ORIGINAL STUDIES, REVIEWS,
AND SCHOLARLY DIALOG
THYROID CANCER AND NODULES
Revised American Thyroid Association Management
Guidelines for Patients with Thyroid Nodules
and Differentiated Thyroid Cancer
The American Thyroid Association (ATA) Guidelines Taskforce
on Thyroid Nodules and Differentiated Thyroid Cancer
David S. Cooper, M.D.1(Chair)*, Gerard M. Doherty, M.D.,2Bryan R. Haugen, M.D.,3
Richard T. Kloos, M.D.,4Stephanie L. Lee, M.D., Ph.D.,5Susan J. Mandel, M.D., M.P.H.,6
Ernest L. Mazzaferri, M.D.,7Bryan McIver, M.D., Ph.D.,8Furio Pacini, M.D.,9Martin Schlumberger, M.D.,10
Steven I. Sherman, M.D.,1 1David L. Steward, M.D.,12and R. Michael Tuttle, M.D.13
Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming
increasingly prevalent. Since the publication of the American Thyroid Association’s guidelines for the man-
agement of these disorders was published in 2006, a large amount of new information has become available,
prompting a revision of the guidelines.
Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and
level of evidence according to a modified schema used by the United States Preventative Services Task Force.
Results: The revised guidelines for the management of thyroid nodules include recommendations regarding
initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle
aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial
management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant
ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of
differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and
serum thyroglobulin as well as those related to management of recurrent and metastatic disease.
Conclusions: We created evidence-based recommendations in response to our appointment as an independent
task force by the American Thyroid Association to assist in the clinical management of patients with thyroid
nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for pa-
tients with these disorders.
in men living in iodine-sufficient parts of the world (1,2). In
contrast, high-resolution ultrasound (US) can detect thyroid
hyroid nodules are a common clinical problem. Epi-
demiologic studies have shown the prevalence of palpa-
nodules in 19–67% of randomly selected individuals with
higher frequencies in women and the elderly (3). The clinical
importance of thyroid nodules rests with the need to exclude
thyroid cancer which occurs in 5–15% depending on age, sex,
radiation exposure history, family history, and other factors
*Authors are listed in alphabetical order and were appointed by ATA to independently formulate the content of this manuscript. None of
the scientific or medical content of the manuscript was dictated by the ATA.
1The Johns Hopkins University School of Medicine, Baltimore, Maryland.
2University of Michigan Medical Center, Ann Arbor, Michigan.
3University of Colorado Health Sciences Center, Denver, Colorado.
4The Ohio State University, Columbus, Ohio.
5Boston University Medical Center, Boston, Massachusetts.
6University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
7University of Florida College of Medicine, Gainesville, Florida.
8The Mayo Clinic, Rochester, Minnesota.
9The University of Siena, Siena, Italy.
10Institute Gustave Roussy, Paris, France.
11University of Texas M.D. Anderson Cancer Center, Houston, Texas.
12University of Cincinnati Medical Center, Cincinnati, Ohio.
13Memorial Sloan-Kettering Cancer Center, New York, New York.
Volume 19, Number 11, 2009
ª Mary Ann Liebert, Inc.
(4,5). Differentiated thyroid cancer (DTC), which includes
papillary and follicular cancer, comprises the vast majority
(90%) of all thyroid cancers (6). In the United States, approx-
imately 37,200 new cases of thyroid cancer will be diagnosed
in 2009 (7). The yearly incidence has increased from 3.6 per
100,000 in 1973 to 8.7 per 100,000 in 2002, a 2.4-fold increase
(p<0.001 for trend) and this trend appears to be continuing
(8). Almost the entire change has been attributed to an in-
crease in the incidence of papillary thyroid cancer (PTC),
which increased 2.9-fold between 1988 and 2002. Moreover,
49% of the rising incidence consisted of cancers measuring
1cm or smaller and 87% consisted of cancers measuring 2cm
or smaller (8). This tumor shift may be due to the increasing
use of neck ultrasonography and early diagnosis and treat-
ment (9), trends that are changing the initial treatment and
follow-up for many patients with thyroid cancer.
In 1996, the American Thyroid Association (ATA) pub-
lished treatment guidelines for patients with thyroid nodules
and DTC (10). Over the last decade, there have been many
and DTC. Controversy exists in many areas, including the
most cost-effective approach in the diagnostic evaluation of a
thyroidectomy, the appropriate use of thyroxine suppression
therapy, and the role of human recombinant thyrotropin
(rhTSH). In recognition of thechanges that havetaken place in
the overall management of these clinically important prob-
strategies that are used to diagnose and treat thyroid nodules
evidence-based medicine. Members of the taskforce included
experts in thyroid nodule and thyroid cancer management
with representation from the fields of endocrinology, surgery,
and nuclear medicine. The medical opinions expressed here
are those of the authors; none were dictated by the ATA. The
final document was approved by the ATA Board of Directors
and endorsed (in alphabetical order) by the American Asso-
of Endocrinology, British Association of Head and Neck
Oncologists (BAHNO), The Endocrine Society, European As-
sociation for Cranio-Maxillo-Facial Surgery (EACMFS), Eur-
opean Association of Nuclear Medicine (EANM), European
Society of Endocrine Surgeons (ESES), European Society for
Paediatric Endocrinology (ESPE), International Association of
Endocrine Surgeons (IAES), and Latin American Thyroid So-
Other groups have previously developed guidelines, in-
and the American Association ofEndocrine Surgeons (11), the
British Thyroid Association and The Royal College of Physi-
cians (12), and the National Comprehensive Cancer Network
(13) that have provided somewhat conflicting recommenda-
tions due to the lack of high quality evidence from random-
ized controlled trials. The European Thyroid Association has
published consensus guidelines for the management of DTC
(14). The European Association of Nuclear Medicine has also
therapy of DTC (15).
The ATA guidelines taskforce used a strategy similar to that
employed by the National Institutes of Health for its Consen-
sus Development Conferences (http:==consensus.nih.gov=
aboutcdp.htm), and developed a series of clinically relevant
questions pertaining to thyroid nodule and thyroid cancer di-
agnosis and treatment. These questions were as follows:
—Questions regarding thyroid nodules
? What is the appropriate evaluation of clinically or inci-
dentally discovered thyroid nodule(s)?
*What laboratory tests and imaging modalities are in-
*What is the role of fine-needle aspiration (FNA)?
? What is the best method of long-term follow up of pa-
tients with thyroid nodules?
? What is the role of medical therapy of patients with
benign thyroid nodules?
? How should thyroid nodules in children and pregnant
women be managed?
—Questions regarding the initial management of DTC
? What is the role of preoperative staging with diagnostic
imaging and laboratory tests?
? What is the appropriate operation for indeterminate
thyroid nodules and DTC?
? What is the role of postoperative staging systems and
which should be used?
? What is the role of postoperative RAI remnant ablation?
? What is the role of thyrotropin (TSH) suppression
? Is there a role for adjunctive external beam irradiation or
—Questions regarding the long term management of DTC
? What are the appropriate features of long-term man-
? What is the role of serum thyroglobulin (Tg) assays?
? What is the role of US and other imaging techniques
? What is the role of TSH suppression in long-term follow-
? What is the most appropriate management of patients
with metastatic disease?
? How should Tg-positive, scan-negative patients be
? What is the role of external radiation therapy?
? What is the role of chemotherapy?
—What are directions for future research?
The initial ATA guidelines were published in 2006 (16).
Because of the rapid growth of the literature on this topic,
plans for revising the guidelines within 24–36 months of
publication were made at the inception of the project. Re-
levant articles on thyroid cancer were identified using the
same search criteria employed for the original guidelines (16).
Individual task force members submitted suggestions for
clarification of prior recommendations, as well as new infor-
mation derived from studies published since 2004. Relevant
literature continued to be reviewed through December 2008.
To begin the revision process, a half-day meeting was held
on June 2, 2007. The Task Force was broadened to include
European experts and a head and neck surgeon. Three sub-
sequent half-day meetings were held on October 5, 2007; July
13, 2008; and October 5, 2008, to review these suggestions and
2008 also included a meeting with six additional surgeons in
1168COOPER ET AL.
Table 1. Organization of Management Guideline Recommendations, Tables, and Figures
for Patients with Thyroid Nodules and Differentiated Thyroid Cancer
Sections and subsectionsItemb
THYROID NODULE GUIDELINES
Evaluation of Newly Discovered Thyroid Nodules
Serum thyroglobulin (Tg)
Role of fine-needle aspiration (FNA)
Ultrasound (US) with FNA
Cytopathological interpretation of FNA samples
Cytology suggesting papillary thyroid cancer (PTC)
Multinodular goiter (MNG)=multiple thyroid nodules
Long-Term Follow-Up of Thyroid Nodules
Medical therapy for benign thyroid nodules
Thyroid nodules in children
Thyroid nodules in pregnant women
DIFFERENTIATED THYROID CANCER (DTC):
INITIAL MANAGEMENT GUIDELINES
Goals of Initial Therapy of DTC
Preoperative staging of DTC
Surgery for nondiagnostic biopsy
Surgery for biopsy diagnostic of malignancy
Lymph node dissection
Postoperative staging systems
Role of postoperative staging
AJCC=UICC TNM staging
Role of postoperative remnant ablation
Preparation for radioiodine (RAI) remnant ablation
RAI scanning before RAI ablation
Radiation doses for RAI ablation
Low-iodine diet for RAI ablation
Post RAI ablation whole-body RAI scan
Post Initial Therapy of DTC
Role of TSH suppression therapy
Degree of initial TSH suppression required
External beam irradiation
DTC: LONG-TERM MANAGEMENT
Appropriate Features of Long-Term Management
Appropriate method of follow-up after surgery
Criteria for absence of persistent tumor
Role of serum Tg assays
Whole body RAI scans, US, and other imaging
bR, recommendation; T, table; F, figure.
REVISED ATA THYROID CANCER GUIDELINES1169
Table 1. (Continued)
Page Location keya
Sections and subsections Itemb
Diagnostic whole-body RAI scans
Role of thyroxine suppression of TSH
Management of Metastatic Disease
Surgery for locoregional metastases
Surgery for aerodigestive invasion
RAI for local or distant metastatic disease
Methods for administering RAI
The use of lithium in RAI therapy
Metastasis to various organs
Non–RAI-avid pulmonary disease
Management of Complications of RAI Therapy
Secondary malignancies and leukemia from RAI
Other risks to bone marrow from RAI
Effects of RAI on gonads and in nursing women
Management of Tg Positive, RAI Scan–Negative Patients
Patients with a negative post-treatment whole-body scan
External beam radiation for metastatic disease
DIRECTIONS FOR FUTURE RESEARCH
Novel Therapies and Clinical Trials
Inhibitors of oncogenic signaling pathways
Modulators of growth or apoptosis
Better Understanding of the Long-Term Risks of RAI
Clinical Significance of Persistent Low-Level Tg
The Problem of Tg Antibodies
Small Cervical Lymph Node Metastases
Improved Risk Stratification
Table 2. Strength of Panelists’ Recommendations Based on Available Evidence
A Strongly recommends. The recommendation is based on good evidence that the service or intervention can improve
important health outcomes. Evidence includes consistent results from well-designed, well-conducted studies in
representative populations that directly assess effects on health outcomes.
Recommends. The recommendation is based on fair evidence that the service or intervention can improve
important health outcomes. The evidence is sufficient to determine effects on health outcomes, but the strength
of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to
routine practice; or indirect nature of the evidence on health outcomes.
Recommends. The recommendation is based on expert opinion.
Recommends against. The recommendation is based on expert opinion.
Recommends against. The recommendation is based on fair evidence that the service or intervention does not
improve important health outcomes or that harms outweigh benefits.
Strongly recommends against. The recommendation is based on good evidence that the service or intervention
does not improve important health outcomes or that harms outweigh benefits.
Recommends neither for nor against. The panel concludes that the evidence is insufficient to recommend for
or against providing the service or intervention because evidence is lacking that the service or intervention
improves important health outcomes, the evidence is of poor quality, or the evidence is conflicting. As a result, the
balance of benefits and harms cannot be determined.
Adapted from the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality (17).
an effort to produce guidelines related to central neck dis-
section that would be as authoritative as possible. The orga-
nization of management guideline recommendations is
shown in Table 1. It was agreed to continue to categorize the
published data and strength of recommendations using a
modified schema proposed by the U.S. Preventive Services
Task Force (17) (Table 2).
[A1] THYROID NODULE GUIDELINES
A thyroid nodule is a discrete lesion within the thyroid
gland that is radiologically distinct from the surrounding
thyroid parenchyma. Some palpable lesions may not corre-
spond to distinct radiologic abnormalities (18). Such abnor-
malities do not meet the strict definition for thyroid nodules.
Nonpalpable nodules detected on US or other anatomic im-
aging studies are termed incidentally discovered nodules or
‘‘incidentalomas.’’ Nonpalpable nodules have the same risk of
malignancy as palpable nodules with the same size (19).
Generally, only nodules >1cm should be evaluated, since
they have a greater potential to be clinically significant can-
cers. Occasionally, there may be nodules <1cm that require
evaluation because of suspicious US findings, associated
history of thyroid cancer in one or more first-degree relatives.
However, some nodules <1cm lack these warning signs yet
eventually cause morbidity and mortality. These are rare and,
given unfavorable cost=benefit considerations, attempts to
diagnose and treat all small thyroid cancers in an effort to
prevent these rare outcomes would likely cause more harm
than good. Approximately 1–2% of people undergoing 2-
deoxy-2[18F]fluoro-d-glucose positron emission tomography
(18FDG-PET) imaging for other reasons have thyroid nodules
discovered incidentally. Since the risk of malignancy in these
18FDG-positive nodules is about 33% and the cancers may be
more aggressive (20), such lesions require prompt evaluation
(21–23). When seen, diffuse18FDG uptake is likely related to
underlying autoimmune thyroiditis.
[A2] What is the appropriate evaluation of clinically
or incidentally discovered thyroid nodule(s)?
(See Fig. 1 for algorithm)
With the discovery of a thyroid nodule, a complete history
and physical examination focusing on the thyroid gland and
historical factors predicting malignancy include a history of
childhood head and neck irradiation, total body irradiation
for bone marrow transplantation (24), family history of thy-
roid carcinoma, or thyroid cancer syndrome (e.g., Cowden’s
syndrome, familial polyposis, Carney complex, multiple en-
docrine neoplasia [MEN] 2, Werner syndrome) in a first-
degree relative, exposure to ionizing radiation from fallout
in childhood or adolescence (25), and rapid growth and
hoarseness. Pertinent physical findings suggesting possible
malignancy include vocal cord paralysis, lateral cervical
lymphadenopathy, and fixation of the nodule to surrounding
[A3] What laboratory tests and imaging modalities are
[A4] Serum TSH with US and with or without scan.
the discovery of a thyroid nodule >1cm in any diameter or
diffuse or focal thyroidal uptake on18FDG-PET scan, a se-
rum TSH level should be obtained. If the serum TSH is
subnormal, a radionuclide thyroid scan should be obtained
to document whether the nodule is hyperfunctioning (i.e.,
tracer uptake is greater than the surrounding normal thy-
roid), isofunctioning or‘‘warm’’(i.e.,traceruptake isequal to
the surrounding thyroid), or nonfunctioning (i.e., has uptake
less than the surrounding thyroid tissue). Since hyperfunc-
tioning nodules rarely harbor malignancy, if one is found
that corresponds to the nodule in question, no cytologic
evaluation is necessary. If overt or subclinical hyperthy-
roidism is present, additional evaluation is required. Higher
serum TSH, even within the upper part of the reference
range, is associated with increased risk of malignancy in a
thyroid nodule (26).
