity for disease detection is in the
range of 70%-95%.81,88,109-116 For instance, Wang et al81 reported that FDG PET detected metastatic disease in 12/17
patients (71%) with elevated thyroglobulin and negative 131I
WBS. In this series, PET was also true positive in 2 of 16
patients with low thyroglobulin levels but high clinical suspicion. Schlüter et al88 reviewed 118 PET scans in 64 patients
Thyroid cancer: indications and opportunities for PET/CT imaging
127
Figure 1 Diffuse FDG uptake in the thyroid gland, consistent with chronic lymphocytic thyroiditis (Hashimoto).
with elevated thyroglobulin (n ⫽ 48) or clinical suspicion of
metastases (n ⫽ 16) and negative 131I WBS. The positive
predictive value of FDG-PET was 83% (34/41), and the negative predictive value was 25% (5/20). A recent meta-analysis
of 17 studies in 571 patients showed a pooled sensitivity of
88% in this setting.117 Imaging with integrated PET/CT yields
greater detection rates.113 The CT component of the PET/CT
will aid in localization of focal FDG uptake, and will also be
useful in detecting small lesions with low or absent FDG
uptake, such as small lung nodules. PET/CT and “diagnostic”
Figure 2 Thyroid incidentaloma. Incidental FDG uptake in the thyroid gland in a patient undergoing PET/CT for rectal
cancer. The lesion was proven to be a Hürthle cell carcinoma.
T. Abraham and H. Schöder
128
Figure 3 A patient with well-differentiated FTC with extensive capsular invasion and a microscopic focus of papillary
carcinoma. The patient underwent rhTSH stimulation with a thyroglobulin of 72,000 ng/mL and a TSH of 67. The
TSH-stimulated FDG scan showed no disease (A); however, the 131I pretherapy (B) and posttherapy (C) scans show
extensive disease, including brain, lungs, medias tium, and osseous structures in a patient with history of differentiated
FTC.
chest CT (standard tube settings for mA and kV) can be
combined in 1 imaging session. Readers are encouraged to
pay careful attention to detail when interpreting many of the
published studies. For instance, some studies may report
only baseline thyroglobulin levels, whereas other studies report both baseline and stimulated thyroglobulin levels; some
studies report findings per patient, other studies per lesion.
In addition, some studies may report “inflated sensitivities”
by counting the lack of disease detection on FDG-PET, WBS
and conventional imaging modalities as “true negative.” It is
clear, however, that small volume disease must be present to
cause persistently elevated thyroglobulin levels after thyroidectomy. “True-negative” imaging studies are therefore not
really true negative; instead, the lack of detectable disease
only reflects the limits of our current technologies.
Some studies investigated the utility of FDG-PET/CT for
the detection of bone metastases in patients with thyroid
carcinoma.118 The results suggest a slightly greater sensitivity
and significantly better specificity of PET over 99mTc methylene diphosphate bone scan. It should be emphasized that the
CT images of the integrated PET/CT must be reviewed carefully, so that FDG-negative lesions are not missed. In general,
the role for bone scintigraphy in differentiated thyroid cancer
is limited. When a symptom-based approach in conjunction
with 131I WBS and/or FDG-PET/CT is used, it is extremely
unlikely that osseus lesions will be missed.
Depending on the specific clinical setting, FDG-PET findings in patients with elevated Tg levels but negative WBS may
affect patient management in 20%-40% of cases.86,88,91,111,114
These management changes may include the initiation or
Thyroid cancer: indications and opportunities for PET/CT imaging
129
Figure 4 A patient with a 2-cm PTC with extensive capsular invasion with extrathyroid extension into adjacent skeletal
muscle. There was no vascular invasion. Three of six lymph nodes in right level VI were positive for cancer. The patient
underwent rhTSH stimulation with high thyroglobulin antibody of 6290 U/mL and a TSH of 241. Intense uptake is
associated with a right upper paratracheal mass and bilateral lung nodules seen on the coronal PET and axial PET/CT
images (A), whereas the Iodine pre- and posttherapy scans (B) show no abnormal uptake in these regions.
avoidance of surgical procedures, further work-up with imaging studies or biopsies, initiation and guidance of external
beam radiotherapy, and diversion from treatment with curative intent to palliative management in the setting of advanced disease.
Beyond its diagnostic utility, FDG PET also provides prognostic information in patients with differentiated thyroid
cancer.119,120 Wang et al119 initially reported on the prognostic value of FDG-PET in a group of 125 patients with elevated
thyroglobulin and negative 131I WBS who were followed for
up to 41 months. The study population included 93 patients
with papillary, 18 with follicular, 12 with Hürthle cell, and 2
with anaplastic carcinoma. In univariate analysis, age presence of distant metastases, FDG-positivity and FDG disease volume and SUV were significant. In subsequent multivariate analysis, the volume of FDG-avid disease was the
single strongest predictor of survival. Subsequently, the
same group120 reported on 400 patients with differentiated
thyroid cancer who underwent FDG-PET for a variety of
reasons, including elevated thyroglobulin levels and negative WBS, and surveillance of patients with high risk
features. The median follow up was 7.9 years. In univariate analysis, age, initial stage, histology, thyroglobulin
level, 131I uptake, and PET findings all correlated with
survival. The outcome was worse for patients with positive
FDG scan, regardless of findings on 131I WBS (Fig. 5).
Greater SUV and greater number of FDG-positive lesions
conferred a worse prognosis. In multivariate analysis, only
age and FDG-PET findings (FDG-positivity, number of
FDG-positive lesions and SUV) continued to be strong
predictors of survival. When SUV numbers were divided
into quintiles, the best outcome was noted for patients
T. Abraham and H. Schöder
130
fied as negative 3 patients with false-positive CT findings. Of
note, SUVmax provided prognostic information: in a stepwise fashion, each increase in intensity by SUVmax unit was
associated with a 6% increase in mortality. The 5-year overall
survival in patients with SUVmax ⬍10 was 92%, but declined to 64% in those with SUVmax ⬎10. In summary,
FDG-PET is recommended as part of the initial, post thyroidectomy work-up in all pati8ents with invasive or suspected
metastatic Hürthle cell carcinoma.
FDG-PET in Poorly Differentiated
and Anaplastic Thyroid Carcinoma
Figure 5 Kaplan–Meier survival plots of thyroid cancer patients
based on combination radioactive iodine and FDG-PET scanning
(⫺). scan negative; ⫹, scan positive. Reproduced from Robbins et
al,120 original copyright 2006, The Endocrine Society, permission
granted by The Endocrine Society in 2010.
with negative PET scan, the worst for patients with lesions
showing an SUV ⬎13.