Measure serum TSH in the initial evaluation of a patient
with a thyroid nodule. If the serum TSH is subnormal, a
radionuclide thyroidscan shouldbe performedusingeither
technetium99mTc pertechnetate or123I. Recommendation
Diagnostic thyroid US should be performed in all
patients with a suspected thyroid nodule, nodular goiter, or
radiographic abnormality; e.g., a nodule found incidentally
on computed tomography (CT) or magnetic resonance im-
aging (MRI) or thyroidal uptake on
Thyroid US can answer the following questions: Is there
truly a nodule that corresponds to the palpable abnormal-
ity? How large is the nodule? Does the nodule have benign
or suspicious features? Is suspicious cervical lymphade-
nopathy present? Is the nodule greater than 50% cystic? Is
the nodule located posteriorly in the thyroid gland? These
last two features might decrease the accuracy of FNA bi-
opsy performed with palpation (27,28). Also, there may
be other thyroid nodules present that require biopsy based
on their size and appearance (18,29,30). As already noted,
FNA is recommended especially when the serum TSH
is elevated because, compared with normal thyroid glands,
the rate of malignancy in nodules in thyroid glands
involved with Hashimoto’s thyroiditis is as least as high or
possibly higher (31,32).
Thyroid sonography should be performed in all patients
with known or suspected thyroid nodules. Recommenda-
tion rating: A
[A5] Serum Tg measurement.
vated in most thyroid diseases and are an insensitive and
nonspecific test for thyroid cancer (33).
Serum Tg levels can be ele-
Routine measurement of serum Tg for initial evaluation of
thyroid nodules is not recommended. Recommendation
[A6] Serum calcitonin measurement.
calcitonin has been evaluated in a series of prospective,
nonrandomized studies (34–37). The data suggest that the
The utility of serum
REVISED ATA THYROID CANCER GUIDELINES1171
use of routine serum calcitonin for screening may detect
C-cell hyperplasia and medullary thyroid cancer at an
earlier stage and overall survival may be improved. How-
ever, most studies rely on pentagastrin stimulation test-
ing to increase specificity. This drug is no longer available
in the United States, and there remain unresolved issues
of sensitivity, specificity, assay performance and cost-
effectiveness. A recent cost-effectiveness analysis suggested
that calcitonin screening would be cost effective in the
United States (38). However, the prevalence estimates of
medullary thyroid cancer in this analysis included patients
with C-cell hyperplasia and micromedullary carcinoma,
123I or 99Tc Scana
Normal or High TSH
History, Physical, TSH
RESULTS of FNA
Evaluate and Rx
Nodule on US
No Nodule on US
Suspicious for PTC
or Surgery (See
Consider 123I Scan
WORKUP OF THYROID NODULE
DETECTED BY PALPATION OR IMAGING
aIf the scan does not show uniform distribution of tracer activity, ultrasound may be considered to assess for the presence
of a cystic component.
Algorithm for the evaluation of patients with one or more thyroid nodules.
1172 COOPER ET AL.
which have an uncertain clinical significance. If the un-
stimulated serum calcitonin determination has been ob-
tained and the level is greater than 100pg=mL, medullary
cancer is likely present (39).
The panel cannot recommend either for or against the
routine measurement of serum calcitonin. Recommenda-
tion rating: I
[A7] What is the role of FNA biopsy?
accurate and cost-effective method for evaluating thyroid
nodules. Retrospective studies have reported lower rates of
both nondiagnostic and false-negative cytology specimens
from FNA procedures performed via US guidance compared
to palpation (40,41). Therefore, for nodules with a higher
likelihood of either a nondiagnostic cytology (>25–50% cystic
component) (28) or sampling error (difficult to palpate or
posteriorly locatednodules),US-guided FNAispreferred (see
Table 3). If the diagnostic US confirms the presence of a pre-
dominantly solid nodule corresponding to what is palpated,
the FNA may be performed via palpation or US guidance.
Traditionally FNA biopsy results are divided into four cate-
gories: nondiagnostic, malignant (risk of malignancy at sur-
gery >95%), indeterminate or suspicious for neoplasm, and
benign. The recent National Cancer Institute Thyroid Fine-
Needle Aspiration State of the Science Conference proposed a
more expanded classification for FNA cytology that adds two
additional categories: suspicious for malignancy (risk of ma-
lignancy 50–75%) and follicular lesion of undetermined sig-
nificance (risk of malignancy 5–10%). The conference further
recommended that ‘‘neoplasm, either follicular or Hu ¨rthle cell
FNA is the most
neoplasm’’ be substituted for ‘‘indeterminate’’ (risk of malig-
nancy 15–25%) (42).
[A8] US for FNA decision making (see Table 3).
sonographic characteristics of a thyroid nodule have been
associated with a higher likelihood of malignancy (43–48).
These include nodule hypoechogenicity compared to the
normal thyroid parenchyma, increased intranodular vascu-
larity, irregular infiltrative margins, the presence of micro-
measured in the transverse dimension. With the exception of
suspicious cervical lymphadenopathy, which is a specific but
insensitive finding, no single sonographic feature or combi-
nations of features is adequately sensitive or specific to
identify all malignant nodules. However, certain features and
combination of features have high predictive value for ma-
lignancy. Furthermore, the most common sonographic ap-
pearances of papillary and follicular thyroid cancer differ. A
PTC is generally solid or predominantly solid and hy-
poechoic, often with infiltrative irregular margins and in-
creased nodular vascularity. Microcalcifications, if present,
are highly specific for PTC, but may be difficult to distinguish
fromcolloid. Conversely,follicular canceris moreoften iso- to
hyperechoic and has a thick and irregular halo, but does not
in diameter have not been shown to be associated with met-
astatic disease (50).
Certain sonographic appearances may also be highly pre-
dictive of a benign nodule. A pure cystic nodule, although rare
(<2% of all nodules), is highly unlikely to be malignant (47). In
addition, a spongiform appearance, defined as an aggregation
of multiple microcystic components in more than 50% of the
nodule volume, is 99.7% specific for identification of a benign
Table 3. Sonographic and Clinical Features of Thyroid Nodules and Recommendations for FNA
Nodule sonographic or clinical featuresRecommended nodule threshold size for FNA
Nodule WITH suspicious sonographic featuresb
Nodule WITHOUT suspicious sonographic featuresb
Abnormal cervical lymph nodes
Microcalcifications present in nodule
AND iso- or hyperechoic
Mixed cystic–solid nodule
WITH any suspicious ultrasound featuresb
WITHOUT suspicious ultrasound features
Purely cystic nodule
FNA not indicatede
aHigh-risk history: History of thyroid cancer in one or more first degree relatives; history of external beam radiation as a child; exposure to
ionizing radiation in childhood or adolescence; prior hemithyroidectomy with discovery of thyroid cancer,18FDG avidity on PET scanning;
MEN2=FMTC-associated RETprotooncogene mutation,calcitonin>100pg=mL.MEN, multiple endocrine neoplasia;FMTC, familialmedullary
bSuspicious features: microcalcifications; hypoechoic; increased nodular vascularity; infiltrative margins; taller than wide on transverse view.
cFNA cytology may be obtained from the abnormal lymph node in lieu of the thyroid nodule.
dSonographic monitoring without biopsy may be an acceptable alternative (see text) (48).
eUnless indicated as therapeutic modality (see text).
REVISED ATA THYROID CANCER GUIDELINES1173
thyroid nodule (48,51,52). In a recent study, only 1 of 360
malignant nodules demonstrated this appearance (48) and in
another report, a spongiform appearance had a negative pre-
dictive value for malignancy of 98.5% (52). Elastography is an
emerging and promising sonographic technique that requires
additional validation with prospective studies (53).
Routine FNA is not recommended for subcentimeter nod-
ules. However, the presence of a solid hypoechoic nodule with
microcalcifications is highly suggestive of PTC. Althoughmost
may be more clinically relevant, especially those >5mm in
diameter (54). These include nodules that have abnormal
lymph nodes detected clinically or with imaging at presenta-
tion (55,56). Therefore, after imaging a subcentimeter nodule
with a suspicious appearance, sonographic assessment of lat-
eral neck and central neck lymph nodes (more limited due to
the presence of the thyroid) must be performed. Detection of
Other groups of patients for whom consideration of FNA of a
subcentimeter nodule may be warranted include those with a
higher likelihood of malignancy (high risk history): 1) family
history of PTC (57); 2) history of external beam radiation ex-
posure as a child (58); 3) exposure to ionizing radiation in
childhood or adolescence (59); 4) history of prior hemi-
PET–positive thyroid nodules.
Mixed cystic–solid nodules and predominantly cystic with
>50% cystic component are generally evaluated by FNA with
directed biopsy of the solid component (especially the vas-
cular component.) Cyst drainage may also be performed, es-
pecially in symptomatic patients.
&RECOMMENDATION 5 (see Table 3)
(a) FNA is the procedure of choice in the evaluation of
thyroid nodules. Recommendation rating: A
(b) US guidance for FNA is recommended for those nod-
ules that are nonpalpable, predominantly cystic, or
located posteriorly in the thyroid lobe. Recommenda-
tion rating: B
[A9] What are the principles of the cytopathological inter-
pretation of FNA samples?
[A10] Nondiagnostic cytology.
those that fail to meet specified criteria for cytologic adequacy
that have been previously established (the presence of at least
six follicular cell groups, each containing 10–15cells derived
from at least two aspirates of a nodule) (5). After an initial
nondiagnostic cytology result, repeat FNA with US guidance
will yield a diagnostic cytology specimen in 75% of solid
nodules and 50% of cystic nodules (28). Therefore, such bi-
opsies need to be repeated using US guidance (60) and, if
available, on-site cytologic evaluation, which may substan-
tially increase cytology specimen adequacy (61,62). However,
up to 7% of nodules continue to yield nondiagnostic cytology
results despite repeated biopsies and may be malignant at the
time of surgery (63,64).
Nondiagnostic biopsies are
(a) US guidance should be used when repeating the FNA
procedure for a nodule with an initial nondiagnostic
cytology result. Recommendation rating: A
(b) Partially cystic nodules that repeatedly yield non-
diagnostic aspirates need close observation or surgical
excision. Surgery should be more strongly considered
if the cytologically nondiagnostic nodule is solid. Re-
commendation rating: B
[A11] Cytology suggesting PTC.
If a cytology result is diagnostic of or suspicious for PTC,
surgery is recommended (65). Recommendation rating: A
[A12] Indeterminate cytology (follicular or Hu ¨rthle cell neoplasm
follicular lesion of undetermined significance, atypia).
nate cytology, reported as ‘‘follicular neoplasm’’ or ‘‘Hu ¨rthle
cell neoplasm’’ can be found in 15–30% of FNA specimens (4)
and carries a 20–30% risk of malignancy (42), while lesions
reported as atypia or follicular lesion of undetermined signifi-
size (>4cm) (66), older patient age (67), or cytologic features
such as presence of atypia (68) can improve the diagnostic ac-
improve diagnostic accuracy for indeterminate nodules (70–
(galectin-3) to improve preoperative diagnostic accuary for
patients with indeterminate thyroid nodules (69,73,74). Many
of these markers are available for commercial use in reference
laboratories but have not yet been widely applied in clinical
practice. It is likely that some combination of molecular
markers will be used in the future to optimize management of
patients with indeterminate cytology on FNA specimens.
Recently,18FDG-PET scanning has been utilized in an ef-
fort to distinguish those indeterminate nodules that are be-
nignfromthose thatare malignant(75–78).18FDG-PETscans
appear to have relatively high sensitivity for malignancy but
low specificity, but results vary among studies (79).
(a) The use of molecular markers (e.g., BRAF, RAS,
RET=PTC, Pax8-PPARg, or galectin-3) may be consid-
ered for patients with indeterminate cytology on FNA
to help guide management. Recommendation rating: C
(b) The panel cannot recommend for or against routine
clinical use of18FDG-PET scan to improve diagnostic
accuracy of indeterminate thyroid nodules. Recom-
mendation rating: I
If the cytology reading reports a follicular neoplasm, a123I
thyroid scan may be considered, if not already done, es-
pecially if the serum TSH is in the low-normal range. If a
concordant autonomously functioning nodule is not seen,
lobectomy or total thyroidectomy should be considered.
Recommendation rating: C
If the reading is ‘‘suspicious for papillary carcinoma’’ or
‘‘Hu ¨rthle cell neoplasm,’’ a radionuclide scan is not needed,
1174COOPER ET AL.
and either lobectomy or total thyroidectomy is re-
commended, depending on the lesion’s size and other risk
factors. Recommendation rating: A
[A13] Benign cytology.
If the nodule is benign on cytology, further immediate di-
agnostic studies or treatment are not routinely required.
Recommendation rating: A
[A14] How should multinodular thyroid glands or multi-
nodular goiters be evaluated for malignancy?
multiple thyroid nodules have the same risk of malignancy as
those with solitary nodules (18,44). However, one large study
found that a solitary nodule had a higher likelihood of malig-
nancy than did a nonsolitary nodule (p<0.01), although the
risk of malignancy per patient was the same and independent
of the number of nodules (47). A diagnostic US should be
performed to delineate the nodules, but if only the ‘‘dominant’’
(44). Radionuclide scanning should also be considered in pa-
tients with multiple thyroid nodules, if the serum TSH is in the
low or low-normal range, with FNA being reserved for those
nodules that are shown to be hypofunctioning.
(a) In the presence of two or more thyroid nodules >1cm,
those with a suspicious sonographic appearance (see
text and Table 3) should be aspirated preferentially.
Recommendation rating: B
(b) If none of the nodules has a suspicious sonographic
appearance and multiple sonographically similar coa-
lescent nodules with no intervening normal paren-
chyma are present, the likelihood of malignancy is low
and it is reasonable to aspirate the largest nodules only
and observe the others with serial US examinations.
Recommendation rating: C
A low or low-normal serum TSH concentration may sug-
gest the presence of autonomous nodule(s). A technetium
99mTc pertechnetate or123I scan should be performed and
directly compared to the US images to determine func-
tionality of each nodule >1–1.5cm. FNA should then be
considered only for those isofunctioning or nonfunctioning
nodules, among which those with suspicious sonographic
features should be aspirated preferentially. Recommenda-
tion rating: B
[A15] What are the best methods for long-term
follow-up of patients with thyroid nodules?
Thyroid nodules diagnosed as benign require follow-up
because of a low, but not negligible, false-negative rate of up
to 5% with FNA (41,80), which may be even higher with
nodules >4cm (81). While benign nodules may decrease in
size, they often increase in size, albeit slowly (82). One study
of cytologically benign thyroid nodules <2cm followed by
ultrasonography for about 38 months found that the rate of
thyroid nodule growth did not distinguish between benign
and malignant nodules (83).
Nodule growth is not in and of itself pathognomonic of
malignancy,but growth is anindication for repeat biopsy.For
mixed cystic–solid nodules, the indication for repeat biopsy
should be based upon growth of the solid component. For
nodules with benign cytologic results, recent series report
a higher false-negative rate with palpation FNA (1–3%)
(40,84,85) than with US FNA (0.6%) (40). Since the accuracy of
US (30), it is recommended that serial US be used in follow-up
of thyroid nodules to detect clinically significant changes in
however, or the threshold that would require rebiopsy. Some
groupssuggest a15%increaseinnodule volume,whileothers
recommend measuring a changeinthemean nodule diameter
(82,86). One reasonable definition of growth is a 20% increase
in nodule diameter with a minimum increase in two or more
dimensions of at least 2mm. This approximates the 50% in-
crease in nodule volume that was found by Brauer et al.(87) to
be the minimally significant reproducibly recorded change in
nodule size. These authors suggested that only volume
changes of at least 49% or more can be interpreted as nodule
shrinkage or growth and consequently suggest that future
investigations should not describe changes in nodule volume
<50% as significant. A 50% cutoff for nodule volume reduc-
tion or growth, which is used in many studies, appears to
appropriate and safe, since the false-negative rate for malig-
nant thyroid nodules on repeat FNA is low (88,89).
(a) It is recommended that all benign thyroid nodules be
followed with serial US examinations 6–18 months
after the initial FNA. If nodule size is stable (i.e., no
more than a 50% change in volume or <20% increase
in at least two nodule dimensions in solid nodules or
in the solid portion of mixed cystic–solid nodules), the
interval before the next follow-up clinical examination
or US may be longer, e.g., every 3–5 years. Recom-
mendation rating: C
a 20% increase in at least two nodule dimensions with
a minimal increase of 2mm in solid nodules or in the
solid portion of mixed cystic–solid nodules), the FNA
should be repeated, preferably with US guidance. Re-
commendation rating: B
Cystic nodules that are cytologically benign can be moni-
tored for recurrence (fluid reaccumulation) which can be seen
in 60–90% of patients (90,91). For those patients with subse-
quent recurrent symptomatic cystic fluid accumulation,
surgical removal, generally by hemithyroidectomy, or per-
cutaneous ethanol injection (PEI) are both reasonable strate-
gies. Four controlled studies demonstrated a 75–85% success
rate after PEI compared with a 7–38% success rate in controls
treated by simple cyst evacuation or saline injection. Success
was achieved after an average of two PEI treatments. Com-
plications included mild to moderate local pain, flushing,
dizziness, and dysphonia (90–93).
Recurrent cystic thyroid nodules with benign cytology
should be considered for surgical removal or PEI based on
REVISED ATA THYROID CANCER GUIDELINES1175
compressive symptoms and cosmetic concerns. Recom-
mendation rating: B
[A16] What is the role of medical therapy for benign thyroid
Evidence from multiple randomized control trials
that suppressthe serum TSH tosubnormal levels mayresult in
a decrease in nodule size and may prevent the appearance of
intake. Data in iodine-sufficient populations are less compel-
ling (94–96), with large studies suggesting that only about
17–25% of thyroid nodules shrink more than 50% with le-
vothyroxine (LT4) suppression of serum TSH (94–96).
Routine suppression therapy of benign thyroid nodules in
iodine sufficient populations is not recommended. Re-
commendation rating: F
Patients with growing nodules that are benign after repeat
biopsy should be considered for continued monitoring or
intervention with surgery based on symptoms and clinical
concern. There are no data on the use of LT4in this sub-
population of patients. Recommendation rating: I
[A17] How should thyroid nodules in children be man-
Thyroid nodules occur less frequently in children
than in adults. In one study in which approximately 5000
children aged 11–18 years were assessed annually in the
southwestern United States, palpable thyroid nodules oc-
curred in approximately 20 per 1000 children, with an annual
incidence of 7 new cases per 1000 children (97). Some studies
have shown the frequency of malignancy to be higher in
other data have suggested that the frequency of thyroid can-
cer in childhood thyroid nodules is similar to that of adults
of childhood thyroid nodules (99–101).
The diagnostic and therapeutic approach to one or more
in an adult (clinical evaluation, serum TSH, US, FNA).
Recommendation rating: A
[A18] How should thyroid nodules in pregnant women be
It is uncertain if thyroid nodules discovered in
pregnant women are more likely to be malignant than those
found in nonpregnant women (103), since there are no popu-
as for a nonpregnant patient, with the exception that a radio-
nuclide scan is contraindicated. In addition, for patients with
nodules diagnosed as DTC by FNA during pregnancy, delay-
ing surgery until after delivery does not affect outcome (104).
For euthyroid and hypothyroid pregnant women with
thyroid nodules, FNA should be performed. For women
trimester, FNA may be deferred until after pregnancy and
cessation of lactation, when a radionuclide scan can be
performed to evaluate nodule function. Recommendation
If the FNA cytology is consistent with PTC, surgery is re-
commended. However, there is no consensus about whether
surgery should be performed during pregnancy or after de-
livery. To minimize the risk of miscarriage, surgery during
pregnancy should be done in the second trimester before
24 weeks gestation (105). However, PTC discovered during
pregnancy does not behave more aggressively than that di-
agnosed in a similar-aged group of nonpregnant women
(104,106). Aretrospective studyofpregnant womenwithDTC
rates, between women operated on during or after their
pregnancy (104). Further, retrospective data suggest that
treatment delays of less than 1 year from the time of thyroid
Finally, a recent study reported a higher rate of complications
in pregnant women undergoing thyroid surgery compared
with nonpregnant women (108). Some experts recommend
thyroid hormone suppression therapy for pregnant women
with FNA suspicious for or diagnostic of PTC, if surgery is
deferred until the postpartum period (109).
(a) A nodule with cytology indicating PTC discovered early
in pregnancy should be monitored sonographically and
if it grows substantially (as defined above) by 24 weeks
gestation, surgery should be performed at that point.
However, if it remains stable by midgestation or if it is
diagnosed in the second half of pregnancy, surgery may
be performed after delivery. In patients with more ad-
vanced disease, surgery in the second trimester is rea-
sonable. Recommendation rating: C
(b) In pregnant women with FNA that is suspicious for or
diagnostic of PTC, consideration could be given to
administration of LT4therapy to keep the TSH in the
range of 0.1–1mU=L. Recommendation rating: C
[B1] DIFFERENTIATED THYROID CANCER:
INITIAL MANAGEMENT GUIDELINES
epithelial cells, accounts for the vast majority of thyroid can-
cers. Of the differentiated cancers, papillary cancer comprises
about 85%of cases compared to about 10% that have follicular
In general, stage for stage, the prognoses of PTC and follicular
of follicular cancer. These are characterized by extensive vas-
cular invasion and invasion into extrathyroidal tissues or
extensive tumor necrosis and=or mitoses. Other poorly dif-
ferentiated aggressive tumor histologies include trabecular,
insular, and solid subtypes (111). In contrast, minimally in-
vasive follicular thyroid cancer, is characterized histologically
by microscopic penetration of the tumor capsule without
vascular invasion, and carries no excess mortality (112–115).
[B2] Goals of initial therapy of DTC
The goals of initial therapy of DTC are follows:
1176 COOPER ET AL.
1. To remove the primary tumor, disease that has ex-
tended beyond the thyroid capsule, and involved cer-
vical lymph nodes. Completeness of surgical resection
is an important determinant of outcome, while residual
metastatic lymph nodes represent the most common
site of disease persistence=recurrence (116–118).
2. To minimize treatment-related morbidity. The extent of
surgery and the experience of the surgeon both play
important roles in determining the risk of surgical
3. To permit accurate staging of the disease. Because dis-
ease staging can assist with initial prognostication,
disease management, and follow-up strategies, accurate
postoperative staging is a crucial element in the man-
agement of patients with DTC (121,122).
4. To facilitate postoperative treatment with radioactive
iodine, where appropriate. For patients undergoing RAI
remnant ablation, or RAI treatment of residual or met-
astatic disease, removal of all normal thyroid tissue is
an important element of initial surgery (123). Near total
or total thyroidectomy also may reduce the risk for re-
currence within the contralateral lobe (124).
5. To permit accurate long-term surveillance for disease
recurrence. Both RAI whole-body scanning (WBS) and
measurement of serum Tg are affected by residual
normal thyroid tissue. Where these approaches are
utilized for long-term monitoring, near-total or total-
thyroidectomy is required (125).
6. To minimize the risk of disease recurrence and meta-
static spread. Adequate surgery is the most important
treatment variable influencing prognosis, while radio-
active iodine treatment, TSH suppression, and external
beam irradiation each play adjunctive roles in at least
some patients (125–128).
[B3] What is the role of preoperative staging with diag-
nostic imaging and laboratory tests?
[B4] Neck imaging.
(particularly papillary carcinoma) involves cervical lymph
nodes in 20–50% of patients in most series using standard
pathologic techniques (45,129–132), and may be present even
frequency of micrometastases may approach 90%, depending
on the sensitivityof thedetection method (134,135).However,
the clinical implications of micrometastases are likely less
significant compared to macrometastases. Preoperative US
identifies suspicious cervical adenopathy in 20–31% of cases,
as 20% of patients (138,139). However, preoperative US
identifies only half of the lymph nodes found at surgery, due
to the presence of the overlying thyroid gland (140).
Sonographic features suggestive of abnormal metastatic
lymph nodes include loss of the fatty hilus, a rounded rather
than oval shape, hypoechogenicity, cystic change, calcifica-
tions, and peripheral vascularity. No single sonographic fea-
ture is adequately sensitive for detection of lymph nodes with
metastatic thyroid cancer. A recent study correlated the sono-
graphic features acquired 4 days preoperatively directly with
the histology of 56 cervical lymph nodes. Some of the most
areas (100%), presence of hyperechogenic punctuations re-
Differentiated thyroid carcinoma
presenting either colloid or microcalcifications (100%), and
peripheral vascularity (82%). Of these, the only one with suf-
ficient sensitivity was peripheral vascularity (86%). All of the
others had sensitivities <60% and would not be adequate to
use as single criterion for identification of malignant involve-
ment (140). As shown by earlier studies (141,142), the feature
with the highest sensitivity was absence of a hilus (100%), but
nodes may also be useful for decision-making. Malignant
lymph nodes are much more likely to occur in levels III, IV,
and VI than in level II (140,142). Figure 2 illustrates the delin-
eation of cervical lymph node Levels I through VI.
Confirmation of malignancy in lymph nodes with a sus-
picious sonographic appearance is achieved by US-guided
FNA aspiration for cytology and=ormeasurement ofTg in the
patients with circulating Tg autoantibodies (143,144).
Accurate staging is important in determining the prognosis
and tailoring treatment for patients with DTC. However,
unlike many tumor types, the presence of metastatic disease
does not obviate the need for surgical excision of the primary
tumor in DTC (145). Because metastatic disease may respond
to RAI therapy, removal of the thyroid as well as the primary
tumor and accessible locoregional disease remains an im-
portant component of initial treatment even in metastatic
As US evaluation is uniquely operator dependent, alter-
native imaging procedures may be preferable in some clinical
settings, though the sensitivities of CT, MRI, and PET for the
detection of cervical lymph node metastases are all relatively
low (30–40%) (146). These alternative imaging modalities, as
well as laryngoscopy and endoscopy, may also be useful in
the assessment of large, rapidly growing, or retrosternal or
invasive tumors to assess the involvement of extrathyroidal
Preoperative neck US for the contralateral lobe and cervical
(central and especially lateral neck compartments) lymph
nodes is recommended for all patients undergoing thy-
guided FNA of sonographically suspicious lymph nodes
should be performed to confirm malignancy if this would
change management. Recommendation rating: B
Routine preoperative use of other imaging studies (CT,
[B5] Measurement of serum Tg.
that high preoperative concentrations of serum Tg may pre-
dict a higher sensitivity for postoperative surveillance with
serum Tg (149). Evidence that this impacts patient manage-
ment or outcomes is not yet available.
There is limited evidence
Routine preoperative measurement of serum Tg is not re-
commended. Recommendation rating: E
[B6] What is the appropriate operation for indeterminate
thyroid nodules and DTC?
can include provision of a diagnosis after a nondiagnostic or
The goals of thyroid surgery
REVISED ATA THYROID CANCER GUIDELINES1177
indeterminate biopsy, removal of the thyroid cancer, staging,
and preparation for radioactive ablation and serum Tg moni-
toring. Surgical options to address the primary tumor should
be limited to hemithyroidectomy with or without isthmu-
sectomy, near-total thyroidectomy (removal of all grossly vis-
iblethyroid tissue, leavingonlya smallamount[<1g]oftissue
adjacent to the recurrent laryngeal nerve near the ligament of
Berry), and total thyroidectomy (removal of all grossly visible
thyroid tissue). Subtotal thyroidectomy, leaving >1g of tissue
with the posterior capsule on the uninvolved side, is an inap-
propriate operation for thyroid cancer (150).
[B7] Surgery for a nondiagnostic biopsy, a biopsy suspicious for
papillary cancer or suggestive of ‘‘follicular neoplasm’’ (including
solitary thyroid nodules with an indeterminate (‘‘follicular
neoplasm’’ or Hu ¨rthle cell neoplasm) biopsy, the risk of
malignancy is approximately 20% (151–153). The risk is
higher with large tumors (>4cm), when atypical features
(e.g., cellular pleomorphism) are seen on biopsy, when the
biopsy reading is ‘‘suspicious for papillary carcinoma,’’ in
patients with a family history of thyroid carcinoma, and in
patients with a history of radiation exposure (66,154,155). For
solitary nodules that are repeatedly nondiagnostic on biopsy,
the riskof malignancy is unknown but is probably closer to 5–
For patients with an isolated indeterminate solitary nodule
who prefer a more limited surgical procedure, thyroid lo-
bectomy is the recommended initial surgical approach.
Recommendation rating: C
(a) Because of an increased risk for malignancy, total
thyroidectomy is indicated in patients with indeter-
minate nodules who have large tumors (>4cm), when
marked atypia is seen on biopsy, when the biopsy
reading is ‘‘suspicious for papillary carcinoma,’’ in
patients with a family history of thyroid carcinoma,
and in patients with a history of radiation exposure.
Recommendation rating: A
(b) Patients with indeterminate nodules who have bilat-
eral nodular disease, or those who prefer to undergo
bilateral thyroidectomy to avoid the possibility of re-
quiring a future surgery on the contralateral lobe,
should also undergo total or near-total thyroidectomy.
Recommendation rating: C
[B8] Surgery for a biopsy diagnostic for malignancy.
total or total thyroidectomy is recommended if the primary
thyroid carcinoma is >1cm (156), there are contralateral
Spinal accessory nerve
adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally on
each side by the carotid sheaths. The level II, III, and IV nodes are arrayed along the jugular veins on each side, bordered
anteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes are
bounded superiorly by the level of the hyoid bone, and inferiorly by the cricoid cartilage; levels II and IV are above and below
level III, respectively. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone,
and anterior to the posterior edge of the submandibular gland. Finally, the level V nodes are in the posterior triangle, lateral
to the lateral edge of the sternocleidomastoid muscle. Levels I, II, and V can be further subdivided as noted in the figure. The
inferior extent of level VI is defined as the suprasternal notch. Many authors also include the pretracheal and paratracheal
superior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neck
Lymph node compartments separated into levels and sublevels. Level VI contains the thyroid gland, and the
1178 COOPER ET AL.
thyroid nodules present or regional or distant metastases are
to the head and neck, or the patient has first-degree family
history of DTC. Older age (>45 years) may also be a criterion
for recommending near-total or total thyroidectomy even
with tumors <1–1.5cm, because of higher recurrence rates in
this age group (112,116,122,123,157). Increased extent of pri-
mary surgery may improve survival for high-risk patients
(158–160) and low-risk patients (156). A study of over 50,000
patients with PTC found on multivariate analysis that total
thyroidectomy significantly improved recurrence and sur-
vival rates for tumors >1.0cm (156). When examined sepa-
rately, even patients with 1.0–2.0cm tumors who underwent
lobectomy, had a 24% higher risk of recurrence and a 49%
higher risk of thyroid cancer mortality (p¼0.04 and p<0.04,
respectively). Other studies have also shown that rates of re-
currence are reduced by total or near total thyroidectomy
among low-risk patients (122,161,162).
For patients with thyroid cancer >1cm, the initial surgical
procedure should be a near-total or total thyroidectomy
unless there are contraindications to this surgery. Thyroid
lobectomy alone may be sufficient treatment for small
(<1cm), low-risk, unifocal, intrathyroidal papillary carci-
nomas in the absence of prior head and neck irradiation or
radiologically or clinically involved cervical nodal metas-
tases. Recommendation rating: A
[B9] Lymph node dissection.
tases are present at the time of diagnosis in 20–90% of patients
with papillary carcinoma and a lesser proportion of patients
with other histotypes (129,139). Although PTC lymph node
metastases are reported by some to have no clinically impor-
tant effect on outcome in low risk patients, a study of the
Surveillance, Epidemiology, and End Results (SEER) database
found, among 9904 patients with PTC, that lymph node me-
significantly predicted poor outcome on multivariate analysis
(163). All-cause survival at 14 years was 82% for PTC without
lymph node and 79% with lymph node metastases (p<0.05).
Another recent SEER registry study concluded that cervical
lymph node metastases conferred an independent risk of de-
creased survival, but onlyin patients with follicular cancer and
patients with papillarycanceroverage 45years (164).Also,the
risk of regional recurrence is higher in patients with lymph
node metastases, especially in those patients with multiple
metastases and=or extracapsular nodal extension (165).
In many patients, lymph node metastases in the central
compartment (166) do not appear abnormal preoperatively
with imaging (138) or by inspection at the time of surgery.
Central compartment dissection (therapeutic or prophylactic)
can be achieved with low morbidity in experienced hands
(167–171), and may convert some patients from clinical N0 to
pathologic N1a, upstaging patients over age 45 from Ameri-
can Joint Committee on Cancer (AJCC) stage I to III (172). A
Regional lymph node metas-
recent consensus conference statement discusses the relevant
anatomy of the central neck compartment, delineates the no-
dal subgroups within the central compartment commonly
involved with thyroid cancer, and defines the terminology
relevant to central compartment neck dissection (173).