In addition to its aforementioned “traditional” role in patients with elevated thyroglobulin levels but negative 131I
scan, FDG-PET should also be employed in the initial postthyroidectomy assessment of high risk patients, including
those with PTC and invasive or metastatic Hürthle cell carcinoma unlikely to concentrate 131iodine to a meaningful degree, to determine their extent of disease and to derive prognostic information. Moreover, FDG-PET should be part of
the response assessment in patients with metastatic disease
undergoing external beam radiotherapy, radiofrequency ablation or targeted therapies.
FDG-PET in Hürthle Cell Cancer
As stated before, Hürthle cell carcinoma carries a greater risk
of distant metastases than PTC and FTC and in general has a
worse prognosis. Detection rates on 131I WBS and response
rates to 131I therapy are lower than for other differentiated
carcinomas. Among the variety of functional imaging studies
proposed for Hürthle cell carcinoma, FDG-PET appears to be
the most useful.
In a pilot study of 12 patients, FDG-PET detected local or
distant disease in 11 patients; in 7 of these cases PET was the
only imaging modality localizing disease.121 In a larger study,
Pryma et al122 examined 44 patients with Hürthle cell cancer
who underwent PET/CT after thyroidectomy because of elevated thyroglobulin levels or for risk stratification. There
were 24 positive and 20 negative 18F-FDG PET scans (23
were true positive, 20 were considered true negative in light
of stable thyroglobulin ⬍ 10 ng/mL and negative conventional imaging, or because of declining thyroglobulin without intervention during follow-up), yielding a sensitivity of
95% and specificity of 95%. In 5 of 11 patients who had both
positive CT and FDG-PET findings, the PET revealed additional sites of disease. In addition, FDG-PET correctly classi-
Poorly differentiated and anaplastic carcinoma show aggressive clinical behavior. Anaplastic carcinoma can arise de novo
or from stepwise de-differentiation of initially well differentiated tumors. Occasionally, it is found incidentally in thyroidectomy specimens, but the classical presentation is the
patient with rapidly increasing neck mass, and frequently
also distant disease. In patients with PTC, FDG-PET may be
indicated after thyroidectomy to determine the extent of metastatic disease and for prognostic purpose; in the subset of
patients with advanced disease, it may also be helpful for
response assessment. Anaplastic carcinoma usually shows intense FDG uptake, and in selected cases FDG-PET may be
helpful in directing treatment and evaluating the efficacy of
therapy. Data from the Mayo Clinic confirm this clinical impression. In a study of 16 patients with anaplastic thyroid
cancer,123 all primary tumors showed intense FDG uptake, as
well as all 9 patients with lymph node metastases and the
majority (7/10) of patients with distant metastases. PET findings had a direct impact on patient management in 50% of
cases. Similar findings were reported by Poisson et al from
the Institute Gustave Roussy.124 Metastatic disease was
shown by FDG PET/CT or diagnostic CT in 63 organs in 18 of
20 evaluable patients. In 35% of involved organs, disease was
only shown by FDG scan. PET/CT findings changed patient
management in 25% of cases. Of note, although the prognosis is generally poor in ATC, even in this group of patients a
high volume of FDG-positive disease (⬎300 mL) and an
SUVmax ⬎18 identified patients with shorter survival.
PET in MTC
The primary treatment modality for MTC is surgical resection. PET imaging is not generally indicated for preoperative
disease staging. However, a PET study may be requested in
patients with high serum calcitonin and/or high CEA levels
after surgery. First serum marker measurements should be
obtained approximately 2-3 months after thyroidectomy.
When postoperative calcitonin is undetectable, the risk for
persistent disease is low and further work-up not indicated.40
In patients with elevated postoperative calcitonin, it is believed that values ⬍150 pg/mL are mostly associated with
locoregional disease, and therefore the first imaging study
should be neck ultrasound. In contrast, patients with calcitonin levels ⬎150 pg/mL are more likely to have distant
disease.
Thyroid cancer: indications and opportunities for PET/CT imaging
FDG-PET and PET/CT have been used in several studies in
patients with MTC; studies with at least 20 patients125-135 will
be considered for this review (Table 2). De Groot, et al129
compared FDG-PET,111 in octreotide somatostatin receptor
scintigraphy and 99mTc (V) dimercaptosuccinic acid (DMSA)
in 26 patients with elevated calcitonin after total thyroidectomy. FDG-PET detected more true-positive lesions than the
other modalities and was positive in 13 of the 26 patients.
PET findings lead to surgical intervention in 9 patients; histopathology of the specimens showed MTC in 8 cases (all
with postsurgical decline in calcitonin) and normal thymus
in 1 case.
Ong et al130 studied 28 patients with MTC after thyroidectomy. PET detected sites of metastatic disease in 23 patients.
Calcitonin levels were greater in PET-positive patients than
PET-negative patients, but with considerable overlap. There
was no positive PET scan in patients with calcitonin ⬍500
pg/mL. In several patients all imaging studies were negative
and remained so during short-term follow up, reflecting
small volume disease that cannot be localized with current
techniques.
Giraudet et al131 compared various imaging modalities in
55 patients with elevated calcitonin levels after thyroidectomy and at least 3 months after other recent therapies. In 18
patients, all previous imaging studies were negative, whereas
37 patients were known to have metastatic disease. Tumor
marker levels tended to be greater in PET-positive cases, but
again with considerable overlap. Neck ultrasound proved
most sensitive for detection of neck lymph node metastases,
and lung metastases were best detected by chest CT. For the
detection of liver metastases, magnetic resonance imaging
(MRI) proved most sensitive and FDG-PET least sensitive.
The combination of bone scan and whole-body MRI proved
most sensitive for the detection of bone lesions. Therefore,
these authors concluded that there is only a limited role for
FDG-PET in the assessment of this patient population. Overall, the median calcitonin in patients with disease noted on
any imaging study was 1534 pg/mL (range: 21-247,000). In
the 10 patients with completely negative imaging studies the
median calcitonin level was 196 pg/mL (range: 39-816). Finally, although SUV numbers tend to be higher in patients
with progressing disease, there was considerable overlap
with the group with stable disease, limiting the prognostic
value of SUV in this setting. However, a multicenter study in
33 patients with progressive MTC (median calcitonin doubling time 1.5 years) arrived at the opposite conclusion.132 All
patients underwent CT of the neck, chest, abdomen, and
pelvis; MRI of spine and pelvis; and whole-body FDG-PET/
CT. FDG PET/CT was more sensitive than CT for detection of
nodal metastases in the neck and mediastinum. Overall,
PET/CT showed a reasonable sensitivity of 76%, compared
with 74% for whole body CT and 85% for bone MRI. Of note,
in this study the SUVmax was inversely related to calcitonin
doubling time, a measure of tumor proliferation and aggressiveness.
In summary, FDG-PET/CT may have a role in the assessment of patients with suspected recurrent or metastatic MTC,
in particular with increasing calcitonin levels and short dou-
131
bling time (what exactly constitutes a short doubling time,
however, is not well defined). The reported studies are difficult to reconcile; some reported lack of any true positive scan
when the calcitonin is ⬍500 pg/mL, whereas other studies
reported true positive findings with calcitonin levels as low as
33 pg/mL. In our experience, FDG-PET is not a meaningful
test in patients with low to moderate calcitonin levels. Indeed, at least 2 studies reported that the sensitivity of FDGPET increases markedly with calcitonin levels ⬎1000 pg/mL.
Nevertheless, even with very high calcitonin levels, FDG-PET
(and, in fact, all imaging studies) can occasionally be negative. Our experience and that from other groups suggests that
this is not an uncommon finding in the setting of small subcapsular metastases in the liver, which are only identified
upon laparoscopy.
Because FDG appears to have significant limitations in
the assessment of MTC, there is now a growing interest in
using other PET radiotracers, in particular FDOPA, which
may have better sensitivity (Fig. 6). FDOPA is a labeled
amino acid and has been used for the imaging of Parkinson’s disease as well as for tumor imaging. In a small group
of 11 patients, Hoegerle et al136 first reported that FDOPAPET showed more true positive findings than did FDG-PET.
Subsequently, other publications have confirmed these
data.133,135,137-139 Koopmans et al135 prospectively studied 21
patients with MTC (12 sporadic, 9 MEN) and elevated calcitonin levels after thyroidectomy. All patients underwent
FDOPA PET; most patients were also imaged with FDG PET,
diagnostic CT or MRI and DMSA (V) scintigraphy. All imaging studies were negative in 6 of the 21 patients (29%); their
calcitonin levels ranged from 24 to 418 pg/mL (doubling
time (-43) to 53 months). Overall, FDG and FDOPA PET/CT
showed a sensitivity of 24% and 62% in a patient-based
analysis, and CT/MRI had a sensitivity of 34%. In a lesion
based-analysis, when a composite of all clear imaging findings, histopathology, and imaging follow-up as standard of
reference was used, the same modalities showed sensitivities
of 30%, 71%, and 64%. In patients who were imaged with all
4 modalities, FDOPA PET results were still slightly better
than the combination of FDG-PET, CT/MRI, and DMSA (V)
scintigraphy. In the few patients with a shorter calcitonin
doubling time (indicating rapid disease progression and thus
likely more aggressive disease), FDG performed slightly better than FDOPA. Beheshti et al133 compared FDG-PET/CT
and FDOPA PET/CT in 26 patients with MTC either preoperatively (n ⫽ 7) or postoperatively (n ⫽ 19). One CT of the
2 PET/CT scans was performed with diagnostic tube settings,
and CT findings were evaluated independently. In 4 of the 19
postsurgical patients, all imaging studies were negative (calcitonin, 440-1318 pg mL⫺1, doubling time ⬎ 2 years).
Among the remaining 15 patients, all showed at least one
lesion on FDOPA PET, compared with 10 patients on FDGPET. FDOPA PET/CT showed 39 lesions (FDG: 26); however, 2 lymph node metastases were only seen on FDG imaging. In lesions that were concordantly positive with both
radiotracers, SUV was greater with FDOPA than with FDG.
FDOPA PET/CT provided important additional information
in 37% of postsurgical cases; in 4 cases limited metastatic
132
Table 2 FDG-PET for Medullar Thyroid Carcinoma
Author, Year
Number of
Patients
Number of FDG True
Positives
Calcitonin in FDG positive,
pg/mL
Calcitonin in FDG negative,
pg/mL
Range: 50-45,000
Range: 280-6400
Brandt-Mainz et al,125
2000
Diehl et al,126 2001
20
13 patients
85
32/55 confirmed lesions
NR
NR
Szakall et al,127 2002
40
38 patients
NR
NR
Gotthardt et al,128 2004
28
104/183 sites
NR
NR
de Groot et al,129 2004
26
13 patients
Ong et al,130 2007
28
23 patients
Giraudet et al,131 2007
55
32 patients
Oudoux et al,132 2007
33
Koopmanns,135 2008
17
NR
Total lesion based
sensitivity 76% (83%
neck, 85% mediastinum,
75% lung, 60% liver,
67% bone)
4
26 total
19 postsurgical
15/26 total
10/19 postsurgical
Skoura et al,134 2010
32 patients (38
scans)
17/38 scans
Marzola et al,139 2010
18
11
485 ⴞ 703
Median: 113
Range: 65-2034
11,257 ⴞ 19,743
Median: 962
Range: 106-55,200
Median: 2311
Range: 51-247,000
NR
Median: 654
Range: 21-24,600
NR
3372 ⴞ 4802
Median: 1473
Range: 73-10,500
13,124 ⴞ 33,263
Median: 418
Range: 48-120,000
Postoperative only,
2016 ⴞ 3410
Median: 609
Range: 88-11,235
3646 ⴞ 6256
Median: 782
Range: 33-21,000
55,244 ⴞ 17,429 (patient data
not provided, cannot
calculate median or range)
Postoperative only,
2148 ⴞ 3504
Median: 530
Range: 181-10,611
422 ⴞ 413
Median: 205
Range: 37-1203
NR
Multicenter study, many details
unclear
PET detects more metastatic
nodes than CT, MR, and
MIBG
Analysis based on consensus ;
CT slightly better than PET,
SRS was worse
No true positive FDG scan
when calcitonin, <500 pg
mLⴚ1; sensitivity increased
to 78% when calcitonin,
>1000 pg mLⴚ1; PET/CT
better than PET-only
Limited role for FDG-PET; other
modalities better
Inverse relationship SUVmax vs
calcitonin doubling time
Total of 21 patients had
FDOPA PET; 17 also had
FDG-PET; FDOPA better
than FDG except for few
cases with short calcitonin
doubling time
FDOPA more often positive;
SUVmax higher for FDOPA
than FDG
Sensitivity 80% when
calcitonin, >1000 pg mLⴚ1
FDOPA shows more lesions
(84 vs 64); SUVmax greater
for FDG than FDOPA
CT, computed tomography; FDG, fluorodeoxyglucose; NR, not reported; PET, positron emission tomography; SRS, somatostatin receptor scintigraphy; SUV, standardized uptake value.