Comprehensive bilateral central compartment node dis-
section may improve survival compared to historic controls
and reduce risk for nodal recurrence (174). In addition, se-
lective unilateral paratracheal central compartment node
dissection increases the proportion of patients who appear
disease free with unmeasureable Tg levels 6 months after
surgery (175). Other studies of central compartment dissec-
laryngeal nerve injury and transient hypoparathyroidism,
with no reduction in recurrence (176,177). In another study,
comprehensive (bilateral) central compartment dissection
demonstrated higher rates of transient hypoparathyroidism
compared to selective (unilateral) dissection with no reduc-
tion in rates of undetectable or low Tg levels (178). Although
some lymph node metastases may be treated with radioactive
iodine, several treatments may be necessary, depending upon
the histology, size, and number of metastases (179).
(a) Therapeutic central-compartment (level VI) neck dis-
section for patients with clinically involved central or
lateral neck lymph nodes should accompany total
thyroidectomy to provide clearance of disease from the
central neck. Recommendation rating: B
(b) Prophylactic central-compartment
(ipsilateral or bilateral) may be performed in patients
with papillary thyroid carcinoma with clinically unin-
volved central neck lymph nodes, especially for ad-
vanced primary tumors (T3 or T4). Recommendation
(c) Near-total or total thyroidectomy without prophylactic
central neck dissection may be appropriate for small
(T1 or T2), noninvasive, clinically node-negative PTCs
and most follicular cancer. Recommendation rating: C
These recommendations (R27a–c) should be interpreted in
light of available surgical expertise. For patients with small,
risk and benefit may favor simple near-total thyroidectomy
with close intraoperative inspection of the central compart-
ment with compartmental dissection only in the presence of
the chance of future locoregional recurrence, but overall this
approach may be safer in less experienced surgical hands.
Lymphnodes in thelateral neck (compartments II–V),level
VII (anterior mediastinum), and rarely in Level I may also be
involved by thyroid cancer (129,180). For those patients in
whom nodal disease is evident clinically, on preoperative US
and nodal FNA or Tg measurement, or at the time of surgery,
surgical resection may reduce the risk of recurrence and
possibly mortality (56,139,181). Functional compartmental
*R27a, 27b, 27c, and 28 were developed in collaboration with an ad hoc committee of endocrinologists (David S. Cooper, M.D., Richard T.
Kloos, M.D., Susan J. Mandel, M.D., M.P.H., and R. Michael Tuttle, M.D.), otolaryngology-head and neck surgeons (Gregory Randolph, M.D.,
David Steward, M.D., David Terris, M.D. and Ralph Tufano, M.D.), and endocrine surgeons (Sally Carty, M.D., Gerard M. Doherty, M.D.,
Quan-Yang Duh, M.D., and Robert Udelsman, M.D., M.B.A.)
REVISED ATA THYROID CANCER GUIDELINES1179
en-bloc neck dissection is favored over isolated lymphade-
nectomy (‘‘berry picking’’) with limited data suggesting im-
proved mortality (118,182–184).
Therapeutic lateral neck compartmental lymph node dis-
section should be performed for patients with biopsy-
proven metastatic lateral cervical lymphadenopathy.
Recommendation rating: B
[B10] Completion thyroidectomy.
tomy may be necessary when the diagnosis of malignancy is
made following lobectomy for an indeterminate or non-
diagnostic biopsy. Some patients with malignancy may re-
quire completion thyroidectomy
resection of multicentric disease (185), and to allow RAI
therapy. Most (186,187) but not all (185) studies of papillary
cancer have observed a higher rate of cancer in the opposite
lobe when multifocal (two or more foci), as opposed to uni-
focal, disease is present in the ipsilateral lobe. The surgical
risks of two-stage thyroidectomy (lobectomy followed by
completion thyroidectomy) are similar to those of a near-total
or total thyroidectomy (188).
to provide complete
Completion thyroidectomy should be offered to those pa-
tients for whom a near-total or total thyroidectomy would
have been recommended had the diagnosis been available
before the initial surgery. This includes all patients with
thyroid cancer except those with small (<1cm), unifocal,
intrathyroidal, node-negative, low-risk tumors. Ther-
apeutic central neck lymph node dissection should be in-
cluded if the lymph nodes are clinically involved.
Recommendation rating: B
Ablation of the remaining lobe with radioactive iodine has
been used as an alternative to completion thyroidectomy
(189). It is unknown whether this approach results in sim-
iodine ablation in lieu of completion thyroidectomy is not
recommended. Recommendation rating: D
[B11] What is the role of postoperative staging systems
and which should be used?
[B12] The role of postoperative staging.
ing for thyroid cancer, as for other cancer types, is used: 1) to
permit prognostication for an individual patient with DTC;
2) to tailor decisions regarding postoperative adjunctive ther-
patient’s risk for disease recurrence and mortality; 3) to make
decisions regarding the frequency and intensity of follow-up,
risk; and 4) to enable accurate communication regarding a
patient among health care professionals. Staging systems also
allow evaluation of differing therapeutic strategies applied to
comparable groups of patients in clinical studies.
[B13] AJCC=UICC TNM staging.
AJCC=International Union against Cancer (AJCC=UICC)
classification system based on pTNM parameters and age is
recommended for tumors of all types, including thyroid
cancer (121,190), because it provides a useful shorthand
classification is also used for hospital cancer registries and
epidemiologic studies. In thyroid cancer, the AJCC=UICC
stage does not take account of several additional independent
prognostic variables and may risk misclassification of some
patients. Numerous other schemes havebeen developed in an
effort to achieve more accurate risk factor stratification, in-
cluding CAEORTC, AGES, AMES, U of C, MACIS, OSU,
MSKCC, and NTCTCS systems. (107,116,122,159,192–195).
These schemes take into account a number of factors identi-
fied as prognostic for outcome in multivariate analysis of
retrospective studies, with the most predictive factors gener-
ally being regarded as the presence of distant metastases, the
risk factors are weighted differently among these systems
according to their importance in predicting outcome, but no
scheme has demonstrated clear superiority (195). Each of the
schemes allows accurate identification of the majority (70–
85%) of patients at low-risk of mortality (T1–3, M0 patients),
allowing the follow-up and management of these patients to
be less intensive than the higher-risk minority (T4 and M1
patients), who may benefit from a more aggressive manage-
ment strategy (195). Nonetheless, none of the examined
staging classifications is able to account for more than a small
proportion of the uncertainty in either short-term, disease-
specific mortality or the likelihood of remaining disease free
(121,195,196). AJCC=IUCC staging was developed to predict
risk for death, not recurrence. For assessment of risk of re-
currence, a three-level stratification can be used:
Application of the
? Low-risk patients have the following characteristics:
1) no local or distant metastases; 2) all macroscopic tu-
mor has been resected; 3) there is no tumor invasion of
locoregional tissues or structures; 4) the tumor does not
have aggressive histology (e.g., tall cell, insular, colum-
nar cell carcinoma) or vascular invasion; 5) and, if131I is
given, there is no131I uptake outside the thyroid bed on
the first posttreatment whole-body RAI scan (RxWBS)
? Intermediate-risk patients have any of the following:
1) microscopic invasion of tumor into the perithyroidal
soft tissues at initial surgery; 2) cervical lymph node
metastases or131I uptake outside the thyroid bed on the
RxWBS done after thyroid remnant ablation (200,201);
or 3) tumor with aggressive histology or vascular inva-
? High-risk patients have 1) macroscopic tumor invasion,
2) incomplete tumor resection, 3) distant metastases, and
possibly 4) thyroglobulinemia out of proportion to what
is seen on the posttreatment scan (205).
Since initial staging is based on clinico-pathologic factors
that are available shortly after diagnosis and initial therapy,
the AJCC stage of the patient does not change over time.
*See footnote, page 1179.
1180 COOPER ET AL.
However, depending on the clinical course of the disease and
response to therapy, the risk of recurrence and the risk of
death may change over time. Appropriate management re-
quires an ongoing reassessment of the risk of recurrence and
the risk of disease-specific mortality as new data are obtained
during follow-up (206).
Because of its utility in predicting disease mortality, and
its requirement for cancer registries, AJCC=UICC staging
is recommended for all patients with DTC. The use of
postoperative clinico-pathologic staging systems is also re-
commended to improve prognostication and to plan
[B14] What is the role of postoperative RAI remnant
Postoperative RAI remnant ablation is increas-
ingly being used to eliminate the postsurgical thyroid rem-
nant (122). Ablation of the small amount of residual normal
thyroid remaining after total thyroidectomy may facilitate the
and=or RAI WBS. Additionally, the posttherapy scan ob-
tained at the time of remnant ablation may facilitate initial
staging by identifying previously undiagnosed disease, es-
pecially in the lateral neck. Furthermore, from a theoretical
point of view, this first dose of RAI may also be considered
adjuvant therapy because of the potential tumoricidal effect on
persistent thyroid cancer cells remaining after appropriate
surgery in patients at risk for recurrence or disease specific
mortality. Depending on the risk stratification of the indi-
vidual patient, the primary goal of the first dose of RAI after
total thyroidectomy may be 1) remnant ablation (to facilitate
detection of recurrent disease and initial staging), 2) adjuvant
therapy (to decrease risk of recurrence and disease specific
mortality by destroying suspected, but unproven metastatic
disease), or 3) RAI therapy (to treat known persistent disease).
While these three goals are closely interrelated, a clearer un-
derstanding of the specific indications for treatment will im-
prove our ability to select patients most likely to benefit from
RAI after total thyroidectomy, and will also influence our
recommendations regarding choice of administered activity
for individual patients. Supporting the use of RAI as adju-
vant therapy, a number of large, retrospective studies show a
significant reduction in the rates of disease recurrence
Table 4. TNM Classification System for Differentiated Thyroid Carcinoma
Tumor diameter 2cm or smaller
Primary tumor diameter >2 to 4cm
Primary tumor diameter >4cm limited to the thyroid or with minimal extrathyroidal extension
Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea,
esophagus, or recurrent laryngeal nerve
Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
Primary tumor size unknown, but without extrathyroidal invasion
No metastatic nodes
Metastases to level VI (pretracheal, paratracheal, and prelaryngeal=Delphian lymph nodes)
Metastasis to unilateral, bilateral, contralateral cervical or superior mediastinal nodes
Nodes not assessed at surgery
No distant metastases
Distant metastases not assessed
Patient age <45 years
Any T, any N, M0
Any T, any N, M1
Patient age 45 years or older
T1, N0, M0
T2, N0, M0
T3, N0, M0
T1, N1a, M0
T2, N1a, M0
T3, N1a, M0
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, N0
T4a, N1b, M0
T4b, Any N, M0
Any T, Any N, M1
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (435).
REVISED ATA THYROID CANCER GUIDELINES1181
(107,159,160,207) and cause-specific mortality (159,160,207–
209). However, other similar studies show no such benefit, at
least among the majority of patients with PTC, who are at the
lowest risk for mortality (110,122,162,209–212). In those
studies that show benefit, the advantage appears to be re-
stricted to patients with tumors >1.5cm, or with residual
disease following surgery, while lower-risk patients do not
Cancer Treatment Cooperative Study Group (NTCTCSG) re-
port (214) of 2936 patients found after a median follow-up of 3
years, that near-total thyroidectomy followed by RAI therapy
and aggressive thyroid hormone suppression therapy pre-
dicted improved overall survival of patients with NTCTCSG
stage III and IV disease, and was also beneficial for patients
with NTCTCSG stage II disease. No impact of therapy was
observed in patients with stage I disease. It should be noted
that the NTCTCSG staging criteria are similar but not iden-
tical to the AJCC criteria. Thus, older patients with micro-
scopic extrathyroidal extension are stage II in the NTCTCSG
system, but are stage III in the AJCC system. There are recent
data suggesting a benefit of RAI in patients with more
aggressive histologies (215). There are no prospective ran-
domized trials that have addressed this question (209). Un-
fortunately, many clinical circumstances have not been
examined with regard to the efficacy of RAI ablative therapy.
Table 5 presents a framework for deciding whether RAI is
worthwhile, solely based on the AJCC classification, and
provides the rationale for therapy and the strength of existing
evidence for or against treatment.
In addition to the major factors listed in Table 5, several
other histological features may place the patient at higher risk
of local recurrence or metastases than would have been pre-
dicted by the AJCC staging system. These include worrisome
histologic subtypes (such as tall cell, columnar, insular, and
solid variants, aswell aspoorly differentiated thyroid cancer),
the presence of intrathyroidal vascular invasion, or the find-
ing of gross or microscopic multifocal disease. While many of
these features have been associated with increased risk, there
are inadequate data to determine whether RAI ablation has a
benefit based on specific histologic findings, independent of
tumor size, lymph node status, and the age of the patient.
Therefore, while RAI ablation is not recommended for all
patients with these higher risk histologic features, the pres-
ence of these features in combination with size of the tumor,
lymph node status, and patient age may increase the risk of
recurrence or metastatic spread to a degree that is high en-
ough to warrant RAI ablation in selected patients. However,
in the absence of data for most of these factors, clinical judg-
ment must prevail in the decision-making process. For mi-
croscopic multifocal papillary cancer, when all foci are <1cm,
recent data suggest that RAI is of no benefit in preventing
Nonpapillary histologies (such as follicular thyroid cancer
and Hu ¨rthle cell cancer) are generally regarded as higher risk
tumors. Expert opinion supports the use of RAI in almost all
of these cases. However, because of the excellent prognosis
associated with surgical resection alone in small follicular
thyroid cancers manifesting only capsular invasion (without
vascular invasion (so-called ‘‘minimally invasive follicular
cancer’’), RAI ablation may not be required for all patients
with this histological diagnosis (112).
(a) RAI ablation is recommended for all patients with
known distant metastases, gross extrathyroidal exten-
sion of the tumor regardless of tumor size, or primary
tumor size >4cm even in the absence of other higher
risk features (see Table 5 for strength of evidence).
(b) RAI ablation is recommended for selected patients
with 1–4cm thyroid cancers confined to the thyroid,
Table 5. Major Factors Impacting Decision Making in Radioiodine Remnant Ablation
T11cm or less, intrathyroidal or
<45 years old
?45 years old
Any size, any age, minimal
Any size with gross
No metastatic nodes documented
<45 years old
>45 years old
Distant metastasis present
I Selective usea
T4 Yes Yes YesYesB
aBecause of either conflicting or inadequate data, we cannot recommend either for or against RAI ablation for this entire subgroup.
However, selected patients within this subgroup with higher risk features may benefit from RAI ablation (see modifying factors in the text).
1182 COOPER ET AL.
who have documented lymph node metastases, or
other higher risk features (see preceding paragraphs)
when the combination of age, tumor size, lymph node
status, and individual histology predicts an interme-
diate to high risk of recurrence or death from thyroid
cancer (see Table 5 for strength of evidence for indi-
vidual features). Recommendation rating: C (for se-
lective use in higher risk patients)
(c) RAI ablation is not recommended for patients with
unifocal cancer <1cm without other higher risk fea-
tures (see preceding paragraphs). Recommendation
(d) RAI ablation is not recommended for patients with
multifocal cancer when all foci are <1cm in the ab-
sence other higher risk features (see preceding para-
graphs). Recommendation rating: E
[B15] How should patients be prepared for RAI ablation?
(see Fig. 3)
Remnant ablation requires TSH stimulation. No
controlled studies have been performed to assess adequate
levels of endogenous TSH for optimal ablation therapy or
follow-up testing. Noncontrolled studies suggest that a TSH
of >30mU=L is associated with increased RAI uptake in
tumors (218), while studies using single dose exogenous TSH
suggest maximal thyrocyte stimulation at TSH levels between
51 and 82mU=L (219, 220). However, the total area under the
TSH curve, and not simply the peak serum TSH concentra-
tion, is also potentially important for optimal RAI uptake by
thyroid follicular cells. Endogenous TSH elevation can be
achieved by two basic approaches to thyroid hormone with-
drawal, stopping LT4and switching to LT3for 2–4 weeks
followed by withdrawal of LT3for 2 weeks, or discontinua-
tion of LT4for 3 weeks without use of LT3. Both methods of
preparation can achieve serum TSH levels >30mU=L in
>90% of patients (220–229). These two approaches have not
been directly compared for efficiency of patient prepara-
tion (efficacy of ablation, iodine uptake, Tg levels, disease
detection), although a recent prospective study showed no
difference in hypothyroid symptoms between these two ap-
proaches (230). Other preparative methods have been pro-
posed, but have not been validated by other investigators
(231,232). Children with thyroid cancer achieve adequate
TSH elevation within 14 days of LT4withdrawal (233). A low
serum Tg level at the time of ablation has excellent negative
predictive value for absence of residual disease, and the risk
of persistent disease increases with higher stimulated Tg
Patients undergoing RAI therapy or diagnostic testing can
be prepared by LT4withdrawal for at least 2–3 weeks or
LT3treatment for 2–4 weeks and LT3withdrawal for 2
weeks with measurement of serum TSH to determine
timing of testing or therapy (TSH >30mU=L). Thyroxine
therapy (with or without LT3for 7–10 days) may be re-
sumed on the second or third day after RAI administration.