T. Abraham and H. Schöder
Beheshti,133 2009
18,068 ⴞ 25,143
Median: 6728
Range: 124-85,000
63,939 ⴞ 118,258
Median: 16,600
Range: 514-541,000
Comments
Thyroid cancer: indications and opportunities for PET/CT imaging
133
⬍60 pg/mL). As expected, the combined PET/CT was more
accurate than either modality alone. This again emphasized
the need to review CT images of the PET/CT carefully. When
a CT is part of the scheduled workup of MTC patients, it
should be done with full “diagnostic” tube settings during the
PET/CT.
For completeness, we want to mention that studies with
other radiotracers are underway in MTC, in particular PET
tracers for somatostatin receptor imaging, such as 68Ga
DOTATOC and DOTATATE, or perhaps soon PET tracers for
imaging of the cholecystokinin receptor expressed on MTC.
It remains to be seen whether these will be superior to
FDOPA, which is clearly the most promising agent for the
assessment of MTC at this time.
Figure 6 A 68-year-old man with MTC, status post thyroidectomy
with elevated calcitonin, 597.2 pg mL⫺1 and CEA (7.2 pg/mL) levels. FDOPA scan on 8/11/06 shows multiple hypermetabolic lesions
on the neck and upper mediastinum (arrow). FDG scan on 8/16/08
was negative. Images courtesy of Dr Mohsen Beheshti, PET/CT Center, Linz, Austria.
disease could be resected. The diagnostic CT had good sensitivity for bone and lung lesions, but was inferior to FDOPA
for assessment of lymph nodes in neck and mediastinum.
Finally, in a study of 26 patients Luster et al138 reported a
100% sensitivity for FDOPA PET/CT when calcitonin levels
were ⬎150 pg/mL (no disease was found when levels were
124Iodine
PET
124I
has a half-life of 4.2 days and a and a relatively complex
decay scheme, with approximately 23% of the disintegrations producing positrons of relatively high energies (1532
keV and 2146 keV), as well as several high-energy gamma
and X-rays, with energy as high as 1691 keV. Despite the high
abundance of high-energy gamma photons images of satisfactory quality can be acquired and quantitation of tracer
uptake can be performed with only minor degradation in
image resolution and quantitation.140 PET with 124I (Fig. 7)
provides images of higher spatial resolution and lesion contrast than either planar imaging or single-photon emission
computed tomography with 131I, resulting in better lesion
Figure 7 Images of a 55-year-old patient with a 7-cm poorly differentiated thyroid carcinoma, exhibiting focal capsular and
vascular invasion, who underwent total thyroidectomy, but refused subsequent radioactive iodine therapy. Several years later
he presented with enlarging lung nodules, measuring up to 2.5 cm. A FDG-PET/CT (A) showed bilateral lung nodules (B)
without abnormal uptake on fusion images (C). In contrast, intense iodine uptake in several lung nodules is noted on 124I PET
maximum intensity projection (D) and PET/CT fusion images (E). This patient was treated with 248 mCi of 131I; the
posttherapy single photon emission computed tomography/CT fusion image (F) shows good iodine accumulation in these
nodules. Decrease in nodule size was observed on subsequent CT scans (not shown). Images D-F are reproduced with
permission by Nature Publishing Group from Tuttle, et al. Nat Clin Practice 4:665-668, 2007, 2007.
T. Abraham and H. Schöder
134
detection141,142; localization of focal tracer uptake is further
improved by integrated PET/CT.143 The impact of improved
lesion detection on diagnostic 124I PET/CT scan (compared
with 131I imaging) in patients with documented or reasonably
suspected metastatic disease remains to be proven. However,
one of the main applications for 124I PET/CT in thyroid cancer
may be found in obtaining lesional dosimetry. This might
provide a more scientific basis for determining the necessary
activity for treatment with 131I.144-146 An emerging indication
is response assessment of patients who undergo targeted
therapies aimed at achieving reestablishment of iodine uptake through inhibition of molecular tumor pathways.
Conclusions
The use of PET imaging in patients with thyroid cancer has
increased over the past decade. The most common indication
is now the assessment of patients with differentiated thyroid
carcinoma after thyroidectomy presenting with elevated Tg
levels but negative 131I WBS. While detection of metastatic
lesions on FDG-PET/CT increases with rising Tg levels, no
absolute minimum cut-off can be established. Instead the
decision to perform FDG scans should be individualized for
each patient based on clinical and laboratory findings and
risk profile. FDG-PET/CT is thus particularly indicated in the
work-up of patients with Hürthle cell carcinoma and other
aggressive subtypes. The prognostic value of FDG-PET in
patients with differentiated thyroid cancers is now clearly
established; this may help in selecting appropriate patients
who are unlikely to respond to further 131I therapy for treatment with novel experimental drugs. Other indications for
FDG-PET include the initial (post thyroidectomy) evaluation
of patients with PTC and the response assessment of noniodine avid disease treated with external beam radiotherapy,
embolization, or systemic medical therapies. Patients with
MTC and elevated or rising tumor markers after thyroidectomy should be assessed with FDOPA PET/CT where available. The current (albeit limited) data suggest that this tracer
has higher sensitivity for detection of metastatic disease than
FDG in most patients, except those with short calcitonin or
CEA doubling times. 124I PET/CT imaging is a promising
technique to improve treatment planning with lesional dosimetry in patients with metastatic thyroid cancer. Its utility
for diagnostic purposes remains to be proven; whereas 124I
PET/CT detects more lesions in patients with known or suspected metastatic disease, the tracer is not widely available
and the impact of these imaging findings for patient management is currently unknown. PET/CT with FDG should be
used as part of clinical trials with novel targeted therapies in
patients with advanced metastatic disease. These drugs may
aim to accomplish tumor redifferentiation with reexpression
of NIS (quantifiable with 124I PET) as prerequisite for subsequent rational treatment with 131iodine, or they may disrupt
tumor-specific pathways in thyroid cancer (such as the MAP
kinase pathway) whose activity can be measured with FDGPET.
Acknowledgments
We thank Dr R. Michael Tuttle, our colleague and co-worker
at MSKCC, for helpful discussions and Dr Joseph Glaser, at
Montefiore Medical Center for his assistance.
References
1. Altekruse S, Kosary C, Krapcho M, et al: SEER cancer statistics review,
1975-2007. Bethesda, MD, National Cancer Institute (based on November 2009 SEER data submission, posted to the SEER web site,
2010). Available at: http://seer.cancer.gov/csr/1975_2007/. Accessed
November 9, 2010
2. Chen AY, Jemal A, Ward EM: Increasing incidence of differentiated
thyroid cancer in the United States, 1988-2005. Cancer 115:38013807, 2009
3. Shaha AR, Shah JP, Loree TR: Low-risk differentiated thyroid cancer:
the need for selective treatment. Ann Surg Oncol 4:328-333, 1997
4. Stojadinovic A, Ghossein RA, Hoos A, et al: Hürthle cell carcinoma: a
critical histopathologic appraisal. J Clin Oncol 19:2616-2625, 2001
5. Hay ID, Grant CS, Taylor WF, et al: Ipsilateral lobectomy versus
bilateral lobar resection in papillary thyroid carcinoma: a retrospective
analysis of surgical outcome using a novel prognostic scoring system.
Surgery 102:1088-1095, 1987
6. Cady B, Rossi R: An expanded view of risk-group definition in differentiated thyroid carcinoma. Surgery 104:947-953, 1988
7. Hay ID, Bergstralh EJ, Goellner JR, et al: Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring
system in a cohort of 1779 patients surgically treated at one institution
during 1940 through 1989. Surgery 114:1050-1057, 1993; discussion: 1057-1058
8. Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid
Association Management guidelines for patients with thyroid nodules
and differentiated thyroid cancer. Thyroidology 19:1167-1214, 2009
9. Tuttle RM: Risk-adapted management of thyroid cancer. Endocr Pract
14:764-774, 2008
10. Viglietto G, Chiappetta G, Martinez-Tello FJ, et al: RET/PTC oncogene
activation is an early event in thyroid carcinogenesis. Oncogene 11:
1207-1210, 1995
11. Kimura ET, Nikiforova MN, Zhu Z, et al: High prevalence of BRAF
mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454-1457, 2003
12. Lodyga M, De Falco V, Bai XH, et al: XB130, a tissue-specific adaptor
protein that couples the RET/PTC oncogenic kinase to PI 3-kinase
pathway. Oncogene 28:937-949, 2009
13. Xu X, Quiros RM, Gattuso P, et al: High prevalence of BRAF gene
mutation in papillary thyroid carcinomas and thyroid tumor cell lines.
Cancer Res 63:4561-4567, 2003
14. Xing M, Westra WH, Tufano RP, et al: BRAF mutation predicts a
poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373-6379, 2005
15. Elisei R, Ugolini C, Viola D, et al: BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median
follow-up study. J Clin Endocrinol Metab 93:3943-3949, 2008
16. Dhillon AS, Hagan S, Rath O, et al: MAP kinase signalling pathways in
cancer. Oncogene 26:3279-3290, 2007
17. Ouyang B, Knauf JA, Smith EP, et al: Inhibitors of ref kinase activity
block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res 12:1785-1793, 2006
18. Groussin L, Fagin JA: Significance of BRAF mutations in papillary
thyroid carcinoma: prognostic and therapeutic implications. Nat Clin
Pract Endocrinol Metab 2:180-181, 2006
19. Salerno P, De Falco V, Tamburrino A, et al: Cytostatic activity of
adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. J Clin Endocrinol Metab 95:450-455,
2010
20. Liu D, Liu Z, Jiang D, et al: Inhibitory effects of the mitogen-activated
protein kinase kinase inhibitor ci-1040 on the proliferation and tumor
Thyroid cancer: indications and opportunities for PET/CT imaging
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
growth of thyroid cancer cells with BRAF or RAS mutations. J Clin
Endocrinol Metab 92:4686-4695, 2007
Inamdar GS, Madhunapantula SV, Robertson GP: Targeting the
MAPK pathway in melanoma: why some approaches succeed and
other fail. Biochem Pharmacol 80:624-637, 2010
Solit DB, Garraway LA, Pratilas CA, et al: BRAF mutation predicts
sensitivity to MEK inhibition. Nature 439:358-362, 2006
Joseph EW, Pratilas CA, Poulikakos PI, et al: The RAF inhibitor
PLX4032 inhibits ERK signaling and tumor cell proliferation in a
V600E BRAF-selective manner. Proc Natl Acad Sci U S A 107:1490314908, 2010
Pratilas CA, Solit DB: Targeting the mitogen-activated protein kinase
pathway: physiological feedback and drug response. Clin Cancer Res
16:3329-3334, 2010
Nikiforova MN, Kimura ET, Gandhi M, et al: BRAF mutations in
thyroid tumors are restricted to papillary carcinomas and anaplastic or
poorly differentiated carcinomas arising from papillary carcinomas.
J Clin Endocrinol Metab 88:5399-5404, 2003
Romei C, Ciampi R, Faviana P, et al: BRAFV600E mutation, but not
RET/PTC rearrangements, is correlated with a lower expression of
both thyroperoxidase and sodium iodide symporter genes in papillary
thyroid cancer. Endocr Relat Cancer 15:511-520, 2008
Durante C, Puxeddu E, Ferretti E, et al: BRAF mutations in papillary
thyroid carcinomas inhibit genes involved in iodine metabolism.
J Clin Endocrinol Metab 92:2840-2843, 2007
Liu D, Hu S, Hou P, et al: Suppression of BRAF/MEK/MAP kinase
pathway restores expression of iodide-metabolizing genes in thyroid
cells expressing the V600E BRAF mutant. Clin Cancer Res 13:13411349, 2007
Marques AR, Espadinha C, Catarino AL, et al: Expression of PAX8PPAR gamma 1 rearrangements in both follicular thyroid carcinomas
and adenomas. J Clin Endocrinol Metab 87:3947-3952, 2002
Lemoine NR, Mayall ES, Wyllie FS, et al: High-frequency of ras oncogene activation in all stages of human thyroid tumorigenesis. Oncogene 4:159-164, 1989
Vasko V, Ferrand M, Di Cristofaro J, et al: Specific pattern of RAS
oncogene mutations in follicular thyroid tumors. J Clin Endocrinol
Metab 88:2745-2752, 2003
Hou P, Liu D, Shan Y, et al: Genetic alterations and their relationship
in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer.