Recommendation rating: B
[B16] Can rhTSH (Thyrogen?) be used in lieu of thyroxine
withdrawal for remnant ablation?
those unable to tolerate hypothyroidism or unable to generate
an elevated TSH, remnant ablation can be achieved with
rhTSH (235,236). A prospective randomized study found that
thyroid hormone withdrawal and rhTSH stimulation were
equally effective in preparing patients for131I remnant abla-
tion with 100mCi with significantly improved quality of life
(237). Another randomized study using rhTSH showed that
ablation rates were comparable with 50mCi compared to
100mCi with a significant decrease (33%) in whole-body ir-
rates were similar with either withdrawal or preparation with
rhTSH using 50mCi of131I (239). In addition, short-term re-
currence rates have been found to be similar in patients pre-
pared with thyroid hormone withdrawal or rhTSH (240).
the United States, Europe, and many other countries around
Remnant ablation can be performed following thyroxine
withdrawal or rhTSH stimulation. Recommendation rat-
[B17] Should RAI scanning be performed before RAI abla-
tion? RAI WBS provides information on the presence of io-
dine-avid thyroid tissue, which may represent the normal
thyroid remnant or the presence of residual disease in the
postoperative setting. In the presence of a large thyroid rem-
nant, the scan is dominated by uptake within the remnant,
potentially masking the presence of extrathyroidal disease
within locoregional lymph nodes, the upper mediastinum, or
even at distant sites, reducing the sensitivity of disease de-
pretherapy RAI scans altogether because of its low impact
on the decision to ablate, and because of concerns over131I-
induced stunning of normal thyroid remnants (242) and dis-
tant metastases from thyroid cancer (243). Stunning is defined
as a reduction in uptake of the131I therapy dose induced by a
pretreatment diagnostic activity. Stunning occurs most
prominently with higher activities (5–10mCi) of
with increasing time between the diagnostic dose and therapy
(245), and does not occur if the treatment dose is given within
72 hours of the scanning dose (246). However, the accuracy of
low-activity131I scanshasbeen questioned,andsomeresearch
threshold of visual detection (247). Although comparison
studies show excellent concordance between123I and131I for
administration are not known (248). Furthermore,123I is ex-
pensive, is not universally available, its short half life (t½¼13
hours) makes handling this isotope logistically more difficult
(249), and stunning may also occur though to a lesser degree
than with131I (245). Furthermore, a recent study showed no
difference in ablation rates between patients that had pre-
therapy scans with123I (81%) compared to those who had
received diagnostic scans using 2mCi of131I (74%, p>0.05)
(250). Alternatively, determination of the thyroid bed uptake,
without scanning, can be achieved using 10–100mCi131I.
Pretherapy scans and=or measurement of thyroid bed up-
take may be useful when the extent of the thyroid remnant
cannot be accurately ascertained from the surgical report
or neck ultrasonography, or when the results would alter
REVISED ATA THYROID CANCER GUIDELINES1183
ALGORITHM FOR REMNANT ABLATION:
Initial Follow-Up in Patients with Differentiated Thyroid
Carcinoma in Whom Remnant Ablation is Indicated
One to Three Months after Surgery
Uptake Only in
Final Surgery is a Total or Near-Total Thyroidectomy
Prior to Ablation
Neck USb, CT scan
Consider PET Scan
Surgery if Feasible
Diagnostic WBS Using
rhTSH or THWf
if Expected to Change
rhTSHe or THWf
30–100 mCi 131Ig
5–8 Days Post 131I
rhTSH or THW
100–200 mCi 131I
6–12 Months with
and Neck US
aEBRT, external beam radiotherapy. The usual indication for EBRT is macroscopic unresectable tumor in a patient older
than 45 years; it is not usually recommended for children and adults less than age 45.
bNeck ultrasonography of operated cervical compartments is often compromised for several months after surgery.
cTg, thyroglobulin with anti-thyroglobulin antibody measurement; serum Tg is usually measured by immunometric assay
and may be falsely elevated for several weeks by injury from surgery or by heterophile antibodies, although a very high
serum Tg level after surgery usually indicates residual disease.
dSome clinicians suspect residual disease when malignant lymph nodes, or tumors with aggressive histologies (as defined
in the text) have been resected, or when there is a microscopically positive margin of resection.
erhTSH is recombinant human TSH and is administered as follows: 0.9mg rhTSH i.m. on two consecutive days, followed
by131I therapy on the third day.
fTHW is levothyroxine and=or triiodothyronine withdrawal.
gSee text for exceptions regarding remnant ablation. The smallest amount of
remnant tissue should be used. DxWBS (diagnostic whole-body scintigraphy) is not usually necessary at this point, but may
be performed if the outcome will change the decision to treat with radioiodine and=or the amount of administered activity.
hRxWBS is posttreatment whole-body scan done 5 to 8 days after therapeutic131I administration.
iUptake in the thyroid bed may indicate normal remnant tissue or residual central neck nodal metastases.
Algorithm for initial follow-up of patients with differentiated thyroid carcinoma.
131I necessary to ablate normal thyroid
either the decision to treat or the activity of RAI that is
administered. If performed, pretherapy scans should uti-
lize123I (1.5–3mCi) or low-activity131I (1–3mCi), with the
therapeutic activity optimally administered within 72
hours of the diagnostic activity. Recommendation rating: C
[B18] What activity of
ablation? Successful remnant ablation is usually defined as
an absence of visible RAI uptake on a subsequent diagnostic
RAI scan or an undetectable stimulated serum Tg. Activities
between 30 and 100mCi of131I generally show similar rates of
successful remnant ablation (251–254) and recurrence rates
(213). Although there is a trend toward higher ablation rates
with higher activities (255,256), a recent prospective ran-
domized study found no significant difference in the remnant
ablation rate using 30 or 100mCi of131I (257). Furthermore,
there are data showing that 30mCi is effective in ablating the
remnant with rhTSH preparation (258). In pediatric patients,
it is preferable to adjust the ablation activity according to the
patient’s body weight (259) or surface area (260).
131I should be used for remnant
The minimum activity (30–100mCi) necessary to achieve
successfulremnant ablationshouldbe utilized,particularly
for low-risk patients. Recommendation rating: B
or if there is a more aggressive tumor histology (e.g., tall
cell, insular, columnar cell carcinoma), then higher activi-
ties (100–200mCi) may be appropriate. Recommendation
radiation dose delivered to the thyroid tissue (261). Low-
iodine diets (<50mg=d of dietary iodine) and simple recom-
mendations to avoid iodine contamination have been
recommended prior to RAI therapy (261–263) to increase the
effective radiation dose. A history of possible iodine exposure
(e.g., intravenous contrast, amiodarone use) should be
sought. Measurement of iodine excretion with a spot urinary
iodine determination may be a useful way to identify patients
whose iodine intake could interfere with RAI remnant abla-
tion (263).Information about low-iodine diets canbe obtained
at the Thyroid Cancer Survivors Association website (www.
Isa low-iodinediet necessarybeforeremnant
The efficacy of radioactive iodine depends on the
A low-iodine diet for 1–2 weeks is recommended for pa-
tients undergoing RAI remnant ablation, particularly for
those patients with high iodine intake. Recommendation
[B20] Should a posttherapy scan be performed following
is typically conducted approximately 1 week after RAI ther-
apy to visualize metastases. Additional metastatic foci have
been reported in 10–26% of patients scanned following high-
dose RAI treatment compared with the diagnostic scan
(264,265). The new abnormal uptake was found most often in
the neck, lungs, and mediastinum, and the newly discovered
disease altered the disease stage in approximately 10% of the
patients, affecting clinical management in 9–15% (264–266).
Iodine 131 single photon emission computed tomography
(SPECT)=CT fusion imaging may provide superior lesion lo-
calization after remnant ablation, but it is still a relatively new
imaging modality (267).
A posttherapy scan is recommended following RAI rem-
nant ablation. This is typically done 2–10 days after the
therapeutic dose is administered, although published data
supporting this time interval are lacking. Recommendation
[B21] Postsurgery and RAI therapy
early management of DTC
[B22] What is the role of TSH suppression therapy?
expresses the TSH receptor on the cell membrane and re-
sponds to TSH stimulation by increasing the expression of
several thyroid specific proteins (Tg, sodium-iodide sym-
porter) and by increasing the rates of cell growth (268). Sup-
commonly to treat patients with thyroid cancer in an effort to
decrease the risk of recurrence (127,214,269). A meta-analysis
supported the efficacy of TSH suppression therapy in pre-
venting major adverse clinical events (RR¼0.73; CI¼0.60–
0.88; p<0.05) (269).
[B23] What is the appropriate degree of initial TSH
Retrospective and prospective studies have
demonstrated that TSH suppression to below 0.1mU=L may
improve outcomes in high-risk thyroid cancer patients
(127,270), though no such evidence of benefit has been docu-
mented in low-risk patients. A prospective cohort study (214)
of 2936 patients found that overall survival improved signifi-
cantly when the TSH was suppressed to undetectable levels in
patients withNTCTCSG stageIII orIVdisease and suppressed
to the subnormal to undetectable range in patients with
NTCTCSG stage II disease; however, in the latter group there
was no incremental benefit from suppressing TSH to unde-
tectable levels. Suppression of TSH was not beneficial in pa-
tients with stage I disease. In another study, there was a
positive association between serum TSH levels and the risk for
recurrent disease and cancer-related mortality (271). Adverse
effects of TSH suppression may include the known conse-
quences ofsubclinical thyrotoxicosis,including exacerbationof
angina in patients with ischemic heart disease, increased risk
osteoporosis in postmenopausal women (273).
Initial TSH suppression to below 0.1mU=L is re-
commended for high-risk and intermediate-risk thyroid
cancer patients, while maintenance ofthe TSHat or slightly
below the lower limit of normal (0.1–0.5mU=L) is appro-
priate for low-risk patients. Similar recommendations ap-
ply to low-risk patients who have not undergone remnant
ablation, i.e., serum TSH 0.1–0.5mU=L. Recommendation
REVISED ATA THYROID CANCER GUIDELINES1185
[B24] Is there a role for adjunctive external beam irradiation
[B25] External beam irradiation.
is used infrequently in the management of thyroid cancer
except as a palliative treatment for locally advanced, other-
among patients with locally advanced disease (275,276) and
improved relapse-free and cause-specific survival in patients
over age 60 with extrathyroidal extension but no gross re-
sidual disease (277). It remains unknown whether external
beam radiation might reduce the risk for recurrence in the
neck following adequate primary surgery and=or RAI treat-
ment in patients with aggressive histologic subtypes (278).
External beam irradiation
The use of external beam irradiation to treat the primary
tumor should be considered in patients over age 45 with
grossly visible extrathyroidal extension at the time of sur-
gery and a high likelihood of microscopic residual disease,
and for those patients with gross residual tumor in whom
further surgery or RAI would likely be ineffective. The se-
quence of external beam irradiation and RAI therapy de-
pends on the volume of gross residual disease and the
likelihood of the tumor being RAI responsive. Re-
commendation rating: B
of adjunctive chemotherapy in the management of DTC.
Doxorubicin may act as a radiation sensitizer in some tumors
of thyroid origin (279), and could be considered for patients
with locally advanced disease undergoing external beam ra-
There are no data to support the use
There is no role for the routine adjunctive use of chemo-
therapy in patients with DTC. Recommendation rating: F
[C1] DTC: LONG-TERM MANAGEMENT GUIDELINES
[C2] What are the appropriate features
of long-term management?
Accurate surveillance for possible recurrence in patients
thought to be free of disease is a major goal of long-term
follow-up. Tests with high negative predictive value allow
identification of patients unlikely to experience disease re-
currence, so that less aggressive management strategies can
be used that may be more cost effective and safe. Similarly,
patients with a higher risk of recurrence are monitored more
aggressively because it is believed that early detection of re-
current disease offers the best opportunity for effective
treatment. A large study (280), found that the residual life
span in disease-free patients treated with total or near-total
thyroidectomy and131I for remnant ablation and, in some
cases, high dose131I for residual disease, was similar to that in
the general Dutch population. In contrast, the life expectancy
in the general population but varied widely depending upon
tumor features. Age was not a factor in disease-specific mor-
tality when patients were compared with aged matched in-
dividuals in the Dutch population. Treatment thus appears
safe and does not shorten life expectancy. Although an in-
creased incidence of second tumors in thyroid cancer patients
RAI therapy in low-risk patients did not affect median overall
survival in another (210). Patients with persistent or recurrent
disease are offered treatment to cure or to delay future mor-
palliate by substantially reducing tumor burden or prevent-
ing tumor growth are utilized, with special attention paid to
tumors threatening critical structures.
A second goal of long-term follow-up is to monitor thy-
roxine suppression or replacement therapy, to avoid under-
replacement or overly aggressive therapy (283).
[C3] What is the appropriate method
for following patients after surgery
with or without remnant ablation?
See Fig. 4 for an algorithm for the first 6–12 months of
[C4] What are the criteria for absence of persistent
In patients who have undergone total or near-total
thyroidectomy and thyroid remnant ablation, disease-free
status comprises all of the following:
1) no clinical evidence of tumor,
2) no imaging evidence of tumor (no uptake outside the
thyroid bed on the initial posttreatment WBS, or, if
uptake outside the thyroid bed had been present, no
imaging evidence of tumor on a recent diagnostic scan
and neck US), and
3) undetectable serum Tg levels during TSH suppression
and stimulation in the absence of interfering antibodies.
[C5] What is the role of serum Tg assays in the follow up of
Measurement of serum Tg levels is an important
modality to monitor patients for residual or recurrent disease.
Most laboratories currently use immunometric assays to
measure serum Tg, and it is important that these assays are
calibrated against the CRM-457 international standard. De-
spite improvements in standardization of thyroglobuin as-
says, there is still a twofold difference between some assays
(149), leading to the recommendation that measurements in
individual patients over time be performed in the same assay.
Immunometric assays are prone to interference from Tg
autoantibodies, which commonly cause falsely low serum
Tg measurements. Radioimmunoassays may be less prone
to antibody interference, but are not as widely available,
and their role in the clinical care of patients is uncertain. In
the absence of antibody interference, serum Tg has a high
degree of sensitivity and specificity to detect thyroid cancer,
especially after total thyroidectomy and remnant ablation,
with thehighestdegrees of sensitivity notedfollowing thyroid
Tg measurements obtained during thyroid hormone sup-
pression of TSH, and, less commonly during TSH stimula-
of residual tumor (197,285,286). Conversely, even TSH-
stimulated Tg measurement may fail to identify patients with
clinically significant tumor, due to anti-Tg antibodies or less
commonly to defective or absent production and secretion of
1186 COOPER ET AL.
ALGORITHM for MANAGEMENT of DTC
SIX to TWELVE MONTHS after REMNANT ABLATION
Tg (R43) and Neck US (R48a)
While on T4
US Suspicious for Lymph
Nodes or Nodules >5–8 mm
Biopsy for Cytology
and Tg Wash (R48b/c)
If Negative, Monitor Positive
Tg Ab Neg
rhTSH or THW
(R45b and R48a)
Tg >1 ,
Tg Ab Neg
Tg Ab Pos
RAI WBS (R47)
and Neck US;
(R56, 58, 61, 75)
Neck US (R77)
Consider Surgery, 131I Therapy, EBRT,
Clinical Trial, or Tyrosine Kinase Inhibitor Therapy (R59b, 78b)
aTgAb is anti-thyroglobulin antibody usually measured by immunometric assay.
bHeterophile antibodies may be a cause of falsely elevated serum Tg levels (436,437). The use of heterophile blocking tubes
or heterophile blocking reagents have reduced, but not completely eliminated this problem. Tg that rises with TSH stimu-
lation and falls with TSH suppression is unlikely to result from heterophile antibodies.
cSee text concerning further information regarding levels of Tg at which therapy should be considered.
dTg radioimmunoassay (RIA) may be falsely elevated or suppressed by TgAb. Tg results following TSH stimulation with
rhTSH or thyroid hormone withdrawal are invalidated by TgAb in the serum even when Tg is measured by most RIA tests.