Clin Cancer Res 13:1161-1170, 2007
Garcia-Rostan G, Zhao H, Camp RL, et al: Ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid
cancer. J Clin Oncol 21:3226-3235, 2003
Volante M, Rapa I, Gandhi M, et al: RAS mutations are the predominant molecular alteration in poorly differentiated thyroid carcinomas
and bear prognostic impact. J Clin Endocrinol Metab 94:4735-4741,
2009
Garcia-Rostan G, Costa AM, Pereira-Castro I, et al: Mutation of the
PIK3CA gene in anaplastic thyroid cancer. Cancer Res 65:1019910207, 2005
Liu Z, Hou P, Ji M, et al: Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J Clin Endocrinol Metab 93:3106-3116, 2008
Santarpia L, El-Naggar AK, Cote GJ, et al: Phosphatidylinositol 3-kinase/Akt and ras/ref-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab 93:278284, 2008
Engelman JA, Chen L, Tan X, et al: Effective use of PI3K and MEK
inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine
lung cancers. Nat Med 14:1351-1356, 2008
Ma WW, Jacene H, Song D, et al: [18F]fluorodeoxyglucose positron
emission tomography correlates with Akt pathway activity but is not
predictive of clinical outcome during mTOR inhibitor therapy. J Clin
Oncol 27:2697-2704, 2009
Kloos RT, Eng C, Evans DB, et al: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroidology
19:565-612, 2009
135
41. Dvorakova S, Vaclavikova E, Sykorova V, et al: Somatic mutations in
the RET proto-oncogene in sporadic medullary thyroid carcinomas.
Mol Cell Endocrinol 284:21-27, 2008
42. Elisei R, Cosci B, Romei C, et al: Prognostic significance of somatic
RET oncogene mutations in sporadic medullary thyroid cancer: a
10-year follow-up study. J Clin Endocrinol Metab 93:682-687, 2008
43. Hundahl SA, Fleming ID, Fremgen AM, et al: A national cancer database report on 53,856 cases of thyroid carcinoma treated in the U.S.,
1985-95 [see commetns]. Cancer 83:2638-2648, 1998
44. Akslen LA, Haldorsen T, Thoresen SO, et al: Survival and causes of
death in thyroid cancer: a population-based study of 2479 cases from
Norway. Cancer Res 51:1234-1241, 1991
45. Azadian A, Rosen IB, Walfish PG, et al: Management considerations in
Hurthle cell carcinoma. Surgery 118:711-714, 1995; discussion:714715
46. Stojadinovic A, Hoos A, Ghossein RA, et al: Hurthle cell carcinoma: a
60-year experience. Ann Surg Oncol 9:197-203, 2002
47. Hundahl SA, Cady B, Cunningham MP, et al: Initial results from a
prospective cohort study of 5583 cases of thyroid carcinoma treated in
the United States during 1996. U.S. and German Thyroid Cancer
Study Group: An American College of Surgeons Commission on Cancer Patient Care Evaluation Study. Cancer 89:202-217, 2000
48. Shaha AR, Shah JP, Loree TR: Patterns of nodal and distant metastasis
based on histologic varieties in differentiated carcinoma of the thyroid. Am J Surg 172:692-694, 1996
49. Kushchayeva Y, Duh QY, Kebebew E, et al: Comparison of clinical
characteristics at diagnosis and during follow-up in 118 patients with
Hürthle cell or follicular thyroid cancer. Am J Surg 195:457-462,
2008
50. Nikiforov YE: Genetic alterations involved in the transition from welldifferentiated to poorly differentiated and anaplastic thyroid carcinomas. Endocr Pathol 15:319-327, 2004
51. McIver B, Hay ID, Giuffrida DF, et al: Anaplastic thyroid carcinoma: a
50-year experience at a single institution. Surgery 130:1028-1034,
2001
52. Gilliland FD, Hunt WC, Morris DM, et al: Prognostic factors for thyroid carcinoma- A population-based study of 15,698 cases from the
surveillance, epidemiology and end results (SEER) program 1973-91.
Cancer 79:564-573, 1997
53. Are C, Shaha AR: Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol
13:453-464, 2006
54. Sherman SI, Angelos P, Ball DW, et al: Thyroid carcinoma. J Natl
Compr Cancer Netw 5:568-621, 2007
55. Pelizzo MR, Boschin IM, Bernante P, et al: Natural history, diagnosis,
treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol 33:493-497, 2007
56. Modigliani E, Cohen R, Campos JM, et al: Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results
in 899 patients. Clin Endocrinol 48:265-273, 1998
57. Baroli A, Pedrazzini L, Lomuscio G, et al: Anaplastic thyroid carcinoma. Practical aspects of multimodal therapy and data emerging
from a 40-year experience at a single Italian Institution. Minerva Endocrinol 35:9-16, 2010
58. Brignardello E, Gallo M, Baldi I, et al: Anaplastic thyroid carcinoma:
clinical outcome of 30 consecutive patients referred to a single institution in the past 5 years. Eur J Endocrinol 156:425-430, 2007
59. Pierie JP, Muzikansky A, Gaz RD, et al: The effect of surgery and
radiotherapy on outcome of anaplastic thyroid carcinoma. Ann Surg
Oncol 9:57-64, 2002
60. Troch M, Koperek O, Scheuba C, et al: High efficacy of concomitant
treatment of undifferentiated (anaplastic) thyroid cancer with radiation and docetaxel. J Clin Endocrinol Metab 95:E54-E57, 2010
61. Swaak-Kragten AT, de Wilt JH, Schmitz PI, et al: Multimodality treatment for anaplastic thyroid carcinoma—treatment outcome in 75
patients. Radiother Oncol 92:100-104, 2009
62. Siragusa M, Zerilli M, Iovino F, et al: MUC1 oncoprotein promotes
refractoriness to chemotherapy in thyroid cancer cells. Cancer Res
67:5522-5530, 2007
136
63. Sugawara I, Arai T, Yamashita T, et al: Expression of multidrug resistance-associated protein (MRP) in anaplastic carcinoma of the thyroid. Cancer Lett 82:185-188, 1994
64. Zito G, Richiusa P, Bommarito A, et al: In vitro identification and
characterization of CD133(pos) cancer stem-like cells in anaplastic
thyroid carcinoma cell lines. PLoS ONE 3:e3544, 2008
65. Borbone E, Berlingieri MT, De Bellis F, et al: Histone deacetylase
inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation. Oncogene 29:105116, 2010
66. Libertini S, Iacuzzo I, Perruolo G, et al: Bevacizumab increases viral
distribution in human anaplastic thyroid carcinoma xenografts and
enhances the effects of E1A-defective adenovirus dl922-947. Clin
Cancer Res 14:6505-6514, 2008
67. Matsuzu K, Segade F, Matsuzu U, et al: Differential expression of
glucose transporters in normal and pathologic thyroid tissue. Thyroidology 14:806-812, 2004
68. Ciampi R, Vivaldi A, Romei C, et al: Expression analysis of facilitative
glucose transporters (GLUTs) in human thyroid carcinoma cell lines
and primary tumors. Mol Cell Endocrinol 291:57-62, 2008
69. Schonberger J, Ruschoff J, Grimm D, et al: Glucose transporter 1 gene
expression is related to thyroid neoplasms with an unfavorable prognosis: an immunohistochemical study. Thyroidology 12:747-754,
2002
70. Hooft L, van der Veldt AA, van Diest PJ, et al: [18F]fluorodeoxyglucose uptake in recurrent thyroid cancer is related to hexokinase i
expression in the primary tumor. J Clin Endocrinol Metab 90:328334, 2005
71. Burrows N, Resch J, Cowen RL, et al: Expression of hypoxia-inducible
factor 1 alpha in thyroid carcinomas. Endocr Relat Cancer 17:61-72,
2010
72. Zerilli M, Zito G, Martorana A, et al: BRAF(V600E) mutation influences hypoxia-inducible factor-1alpha expression levels in papillary
thyroid cancer. Mod Pathol 23:1052-1060, 2010
73. Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer
3:721-732, 2003
74. Semenza GL: HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 20:51-56, 2010
75. Filetti S, Damante G, Foti D: Thyrotropin stimulates glucose transport
in cultured rat thyroid cells. Endocrinology 120:2576-2581, 1987
76. Haraguchi K, Rani CS, Field JB: Effects of thyrotropin, carbachol, and
protein kinase C stimulators on glucose transport and glucose oxidation by primary cultures of dog thyroid cells. Endocrinology 123:
1288-1295, 1988
77. Deichen JT, Schmidt C, Prante O, et al: Influence of TSH on uptake of
[18F]fluorodeoxyglucose in human thyroid cells in vitro. Eur J Nucl
Med Mol Imaging 31:507-512, 2004
78. Prante O, Maschauer S, Fremont V, et al: Regulation of uptake of
18F-FDG by a follicular human thyroid cancer cell line with mutation-activated K-ras. J Nucl Med 50:1364-1370, 2009
79. Blaser D, Maschauer S, Kuwert T, et al: In vitro studies on the signal
transduction of thyroidal uptake of 18F-FDG and 131I-iodide. J Nucl
Med 47:1382-1388, 2006
80. Samih N, Hovsepian S, Aouani A, et al: Glut-1 translocation in FRTL-5
thyroid cells: role of phosphatidylinositol 3-kinase and N-glycosylation. Endocrinology 141:4146-4155, 2000
81. Wang W, Macapinlac H, Larson SM, et al. [18F]-2-fluoro-2-deoxy-Dglucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic (131)I whole body scans and
elevated serum thyroglobulin levels. J Clin Endocrinol Metab 84:
2291-2302, 1999
82. Grunwald F, Kalicke T, Feine U, et al: Fluorine-18 fluorodeoxyglucose positron emission tomography in thyroid cancer: results of a
multicentre study. Eur J Nucl Med 26:1547-1552, 1999
83. Moog F, Linke R, Manthey N, et al: Influence of thyroid-stimulating
hormone levels on uptake of FDG in recurrent and metastatic differentiated thyroid carcinoma. J Nucl Med 41:1989-1995, 2000
T. Abraham and H. Schöder
84. Petrich T, Borner AR, Otto D, et al: Influence of rhTSH on [(18)F]fluorodeoxyglucose uptake by differentiated thyroid carcinoma. Eur
J Nucl Med Mol Imaging 29:641-647, 2002
85. Chin BB, Patel P, Cohade C, et al: Recombinant human thyrotropin
stimulation of fluoro-D-glucose positron emission tomography uptake
in well-differentiated thyroid carcinoma. J Clin Endocrinol Metab
89:91-95, 2004
86. Leboulleux S, Schroeder PR, Busaidy NL, et al: Assessment of the
incremental value of recombinant thyrotropin stimulation before
2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/
computed tomography imaging to localize residual differentiated thyroid cancer. J Clin Endocrinol Metab 94:1310-1316, 2009
87. Ma C, Xie J, Lou Y, et al: The role of TSH for 18F-FDG-PET in the
diagnosis of recurrence and metastases of differentiated thyroid carcinoma with elevated thyroglobulin and negative scan: a meta-analysis. Eur J Endocrinol 163:177-183, 2010
88. Schluter B, Bohuslavizki KH, Beyer W, et al: Impact of FDG PET on
patients with differentiated thyroid cancer who present with elevated
thyroglobulin and negative 131I scan. J Nucl Med 42:71-76, 2001
89. Shammas A, Degirmenci B, Mountz JM, et al: 18F-FDG PET/CT in
patients with suspected recurrent or metastatic well-differentiated
thyroid cancer. J Nucl Med 48:221-226, 2007
90. Vera P, Kuhn-Lansoy C, Edet-Sanson A, et al: Does recombinant human thyrotropin-stimulated positron emission tomography with
[18F]fluoro-2-deoxy-D-glucose improve detection of recurrence of
well-differentiated thyroid carcinoma in patients with low serum thyroglobulin? Thyroidology 20:15-23, 2010
91. Palmedo H, Bucerius J, Joe A, et al: Integrated PET/CT in differentiated thyroid cancer: diagnostic accuracy and impact on patient management. J Nucl Med 47:616-624, 2006
92. Karantanis D, Bogsrud TV, Wiseman GA, et al: Clinical significance of
diffusely increased 18F-FDG uptake in the thyroid gland. J Nucl Med
48:896-901, 2007
93. Cohen MS, Arslan N, Dehdashti F, et al: Risk of malignancy in thyroid
incidentalomas identified by fluorodeoxyglucose-positron emission
tomography. Surgery 130:941-946, 2001
94. Kim TY, Kim WB, Ryu JS, et al: 18F-fluorodeoxyglucose uptake in
thyroid from positron emission tomogram (PET) for evaluation in
cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope 115:1074-1078, 2005
95. Kang KW, Kim SK, Kang HS, et al: Prevalence and risk of cancer of
focal thyroid incidentaloma identified by 18F-fluorodeoxyglucose
positron emission tomography for metastasis evaluation and cancer
screening in healthy subjects. J Clin Endocrinol Metab 88:4100-4104,
2003
96. Are C, Hsu JF, Schoder H, et al: FDG-PET detected thyroid incidentalomas: need for further investigation? Ann Surg Oncol 14:239-247,
2007
97. Nam SY, Roh JL, Kim JS, et al: Focal uptake of (18)F-fluorodeoxyglucose by thyroid in patients with nonthyroidal head and neck cancers,
in Clin Endocrinol (Oxf) 67:135-139, 2007
98. Yi JG, Marom EM, Munden RF, et al: Focal uptake of fluorodeoxyglucose by the thyroid in patients undergoing initial disease staging with