TgAb levels often decline to undetectable levels over years following surgery (306). A rising level of TgAb may be an early
indication of recurrent disease (305).
eSee text for decision regarding surgery versus medical therapy, and surgical approaches to locoregional metastases. FNA
confirmation of malignancy is generally advised. Preoperative chest CT is recommended as distant metastases may change
Longer term follow-up of patients with differentiated thyroid carcinoma.
REVISED ATA THYROID CANCER GUIDELINES1187
immunoreactive Tg by tumor cells (286). Tg levels should be
interpreted in light of the pretest probability of clinically sig-
nificantresidualtumor.An aggressiveorpoorly differentiated
tumor may be present despite low basal or stimulated Tg; in
contrast, a minimally elevated stimulated Tg may occur in
patients at low risk for clinically significant morbidity (287).
in the absence of anti-Tg antibody has an approximately
98–99.5% likelihood of identifying patients completely free of
tumor on follow-up (288,289).
Follow-up of low-risk patients who have undergone total
or near-total thyroidectomy alone without131I remnant ab-
lation or hemithyroidectomy alone may represent a chal-
lenge. A cohort of 80 consecutive patients with very low-risk
papillary thyroid microcarcinoma who had undergone near-
total thyroidectomy without postoperative RAI treatment
was studied over 5 years (290). The rhTSH-stimulated serum
Tg levels were ?1ng=mL in 45 patients (56%) and >1ng=mL
in 35 (44%) patients in whom rhTSH-stimulated Tg levels
were as high as 25ng=mL. The diagnostic WBS (DxWBS)
revealed uptake in the thyroid bed but showed no patho-
logical uptake in any patient, and thyroid bed uptake corre-
lated with the rhTSH-stimulated serum Tg levels (p<0.0001).
Neck ultrasonography identified lymph node metastases
in both Tg-positive and Tg-negative patients. The authors
concluded that for follow-up of this group of patients: 1)
WBS was ineffective in detecting metastases; 2) neck ultra-
sonography as the main surveillance tool was highly sensitive
in detecting node metastases; and 3) detectable rhTSH-
stimulated serum Tg levels mainly depended upon the size of
Initial follow-up for low-risk patients (about 85% of post-
operative patients) who have undergone total or near-total
mainly on TSH-suppressed Tg and cervical US, followed
by TSH-stimulated serum Tg measurements if the TSH-
suppressed Tg testing is undetectable (197,285). However, a
Tg assay with a functional sensitivity of 0.1ng=mL may re-
duce the need to perform TSH-stimulated Tg measurements
during the initial follow-up of some patients. In one study of
this assay, a T4-suppressed serum Tg <0.1ng=mL was only
rarely (2.5%) associated with an rhTSH-stimulated Tg
>2ng=mL; however, 61.5% of the patients had baseline Tg
residual tumor(291). In anotherstudy of thesame assay (292),
a TSH-suppressed serum Tg level was >0.1ng=mL in 14% of
patients, but the false-positive rate was 35% using an rhTSH-
stimulated Tg cutoff of >2ng=mL, raising the possibility of
unnecessary testing and treatment. The only prospective
study also documented increased sensitivity of detection of
disease at the expense of reduced specificity (293).
Approximately 20% of patients who are clinically free of
disease with serum Tg levels <1ng=mL during thyroid hor-
mone suppression of TSH (285) will have a serum Tg level
>2ng=mL after rhTSH or thyroid hormone withdrawal at 12
months after initial therapy with surgery and RAI. In this pa-
tient population, one thirdwill have identification ofpersistent
or recurrent disease and of increasing Tg levels, and the other
two thirds will remain free of clinical disease and will have
There is good evidence that a Tg cutoff level above 2ng=mL
following rhTSH stimulation is highly sensitive in identifying
131I remnant ablation should be based
patients with persistent tumor (285,295–300). However, the
results of serum Tg measurements made on the same serum
specimen differ among assay methods (149). Therefore, the Tg
cutoff may differ significantly among medical centers and
laboratories. Further, the clinical significance of minimally
detectable Tg levels is unclear, especially if only detected fol-
lowing TSH stimulation. In these patients, the trend in serum
Tg over time will typically identify patients with clinically
significant residual disease. A rising unstimulated or stimu-
lated serum Tg indicates disease that is likely to become clini-
cally apparent (294,301).
The presence of anti-Tg antibodies, which occur in ap-
proximately 25% of thyroid cancer patients (302) and 10% of
the general population (303), will falsely lower serum Tg de-
terminations in immunometric assays (304). The use of re-
controversial (201,304). Serial serum anti-Tg antibody quan-
tification using the same methodology may serve as an im-
precise surrogate marker of residual normal thyroid tissue or
tumor (305, 306).
Serum Tg should be measured every 6–12 months by an
immunometric assay that is calibrated against the CRM-
457 standard. Ideally, serum Tg should be assessed in the
same laboratory and using the same assay, during follow-
up of patients with DTC who have undergone total or near
total thyroidectomy with or without thyroid remnant ab-
lation. Thyroglobulin antibodies should be quantitatively
assessed with every measurement of serum Tg. Recom-
mendation rating: A
who have undergone less than total thyroidectomy, and in
patients who have had a total thyroidectomy but not RAI
ablation. While specific cutoff levels during TSH suppres-
sion or stimulation that optimally distinguish normal re-
sidual thyroid tissue from persistent thyroid cancer are
unknown, rising Tg values over time are suspicious for
(a) In low-risk patients who have had remnant ablation and
negative cervical US and undetectable TSH-suppressed
Tg within the first year after treatment, serum Tg should
be measured after thyroxine withdrawal or rhTSH stim-
ulation approximately 12 months after the ablation to
verify absence of disease. Recommendation rating: A
The timing or necessity of subsequent stimulated testing is
uncertain forthose found tobe freeofdisease, because there is
infrequent benefit in this patient cohort from repeated TSH-
stimulated Tg testing (289).
(b) Low-risk patients who have had remnant abla-
tion, negative cervical US, and undetectable TSH-
stimulated Tg can be followed primarily with yearly
clinical examination and Tg measurements on thyroid
hormone replacement. Recommendation rating: B
1188COOPER ET AL.
[C6]Whatare the roles ofdiagnostic whole-body RAI scans,
US, and other imaging techniques during follow-up of DTC?
[C7] Diagnostic whole-body RAI scans.
issues that affect the use of DxWBS during follow-up: stun-
during follow-up when there is little or no remaining normal
thyroid tissue. Disease not visualized on the DxWBS,
regardless of the activity of131I employed, may occasionally
be visualized on the RxWBS images done after larger, thera-
peutic amounts of131I (285,307–310). Following RAI ablation,
when the posttherapy scan does not reveal uptake outside the
thyroid bed, subsequent DxWBS have low sensitivity and are
usually not necessary in low-risk patients who are clinically
free of residual tumor and have an undetectable serum Tg
level on thyroid hormone and negative cervical US
There are two main
After the first RxWBS performed following RAI remnant
ablation, low-risk patients with an undetectable Tg on
thyroid hormone with negative antithyrogolublin anti-
bodies and a negative US do not require routine DxWBS
during follow-up. Recommendation rating: F
DxWBS, either following thyroid hormone withdrawal
or rhTSH, 6–12 months after remnant ablation may be of
value in the follow-up of patients with high or intermedi-
ate risk of persistent disease (see risk stratification system
under AJCC=UICC TNM staging), but should be done
with123I or low activity131I. Recommendation rating: C
[C8] Cervical ultrasonography.
highly sensitive in the detection of cervical metastases in pa-
tients with DTC (139,290,312). Recent data suggest that
measurement of Tg in the needle washout fluid enhances the
sensitivity of FNA of cervical nodes that are suspicious on US
(313,314). Cervical metastases occasionally may be detected
by neck ultrasonography even when TSH-stimulated serum
Tg levels remain undetectable (201,296).
Cervical ultrasonography is
(a) Following surgery, cervical US to evaluate the thyroid
bed and central and lateral cervical nodal compartments
should be performed at 6–12 months and then periodi-
cally, depending on the patient’s risk for recurrent dis-
ease and Tg status. Recommendation rating: B
(b) If a positive result would change management, ultra-
sonographically suspicious lymph nodes greater than
5–8mm in the smallest diameter should be biopsied for
cytology with Tg measurement in the needle washout
fluid. Recommendation rating: A
(c) Suspicious lymph nodes less than 5–8mm in largest di-
ameter may be followed without biopsy with consider-
ation for intervention if there is growth or if the node
threatens vital structures. Recommendation rating: C
clinical application of18FDG-PET scanning in thyroid cancer
was to localize disease in Tg-positive (>10ng=mL), RAI scan–
negative patients (315). When used for this indication, insur-
For many years, the primary
ance providers have usually required documentation that the
patient had a follicular derived thyroid cancer with sup-
pressed or stimulated Tg >10ng=mL in the setting of a neg-
ative DxWBS. Still, the impact of
biochemical cure, survival, orprogression-free survival inthis
setting are not well defined.
More recently, publications provide data that support the
disease localization in Tg-positive, RAI scan–negative pa-
Current additional clinical uses of
18FDG-PET imaging on
18FDG-PET scanning for indications beyond simple
? Initial staging and follow-up of high-risk patients with
poorly differentiated thyroid cancers unlikely to con-
centrate RAI in order to identify sites of disease that may
be missed with RAI scanning and conventional imaging.
? Initial staging and follow-up of invasive or metastatic
Hu ¨rthle cell carcinoma.
? As a powerful prognostic tool for identifying which
patients with known distant metastases are at highest
risk for disease-specific mortality.
? As a selection tool to identify those patients unlikely to
respond to additional RAI therapy.
? As a measurement of posttreatment response following
external beam irradiation, surgical resection, emboliza-
tion, or systemic therapy.
As can be seen from the list of indications above, low-risk
patients are very unlikely to require18FDG-PET scanning as
part of initial staging or follow-up. Additionally, inflamma-
tory lymph nodes, suture granulomas, and increased muscle
activity are common causes of false-positive
findings. Therefore, cytologic or histologic confirmation is
required before one can be certain that an18FDG-positive le-
sion represents metastatic disease.
The sensitivity of18FDG-PET scanning may be marginally
improved with TSH stimulation (especially in patients with
low Tg values), but the clinical benefit of identifying these
additional small foci is yet to be proven (316).
(d) In addition to its proven role in the localization of
disease in Tg-positive, RAI scan–negative patients,
18FDG-PET scanning may be employed 1) as part of
initial staging in poorly differentiated thyroid cancers
and invasive Hu ¨rthle cell carcinomas, especially those
with other evidence of disease on imaging or because
of elevated serum Tg levels, and 2) as a prognostic tool
in patients with metastatic disease to identify those
patients at highest risk for rapid disease progression
and disease-specific mortality, 3) and as an evaluation
of posttreatment response following systemic or local
therapy of metastatic or locally invasive disease. Re-
commendation rating: C
[C10] What is the role of thyroxine TSH suppression
during thyroid hormone therapy in the long-term follow-up of
A meta-analysis has suggested an association (269)
between thyroid hormone suppression therapy and reduction
of major adverse clinical events. The appropriate degree of
TSH suppression by LT4is still unknown, especially in high-
risk patients rendered free of disease. One study found that a
REVISED ATA THYROID CANCER GUIDELINES1189
a longer relapse-free survival than when serum TSH levels
were always 1mU=L or greater, and that the degree of TSH
suppression was an independent predictor of recurrence in
multivariate analysis (270). Conversely, another large study
found that disease stage, patient age, and131I therapy inde-
pendently predicted disease progression, but that the degree
of TSH suppression did not (127). A third study showed that
during LT4therapy the mean Tg levels were significantly
higher when TSH levels were normal than when TSH levels
were suppressed (<0.5mU=L) but only in patients with local
or distant relapse (317). A fourth study of 2936 patients found
that overall survival improved significantly when the TSH
was suppressed to <0.1mU=L in patients with NTCTCSG
stage III or IV disease and to 0.1 to about 0.5 range in patients
with NTCTCSG stage II disease; however, there was no in-
patientswith stageI disease(214).Anotherrecentstudy found
that a serum TSH threshold of 2mU=L differentiated best be-
related mortality (271). No prospective studies have been
performed examining the risk of recurrence and death from
thyroid cancer associated with varying serum TSH levels,
based on the criteria for the absence of tumor at 6–12 months
postsurgery and RAI ablation outlined above in [C3].
(a) In patients with persistent disease, the serum TSH
should be maintained below 0.1mU=L indefinitely
in the absence of specific contraindications. Recom-
mendation rating: B
(b) In patients who are clinically and biochemically free
of disease but who presented with high risk disease,
consideration should be given to maintaining TSH-
suppressive therapy to achieve serum TSH levels of
0.1–0.5mU=L for 5–10 years. Recommendation rating: C
(c) In patients free of disease, especially those at low risk for
recurrence, the serum TSH may be kept within the low
normal range (0.3–2mU=L). Recommendation rating: B
(d) In patients who have not undergone remnant ablation
who are clinically free of disease and have undetect-
able suppressed serum Tg and normal neck US, the
serum TSH may be allowed to rise to the low normal
range (0.3–2mU=L). Recommendation rating: C
[C11] What is the most appropriate management
of DTC patients with metastatic disease?
Metastases discovered during follow-up are likely mani-
festations of persistent disease that has survived initial treat-
ment. Some patients will have a reduction in tumor burden
with additional treatments that may offer a survival or palli-
ative benefit (318–322). The preferred hierarchy of treatment
for metastatic disease (in order) is surgical excision of locor-
egional disease in potentially curable patients,131I therapy for
RAI-avid disease, external beam radiation, watchful waiting
with patients with stable or slowly progressive asymptomatic
disease, and experimental trials, especially for patients with
significantly progressive macroscopic refractory disease. Ex-
perimental trials may be tried before external beam radiation
in special circumstances, in part because of the morbidity of
external beam radiation and its relative lack of efficacy. A
small fraction of patients may benefit from radiofrequency
ablation (323), ethanol ablation (324), or chemo-embolization
(325). Additionally, surgical therapy in selected incurable
patients is important to prevent complications in targeted
areas, such as the central nervous system (CNS) and central
neck compartment. Conversely, watchful waiting may be
appropriate for selected patients with stable asymptomatic
local metastatic disease, and most patients with stable
asymptomatic non-CNS distant metastatic disease.
[C12] What is the surgical management of locoregional
lymph nodes and=orsofttissuetumorintheneck) recurrences,
when distant metastases are not present. Approximately one
term follow-up (288). It is not clear that treatment of locor-
egional disease is beneficial in the setting ofuntreatable distant
metastases, except for possible palliation of symptoms or pre-
vention of airway or aerodigestive obstruction. Impalpable
metastatic lymph nodes, visualized on US or other anatomic
imaging modality, that have survived initial
should be considered for resection. Conversely, the benefit to
removing asymptomatic small (<5–8mm) metastatic lymph
nodes towards improving gross clinical disease recurrences or
disease-specific survival is unproven. When surgery is elected,
most surgeons endorse comprehensive or selective ipsilateral
compartmental dissection of previously unexplored compart-
ments with clinically significant persistent or recurrent disease
(i.e., lymph nodes >0.8cm in diameter,) while sparing vital
structures (e.g., ipsilateral central neck dissection [level VI],
selective neck dissection levels II–IV, or modified neck dissec-
tion[levelsII–V sparing the spinalaccessory nerve,the internal
jugular vein, and sternocleidomastoid muscle] (326) as op-
posed to ‘‘berry picking,’’ limited lymph node resection pro-
cedures, or ethanol ablation (324), because microscopic lymph
node metastases are commonly more extensive than would
appear from imaging studies alone (183,327,328). Conversely,
compartmental surgical dissections may not be feasible in the
setting of compartments that have been previously explored
due to extensive scarring, and only a more limited or targeted
lymph node resection may be possible.
and=or central neck dissection, sparing uninvolved
vital structures, should be performed for patients with
persistent or recurrent disease confined to the neck.
Recommendation rating: B
(b) Limited compartmental lateral and=or central com-
partmental neck dissection may be a reasonable
alternative to more extensive comprehensive dissec-
tion for patients with recurrent disease within com-
partments having undergone prior comprehensive
dissection and=or external beam radiotherapy. Re-
commendation rating: C
[C13] What is the surgical management of aerodigestive
For tumors that invade the upper aerodigestive
tract, surgery combined with additional therapy such as131I
and=or external beam radiation is generally advised (329,330).
Patient outcome is related to complete resection of all gross
1190 COOPER ET AL.
disease with the preservation of function, with techniques
ranging from shaving tumor off the trachea or esophagus for
superficial invasion, to more aggressive techniques when the
trachea is more deeply invaded (e.g., direct intraluminal in-
vasion) includingtracheal resectionandanastomosis(331–333)
or laryngopharyngoesophagectomy. Patients who are not
curable may undergo lessaggressive local treatmentin cases of
asphyxia or significant hemoptysis, and as a preliminary step
prior to subsequent radical or palliative treatments (330).
disease is recommended in combination with RAI and=or
external beam radiotherapy. Recommendation rating: B
[C14] What is the nature of RAI therapy for locoregional or
distant metastatic disease?
For regional nodal metastases
discovered on DxWBS, RAI may be employed, although
surgery is typically used in the presence of bulky disease or
disease amenable to surgery found on anatomic imaging such
as US, CT scanning, or MRI. Radioiodine is also used ad-
junctively following surgery for regional nodal disease or
aerodigestive invasion if residual RAI avid disease is present
[C15] Dose and methods of administering131I for locoregional
or metastatic disease. Despite the apparent effectiveness of
131I therapy in many patients, the optimal therapeutic activity
remains uncertain and controversial (334). There are three
approaches to131I therapy: empiric fixed amounts, therapy
determined by the upper bound limit of blood and body
dosimetry, and quantitative tumor dosimetry (335). Dosi-
metric methods are often reserved for patients with distant
metastases or unusual situations such as renal insufficiency
(336,337) or when therapy with rhTSH stimulation is deemed
necessary. Comparison of outcome among these methods
from published series is difficult (334). No prospective ran-
domized trial to address the optimal therapeutic approach
has been published. Arguments in favor of higher activities
cite a positive relationship between the total131I uptake per
tumor mass and outcome (225), while others have not con-
firmed this relationship (338). In the future, the use of123I or
facilitate whole-body and lesional dosimetry (339,340).
The maximum tolerated radiation absorbed dose (MTRD),
commonly defined as 200 rads (cGy) to the blood, is poten-
tially exceeded in a significant number of patients undergoing
empiric treatment with various amounts of131I. In one study
(341) 1–22% of patients treated with131I according to dosim-
etry calculations would have theoretically exceeded the
MTRD had they been empirically treated with 100–300mCi of
131I. Another study (342) found that an empirically adminis-
8–15% ofpatientsyounger thanage70 and22–38% ofpatients
aged 70 years and older. Administering 250mCi empirically
would have exceeded the MTRD in 22% of patients younger
than 70 and 50% of patients 70 and older.
131I activity of 200mCi would exceed the MTRD in
(a) In the treatment of locoregional or metastatic disease,
no recommendation can be made about the superiority
of one method of RAI administration over another
(empiric high dose vs. blood and=or body dosimetry
vs. lesional dosimetry.) Recommendation rating: I
(b) Empirically administered amounts of
200mCi that often potentially exceed the maximum
tolerable tissue dose should be avoided in patients
over age 70 years. Recommendation rating: A
No randomized trial comparing thyroid hormone with-
drawal therapy to rhTSH-mediated therapy for treatment of
metastatic disease has been reported but there is, despite a
growing body of nonrandomized studies regarding this use
(343–352), one small comparative study that showed the radi-
ation dose to metastatic foci is lower with rhTSH than that
following withdrawal (353). Many of these case reports and
series report disease stabilization or improvement in some
patients following rhTSH-mediated131I therapy. The use of
of rapid swelling of metastatic lesions (348,354–356).
There are currently insufficient outcome data to recom-
mend rhTSH-mediated therapy for all patients with meta-
static disease being treated with
Recombinant human TSH–mediated therapy may be in-
dicated in selected patients with underlying comorbidities
making iatrogenic hypothyroidism potentially risky, in
patients with pituitary disease who are unable to raise their
serum TSH, or in patients in whom a delay in therapy
might be deleterious. Such patients should be given the
same or higher activity that would have been given had
they been prepared with hypothyroidism or a dosime-
trically determined activity. Recommendation rating: C
[C16] Use of lithium in131I therapy.
dine release from the thyroid without impairing iodine up-
take, thus enhancing
tumor cells (357). One study (358) found that lithium in-
creased the estimated131I radiation dose in metastatic tumors
an average of more than twofold, but primarily in those tu-
mors that rapidly cleared iodine. On the other hand, another
more recent study was unable to document any clinical ad-
vantage of lithium therapy on outcome in patients with
metastatic disease, despite an increase in RAI uptake in tumor
Lithium inhibits io-
131I retention in normal thyroid and
Since there are no outcome data that demonstrate a better
outcome of patients treated with lithium as an adjunct to
131I therapy, the dataare insufficient torecommend lithium
therapy. Recommendation rating: I
[C17] How should distant metastatic disease to various
organs be treated?
The overall approach to treatment of
distant metastatic thyroid cancer is based upon the following
observations and oncologic principles:
1. Morbidity and mortality are increased in patients with
distant metastases, but individual prognosis depends
REVISED ATA THYROID CANCER GUIDELINES1191
upon factors including histology of the primary tumor,
distribution and number of sites of metastasis (e.g.,
brain, bone, lung), tumor burden, age at diagnosis
of metastases, and
2. Improved survival is associated with responsiveness to
surgery and=or RAI (320,351,360–366).
3. In the absence of demonstrated survival benefit, certain
interventions can provide significant palliation or re-
duce morbidity (325,367–369).
4. In the absence of improved survival, palliative benefit,
or reduced potential morbidity, the value of empiric
therapeutic intervention is significantly limited by the
potential for toxicity.
5. Treatment of a specific metastatic area must be con-
sidered in light of the patient’s performance status and
other sites of disease; e.g., 5–20% of patients with dis-
tant metastases die from progressive cervical disease
6. Longitudinal re-evaluation of patient status and con-
tinuing re-assessment of potential benefit and risk of
intervention is required.
7. The overall poor outcome of patients with radio-
graphically evident or symptomatic metastases that do
not respond to RAI, the complexity of multidisciplinary
treatment considerations and the availability of pro-
spective clinical trials should encourage the clinician to
refer such patients to tertiary centers with particular
18FDG and RAI avidity (320,351,
[C18] Treatment of pulmonary metastases.
ment of the patient with pulmonary metastases, key criteria
for therapeutic decisions include 1) size of metastatic lesions
(macronodular typically detected by chest radiography; mi-
cronodular typically detected by CT; lesions beneath the res-
olution of CT); 2) avidity for RAI and, if applicable, response
to prior RAI therapy; and 3) stability (or lack thereof) of
metastatic lesions. Pulmonary pneumonitis and fibrosis are
rare complications of high-dose radioactive iodine treatment.
Dosimetry studies with a limit of 80mCi whole-body reten-
tion at 48 hours and 200 cGy to the red bone marrow should
be considered in patients with diffuse131I pulmonary uptake
(371). If pulmonary fibrosis is suspected, then appropriate
periodic pulmonary function testing and consultation should
be obtained. The presence ofpulmonary fibrosis maylimit the
ability to further treat metastatic disease with RAI.
In the manage-
Pulmonary micrometastases should be treated with RAI
continues to concentrate RAI and respond clinically, be-
cause the highest rates of complete remission are reported
in these subgroups (360,365,372,373). Recommendation
The selection of RAI activity to administer for pulmonary
by dosimetry to limit whole-body retention to 80mCi at
48 hours and 200cGy to the red bone marrow. Recom-
mendation rating: B
Macronodular pulmonary metastases may also be treated
with RAI if demonstrated to be iodine avid. How many doses
of RAI to give and how often to give it is a decision that must
be individualized based on the disease response to treatment,
the rate of disease progression in between treatments, age of
and the availability of other treatment options including
clinical trials (360,365).
Radioiodine-avid macronodular metastases should be trea-
ted with RAI and treatment should be repeated when ob-
jective benefit is demonstrated (decrease in the size of the
lesions, decreasing Tg), but complete remission is not com-
to administer can be made empirically (100–200mCi) or
body retention to 80mCi at 48 hours and 200cGy to the red
bone marrow. Recommendation rating: B
[C19] Non–RAI-avid pulmonary disease.
no benefit in patients with non–RAI-avid disease. In the
setting of a negative diagnostic RAI scan, micronodular
pulmonary metastases may demonstrate a positive post-
treatment scan and measurable benefit to RAI therapy,
whereas this is unlikely in the setting of macronodular me-
tastases. In one study, administration of 200–300mCi of RAI
to 10 patients with pulmonary macrometastases who had
negative 3mCi diagnostic scans was associated with a five-
fold increase in the median TSH-suppressed Tg, and death
was reported in several patients within 4 years of treatment
(374). Although not specifically limited to pulmonary lesions,
patients with increasing volumes of18FDG-avid disease seen
on PET scans were less likely to respond to RAI and more
likely to die during a 3-year follow-up compared with18FDG-
negative patients (375). Another study found that RAI ther-
apy of metastatic lesions that were positive on18FDG-PET
scanning was of no benefit (376). In other studies of18FDG-
PET imaging, however, insufficient details exist in patients
known to have pulmonary metastases to assess the utility of
this modality to predict treatment response or prognosis
(377). A study (378) that retrospectively examined the clinical
course of 400 thyroid cancer patients with distant metastases
who had undergone
though age, initial tumor stage, histology, Tg level, RAI up-
take, and PET outcomes all correlated with survival by
univariate analysis, only age and PET results were strong
predictors of survival. There were significant inverse rela-
tionships between survival and both the glycolytic rate of the
most active lesion and the number of18FDG-avid lesions. The
study found tumors that did not concentrate18FDG had a
significantly better prognosis after a median follow-up of
about 8 years than did tumors that avidly concentrated
Most studies evaluating systemic therapy for metastatic
disease have focused on patients with pulmonary metastases.
Traditional cytotoxic chemotherapeutic agents, such as
doxorubicin and cisplatin, are generally associated with no
more than 25% partial response rates, complete remission has
been rare, and toxicities from these treatments are consider-
treatment for metastatic thyroid carcinoma approved by the
Radioiodine is of
18FDG-PET scanning found that al-
1192COOPER ET AL.
U.S. Food and Drug Administration, is occasionally effective
when dosed appropriately (60–75mg=m2every 3 weeks)
(380–383), but durable responses are uncommon. Most stud-
ies ofcombination chemotherapy shownoincreased response
over single agent doxorubicin and increased toxicity (384).
Some specialists recommend consideration of single agent
doxorubicin or paclitaxel, or a combination of these agents,
based on limited data in anaplastic thyroid carcinoma (385).
One recent study evaluated the effect of combination che-
motherapy (carboplatinum and epirubicin) under TSH stim-
ulation (endogenous or rhTSH) (386), demonstrating an
overall rate of complete and partial response of 37%. These
data need to be confirmed prior to consideration for general
use. Recently published phase II trials suggest that anti-
angiogenic therapies may produce partial response rates of
up to 31% and stabilize another 40–50% of patients with
progressive metastatic disease (387–391). Clinical benefit
lasting at least 24 weeks was observed in about half of
patients. The orally available anti-angiogenic tyrosine kinase
inhibitors (axitinib, motesanib, and sorafenib) have numerous
common side effects, including hypertension, diarrhea,
fatigue, skin rashes and erythema, and weight loss, and var-
ious drug-specific toxicities have been reported as well. These
side effects, although often mild and responsive to supportive
care measures, justify suggesting that treatment with these
agents should be limited to specialists experienced in their
use. Similar results are also being reported with use of suni-
tinib, but phase II studies are still ongoing. Serum TSH levels
may increase with the use of these agents. Serum TSH should
be monitored, and the thyroxine dose increased as needed.
Multiple other agents are in clinical trials, targeting pathways
involved in angiogenesis, cell cycle regulation, and tumor
If the patient qualifies for a clinical trial, they should con-
sider bypassing traditional chemotherapy and moving di-
rectly to clinical trials. However, often patients cannot
participate in clinical trials because of the time and expense
required, or failure to meet strict eligibility criteria. Most
available trials can be found listed at www.clinicaltrials.
gov, www.nci.nih.gov, www.centerwatch.com, or www.
(a) Evidence of benefit of routine treatment of non–RAI-
avid pulmonary metastases is insufficient to recom-
mend any specific systemic therapy. For many
patients, metastatic disease is slowly progressive and
patients can often be followed conservatively on TSH-
suppressive therapy with minimal evidence of radio-
graphic or symptomatic progression. For selected
patients, however, other treatment options need to be
considered, such as metastasectomy, endobronchial
laser ablation, or external beam radiation for palliation
of symptomatic intrathoracic lesions (e.g., obstructing
or bleeding endobronchial masses), and pleural or
pericardial drainage for symptomatic effusions. Re-
ferral for participation in clinical trials should be con-
sidered. Recommendation rating: C
(b) Referral for participation in clinical trials should be
considered for patients with progressive or symp-
tomatic metastatic disease. For those patients who do
not participate in clinical trials, treatment with tyrosine
kinase inhibitors should be considered. Recommenda-
tion rating: B
[C20] Treatment of bone metastases.
the patient with bone metastases, key criteria for therapeutic
decisions include 1) the presence of or the risk for pathologic
fracture, particularly in a weight-bearing structure; 2) risk for
neurologic compromise from vertebral lesions; 3) presence of
pain; 4) avidity of RAI uptake; and 5) potential significant
In the management of
Complete surgical resection of isolated symptomatic me-
tastases has been associated with improved survival and
should be considered, especially in patients <45 years old
with slowly progressive disease (320,363). Recommenda-
tion rating: B
RAI therapy of iodine-avid bone metastases has been as-
sociated with improved survival and should be employed
(320,365), although RAI is rarely curative. The RAI activity
administered can be given empirically (100–200mCi) or
determined by dosimetry (225). Recommendation rating: B
When skeletal metastatic lesions arise in locations where
acute swelling may produce severe pain, fracture, or neu-
rologic complications, external radiation and the concom-
itant use of glucocorticoids to minimize potential TSH-
induced and=or radiation-related tumor expansion should
be strongly considered (392). Recommendation rating: C
Painful lesions that cannot be resected can also be treated
by several options individually or in combination, includ-
ing RAI, external beam radiotherapy, intra-arterial embo-
lization (325,393), radiofrequency ablation (394), periodic
pamidronate or zoledronate infusions (with monitoring for
development of possible mandibular osteonecrosis) (369),
or verteboplasty orkyphoplasty (395). Whilemany of these
modalities have been shown to relieve bone pain in cancer,
they have not necessarily been reported to have been used
in thyroid cancer patients. Recommendation rating: C
Evidence is insufficient to recommend treatment of
asymptomatic, non–RAI-responsive, stable lesions that do
not threaten nearby critical structures. Recommendation
[C21] Treatment of brain metastases.
ically occur in older patients with more advanced disease and
are associated with a poor prognosis (351). Surgical resection
and external beam radiotherapy traditionally have been the
mainstays of therapy (351,396). There are few data showing
efficacy of RAI.
Brain metastases typ-
Complete surgical resection of CNS metastases should
be considered regardless of RAI avidity, because it is
REVISED ATA THYROID CANCER GUIDELINES1193
associated with significantly longer survival. Recommen-
dation rating: B
CNS lesions that are not amenable to surgery should be
considered for external beam irradiation. Optimally, very
targeted approaches (such as radiosurgery) are employed
to limit the radiation exposure of the surrounding brain
tissue. Whole brain and spine irradiation could be consid-
ered if multiple metastases are present. Recommendation
If CNS metastases do concentrate RAI, then RAI could be
considered. If RAI is being considered, prior external beam
radiotherapy and concomitant glucocorticoid therapy are
strongly recommended to minimize the effects of a poten-
inflammatory effects of the RAI (392). Recommendation
[C22] What is the management of complications
of RAI therapy?