combined PET/CT for non-small cell lung cancer. Radiology 236:271275, 2005
99. Kwak JY, Kim EK, Yun M, et al: Thyroid incidentalomas identified by
18F-FDG PET: sonographic correlation. AJR Am J Roentgenol 191:
598-603, 2008
100. Bogsrud TV, Karantanis D, Nathan MA, et al: The value of quantifying
18F-FDG uptake in thyroid nodules found incidentally on wholebody PET-CT. Nucl Med Commun 28:373-381, 2007
101. Eloy JA, Brett EM, Fatterpekar GM, et al: The significance and management of incidental [18F]fluorodeoxyglucose-positron-emission
tomography uptake in the thyroid gland in patients with cancer. AJNR
Am J Neuroradiol 30:1431-1434, 2009
102. Zhai G, Zhang M, Xu H, et al: The role of 18F-fluorodeoxyglucose
positron emission tomography/computed tomography whole body
imaging in the evaluation of focal thyroid incidentaloma. J Endocrinol
Invest 33:151-155, 2010
Thyroid Cancer—Indications and
Opportunities for Positron Emission
Tomography/Computed Tomography Imaging
Tony Abraham, DO,* and Heiko Schöder, MD†
Although thyroid cancer is a comparatively rare malignancy, it represents the vast majority
of endocrine cancers and its incidence is increasing. Most differentiated thyroid cancers
have an excellent prognosis if diagnosed early and treated appropriately. Aggressive
histologic subtypes and variants carry a worse prognosis. During the last 2 decades
positron emission tomography (PET) and PET/computed tomography (CT), mostly with
fluorodeoxyglucose (FDG), has been used increasingly in patients with thyroid cancers.
Currently, the most valuable role FDG-PET/CT exists in the work-up of patients with
differentiated thyroid cancer status post thyroidectomy who present with increasing thyroglobulin levels and a negative 131I whole-body scan. FDG-PET/CT is also useful in the
initial (post thyroidectomy) staging of high-risk patients with less differentiated (and thus
less iodine-avid and clinically more aggressive) subtypes, such as tall cell variant and
Hürthle cell carcinoma, but in particular poorly differentiated and anaplastic carcinoma.
FDG-PET/CT may help in defining the extent of disease in some patients with medullary
thyroid carcinoma and rising postoperative calcitonin levels. However, FDOPA has
emerged as an alternate and more promising radiotracer in this setting. In aggressive
cancers that are less amenable to treatment with 131iodine, FDG-PET/CT may help in
radiotherapy planning, and in assessing the response to radiotherapy, embolization, or
experimental systemic treatments. 124Iodine PET/CT may serve a role in obtaining lesional
dosimetry for better and more rationale planning of treatment with 131iodine. Thyroid cancer
is not a monolithic disease, and different stages and histologic entities require different
approaches in imaging and individualized therapy.
Semin Nucl Med 41:121-138 © 2011 Elsevier Inc. All rights reserved.
Clinical Background
T
hyroid cancer is the most common cancer of the endocrine system. Approximately 37,000 new cases of thyroid cancer are diagnosed in the United States each year.1
Papillary cancer is the most common type in the United
States and Europe; women are approximately 3 times more
likely to be diagnosed with thyroid cancer in the most recent
cancer statistics. The incidence of this disease has been increasing during the past several decades, at least in part be*Department of Nuclear Medicine, Montefiore Medical Center and Albert
Einstein College of Medicine, New York, NY.
†Department of Radiology/Nuclear Medicine, Memorial Sloan-Kettering
Cancer Center, New York, NY.
Current address of Tony Abraham: Montefiore Medical Park, 1695A Eastchester Road, Bronx, NY 10461.
Address reprint requests to Heiko Schöder, MD, Memorial Sloan-Kettering
Cancer Center, Department Radiology/Nuclear Medicine, 1275 York
Avenue, Box 77, New York, NY 10065. E-mail: [email protected]
0001-2998/11/$-see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1053/j.semnuclmed.2010.10.006
cause of better clinical surveillance and improved imaging
modalities. For instance, analysis of the Surveillance, Epidemiology and End Results Program (SEER) database from
1988 to 2005 showed that the incidence of differentiated
thyroid cancers has increased across sexes, ages, and for all
tumor sizes, although the greatest rate of increase was seen
for primary tumors ⬍ 1.0 cm. The increased incidence is
largely caused by increased detection of papillary thyroid
cancers. Of note, despite increasing incidence, the mortality
did not change significantly during the same period.2
Classification
Thyroid cancer comprises a group of tumors with very different histopathological and clinical features. We distinguish
broadly between malignant tumors of follicular cell origin
(papillary, follicular, Hürthle cell, poorly differentiated, and
anaplastic carcinomas) and cancers in which the parafollicular C-cell is the cell of origin (medullary thyroid carcinoma).
121
138
142. Van Nostrand D, Moreau S, Bandaru VV, et al: (124)I positron emission tomography versus (131)I planar imaging in the identification of
residual thyroid tissue and/or metastasis in patients who have welldifferentiated thyroid cancer. Thyroid 20:879-883, 2010
143. Freudenberg LS, Antoch G, Jentzen W, et al: Value of (124)I-PET/CT
in staging of patients with differentiated thyroid cancer. Eur Radiol
14:2092-2098, 2004
144. Eschmann SM, Reischl G, Bilger K, et al: Evaluation of dosimetry of
radioiodine therapy in benign and malignant thyroid disorders by
T. Abraham and H. Schöder
means of iodine-124 and PET. Eur J Nucl Med Mol Imaging
29:760-767, 2002
145. Freudenberg LS, Jentzen W, Petrich T, et al: Lesion dose in differentiated thyroid carcinoma metastases after rhTSH or thyroid hormone
withdrawal: (124)I PET/CT dosimetric comparisons. Eur J Nucl Med
Mol Imaging 37:2267-2276, 2010
146. Jentzen W, Freudenberg L, Eising EG, et al: Optimized 124I PET
dosimetry protocol for radioiodine therapy of differentiated thyroid
cancer. J Nucl Med 49:1017-1023, 2008