While RAI appears to be a reasonably safe therapy, it is
associated with a cumulative dose-related low risk of early-
and late-onset complications such as salivary gland damage,
dental caries (397), nasolacrimal duct obstruction (398), and
secondary malignancies (157,281,399,400). Therefore, it is
important to ensure that the benefits of RAI therapy, espe-
cially repeated courses, outweigh the potential risks. There is
probably no dose of RAI that is completely safe nor is there
any maximum cumulative dose that could not be used in
selected situations. However, with higher individual and
cumulative doses there are increased risks of side effects as
For acute transient loss of taste or change in taste and sia-
ladentitis, recommended measures to prevent damage to the
salivary glands have included amifostine, hydration, sour
candies, and cholinergic agents (401), but evidence is insuffi-
cient to recommend for or against these modalities. One re-
cent study suggested sour candy may actually increase
salivary gland damage when given within 1 hour of RAI
therapy, as compared to its use until 24 hours posttherapy
(402). For chronic salivary gland complications, such as dry
mouth and dental caries, cholinergic agents may increase
salivary flow (401).
The evidence is insufficient to recommend for or against
the routine use of preventive measures to prevent salivary
gland damage after RAI therapy. Recommendation rating: I
Patients with xerostomia are at increased risk of dental
caries and should discuss preventive strategies with their
dentists. Recommendation rating: C
Surgical correction should be considered for nasolacrimal
outflow obstruction, which often presents as excessive
tearing (epiphora) but also predisposes to infection. Re-
commendation rating: B
[C23] What is the risk of second malignancies and leu-
kemia from RAI therapy?
Most long-term follow-up studies
variably report a very low risk of secondary malignancies
(bone and soft tissue malignancies, including breast, colo-
rectal, kidney, and salivary cancers, and myeloma and leu-
kemia) in long-term survivors (157,281). A meta-analysis of
two large multicenter studies showed that the risk of second
malignancies was significantly increased at 1.19 (95% CI:
1.04–1.36; p<0.010), relative to thyroid cancer survivors not
treated with RAI (403). The risk of leukemia was also signif-
icantly increased in thyroid cancer survivors treated with
RAI, with a relative risk of 2.5 (95% CI: 1.13–5.53; p<0.024)
with an excess absolute risk of 14.4 solid cancers and of 0.8
leukemias per gigabecquerel of131I at 10,000 person-years of
follow-up. Cumulative131I activities above 500–600mCi are
associated with a significant increase in risk. There appears to
be an increased risk of breast cancer in women with thyroid
cancer (281,399,404). It is unclear whether this is due to
screening bias, RAI therapy, or other factors. An elevated risk
of breast cancer with131I was not observed in another study
(282). The use of laxatives may decrease radiation exposure of
the bowel, and vigorous oral hydration will reduce exposure
of the bladder and gonads (15).
Because there is no evidence demonstrating a benefit of
be encouraged to seek age-appropriate screenings for
cancer according to routine health maintenance recom-
mendations. Patients who receive a cumulative131I activity
in excess of 500–600mCi should be advised that they may
have a small excess risk of developing leukemia and solid
tumors in the future. Recommendation rating: C
[C24] What are other risks to the bone marrow from RAI
Published data indicate that when administered
activities are selected to remain below 200cGy to the bone
marrow, minimal transient effects are noted in white blood
cell and platelet counts (371). However, persistent mild dec-
rements in white blood cell count and=or platelets are not
uncommon in patients who have received multiple RAI
therapies. Further, radiation to the bone marrow is impacted
by several factors, including renal function.
Patients receiving therapeutic doses of RAI should have
baseline CBC and assessment of renal function. Recom-
mendation rating: C
[C25] What are the effects of RAI on gonadal function and
in nursing women?
Women about to receive radioactive
iodine therapy should first undergo pregnancy testing. Go-
nadal tissue is exposed to radiation from RAI in the blood,
urine, and feces. Temporary amenorrhea=oligomenorrhea
lasting 4–10 months occurs in 20–27% of menstruating
women after131I therapy for thyroid cancer. Although the
numbers of patients studied are small, long-term rates of in-
1194 COOPER ET AL.
fertility, miscarriage, and fetal malformation do not appear to
be elevated in women after RAI therapy (405–407). One large
retrospective study suggested that pregnancy should be
postponed for 1 year after therapy because of an increase in
miscarriage rate (408), although this was not confirmed in
another similarly designed study (409).Ovarian damagefrom
RAI therapy may result in menopause occurring approxi-
mately 1 year earlier than the general population, but this
result was not associated with cumulative dose administered
or the age at which the therapy was given (410). In men, RAI
therapy may be associated with a temporary reduction in
sperm counts and elevated serum follicle-stimulating hor-
mone (FSH) levels (411,412). Higher cumulative activities
(500–800mCi) in men are associated with an increased risk of
persistent elevationofserum FSHlevels,but fertility andrisks
of miscarriage or congenital abnormalities in subsequent
pregnancies are not changed with moderate RAI activities
(*200mCi) (413,414). Permanent male infertility is unlikely
with a single ablative activity of RAI, but theoretically there
could be cumulative damage with multiple treatments. It has
may receive cumulative RAI activities ?400mCi (412). Go-
nadal radiation exposure is reduced with good hydration,
frequent micturition to empty the bladder, and avoidance of
Women receiving RAI therapy should avoid pregnancy for
6–12 months. Recommendation rating: C
(a) Radioactive iodine should not be given to nursing
women. Depending on the clinical situation, RAI
therapy could be deferred until a time when lactating
women have stopped breast-feeding for at least 6–8
weeks. Recommendation rating: B
(b) Dopaminergic agents might be useful in decreasing
breast exposure in recently lactating women, although
caution should be exercised given the risk of serious
side effects associated with their routine use to sup-
press postpartum lactation. Recommendation rating: C
[C26] What is the management of Tg-positive,
RAI scan–negative patients?
If the unstimulated Tg is or becomes detectable, or in-
creases over time, or if stimulated Tg levels rise to greater
than 2ng=mL, imaging of the neck and chest should be
performed to search for metastatic disease, typically with
neck US and with thin cut (5–7mm) helical chest CT. Iodi-
nated contrast should be avoided if RAI therapy is planned
within the subsequent few months, although intravenous
contrast may aid in identification of cervical and mediastinal
disease. In addition, for patients with a prior history of
metastatic cervical lymph nodes in the anterior compart-
ments, cross-sectional imaging with either neck CT or MRI
should be considered to evaluate the retropharyngeal lymph
nodes that cannot be imaged by sonography. If imaging is
negative for disease that is potentially curable by surgery, or
the serum Tg appears out of proportion to the identified
surgically resectable disease, then whole-body
imaging may be obtained if the stimulated serum Tg is
>10ng=mL. If the18FDG PET scan is negative, then empiric
therapy with RAI (100–200mCi) should be considered to aid
localization or for therapy of surgically incurable disease
(Fig. 5). This approach may identify the location of persistent
disease in approximately 50% of patients (307,416) with a
wide range of reported success. Some investigators have
reported a fall in serum Tg after empiric RAI therapy in
patients with negative DxWBS (417,418), but there is no ev-
idence for improved survival with empiric therapy in this
setting (374,418). On the other hand, Tg levels may decline
without specific therapy during the first years of follow-up
When the RxWBS after empiric131I therapy is negative,
18FDG-PET scanning is indicated if not already obtained. In-
tegrated18FDG-PET=CT is able to improve diagnostic accu-
astudyof40such patients,inwhom PETandCTimageswere
scored blindly, the diagnostic accuracy was 93% for inte-
grated18FDG-PET=CT and 78% for PET alone (p<0.5) (419).
In 74% of the patients with suspicious18FDG foci, integrated
18FDG-PET=CT added relevant information to the side-by-
side interpretation of PET and CT images by precisely local-
izing the lesions.
change of therapy in 48% of the patients. In another study,
patients, including surgery, radiation therapy, or chemo-
therapy (420). The rate of PET scan positivity is low (11–13%)
in patients with stimulated Tg levels <10ng=mL (421,422).
Some have argued that18FDG-PET scanning should be per-
formed prior to empiric RAI therapy (423), since tumors that
(376), and RAI therapy is unlikely to alter the poorer outcome
in such patients (378).
A cutoff value of Tg above which a patient should be
treated with an empiric dose of RAI is difficult to determine,
due in part to the wide variation in available Tg assays (in-
cluding those used in reports suggesting benefit of such
degree of TSH stimulation or suppression. Recent studies
have reported primarily on patients with Tg levels after T4
withdrawal of 10ng=mL or higher, and it has been suggested
that a corresponding level after rhTSH stimulation would be
5ng=mL (308,374,416,418,424). A Tg level that is rising may
warrant greater concern for the need for empiric therapy, al-
though data regarding the appropriate rate of change are
minimal (301). However a detectable but low Tg level at 9–12
months following remnant ablation may not warrant further
18FDG-PET=CT fusion studies led to a
18FDG-PET positive do not generally concentrate RAI
Empiric radioactive iodine therapy (100–200mCi) might be
considered in patients with elevated (Tg levels after T4
withdrawal of 10ng=mL or higher, or a level of 5ng=mL or
higher after rhTSH stimulation) or rising serum Tg levels in
whomimaginghas failedtoreveala potential tumorsource.
If the posttherapy scan is negative, no further RAI therapy
should be administered. Recommendation rating: C
If persistent nonresectable disease is localized after an
empiric dose of RAI, and there is objective evidence of
REVISED ATA THYROID CANCER GUIDELINES1195
ALGORITHM for MANAGEMENT of DTC
TWELVE or more MONTHS after REMNANT ABLATION
Declining Serum Tg or
Tg <1 with Declining
History of Poor
Response to RAI
Bulky Tumor Present
Grade 3 Blood/Bone
Do Not Treat with
Consider Surgery/EBRT/Clinical Trials
Patient Unable to Raise
TSH or Tolerate THW
History of CT Contrast in Past 3–4 Months or of
Other Iodine Contamination
Consider 131I Therapy
with 100 to 150 mCi
1–2 Week Low-
5–8 Day Post Rx WBS Result
Continue 131I if Beneficiald
False Elevation in Serum
Tg or Evidence of
Interference Present b
Empiric 131I Therapy Under Consideration: Evaluate History of Prior Therapy,
Response to Therapy, Confounding Factors, and Current Staging of Patient as
Assessed by Physical Examination, Laboratory Tests, and Imaging Studiesa
131I Therapy with 100 to 150 mCi
when TSH >30 or after rhTSH e
18FDG-PET/CT if Not Done
aEmpiric131I therapy should be done with meticulous patient preparation, including low-iodine diet and, if iodine con-
tamination is a possibility, urinary iodine measurements. If the RxWBS is negative or subsequent follow-up studies show no
therapeutic benefit, further empiric131I should not be administered.
bTg that rises with TSH stimulation and falls with TSH suppression is unlikely to result from heterophile antibodies.
cNational Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0, (http:==ctep.cancer.gov).
dDosimetry could be considered to allow administration of maximum radioiodine activity if the tumor is life-threatening.
eA dose of 200mCi could exceed the maximum tolerable dose in older individuals (see Recommendation 52b).
Considerations for empiric treatment with radioiodine.
1196 COOPER ET AL.
significant tumor reduction, then RAI therapy should be
repeated until the tumor has been eradicated or the tumor
no longer responds to treatment. The risk of repeated
therapeutic doses of RAI must be balanced against uncer-
tain long-term benefits. Recommendation rating: C
In the absence of structurally evident disease, stimulated
<5ng=mL with rhTSH can be followed with continued LT4
therapy alone, reserving additional therapies for those
patients with rising serum Tg levels over time or other
evidence of structural disease progression. Recommenda-
tion rating: C
[C27] What is the management of patients with a negative
(a) If an empiric dose (100–200mCi) of RAI fails to localize
the persistent disease,18FDG-PET=CT scanning should
be considered, especially in patients with unstimulated
serum Tg levels >10–20ng=mL or in those with ag-
gressive histologies, in order to localize metastatic le-
sions that may require treatment or continued close
observation (425,426). Recommendation rating: B
Stimulation with endogenous TSH following thyroxine
withdrawal or rhTSH (316) and CT fusion (427) may mini-
mally enhance the sensitivity and specificity of18FDG-PET
(b) Tg-positive, RxWBS-negative patients with disease
that is incurable with surgery and is structurally evi-
dent or visualized on
managed with thyroid hormone suppression therapy,
external beam radiotherapy, chemotherapy, radio-
frequency ablation, chemo-embolization, or monitor-
ing without additional therapy if stable. Clinical trials
should also be considered. Recommendation rating: C
18FDG-PET=CT scan can be
Tg-positive, RxWBS-negative patients with no structural
evidence of disease can be followed with serial structural
imaging studies and serial Tg measurements, with both
performed more frequently if the Tg level is rising. When
and how often to repeat18FDG-PET=CT imaging in this
setting is less certain. Recommendation rating: C
[C28] What is the role of external beam radiotherapy
in treatment of metastatic disease?
of unresectable gross residual or recurrent cervical disease,
painful bone metastases, or metastatic lesions in critical
locations likely to result in fracture, neurological, or com-
pressive symptoms that are not amenable to surgery (e.g.,
vertebral metastases, CNS metastases, selected mediastinal
or subcarinal lymph nodes, pelvic metastases) (277). Re-
commendation rating: B
[D1] WHAT ARE DIRECTIONS FOR FUTURE RESEARCH?
[D2] Novel therapies and clinical trials
While surgery and the judicious use of RAI, as described in
these guidelines, is sufficient treatment for the majority of
patients with DTC, a minority of these patients experience
progressive, life-threatening growth and metastatic spread of
the disease. The recent explosion of knowledge regarding the
molecular and cellular pathogenesis of cancer has led to the
development of a range of targeted therapies, now undergoing
clinical evaluation. Efficacy has already been demonstrated for
sorafenib, pazopanib, and thalidomide, whereas many others
are in ongoing trials. Randomized phase III trials to demon-
strate improved survival, improved progression free survival,
or superiority of one therapy over another have not been per-
formed, however, and none of these drugs have been specifi-
cally approved for treatment of metastatic thyroid carcinoma.
These therapies can be grouped into a number of categories.
[D3] Inhibitors of oncogenic signaling pathways.
kinase inhibitors of interest in thyroid carcinoma usually target
transmembrane tyrosine kinase receptors that initiate signal-
ing through the MAP kinase pathway. This signaling pathway
is activated in the majority of PTCs. Inhibitors of RET, RAS,
RAF, and MEK kinases target various members of the same
signaling pathway. Several of these agents are in development
with several clinical trials completed or underway. Specific
cancer awaits better understanding of the pathways involved
in initiation of these tumor types, although responses in pa-
tients with these subtypes have been reported in clinical trials.
[D4] Modulators of growth or apoptosis.
of growth and apoptotic pathways are targeted by PPARg
activators, including COX2 inhibitors; rexinoids, which acti-
vate RXR; bortezomib, which inactivates the cancer pro-
teasome; and derivatives of geldanomycin, which target the
agents are available.
[D5] Angiogenesis inhibitors.
dothelial growth factor (VEGF) receptors and other members
limit the growth of cancers by restricting their blood supply.
Many of the kinase inhibitors that have been studied to date
are very potent inhibitors of the tyrosine kinase of the VEGF
receptors. Trials of several of these agents are currently un-
derway in all subtypes of thyroid cancer.
Targeting of vascular en-
sponse to cancer may be achieved by augmenting the activity
of antigen-presenting dendritic cells. This approach has
shown possible benefits in phase I clinical trials, but has not
yet been studied in thyroid cancer. The apparent immuno-
genicity of thyroid cells makes this an attractive approach for
future clinical trials.
Stimulation of the immune re-
[D7] Gene therapy.
strated some efficacy in thyroid cancer cell lines. Approaches
include introducing toxic genes under the control of thyroid-
specific promoters, orrestoration of the p53 tumor suppressor
Preclinical studies have demon-
REVISED ATA THYROID CANCER GUIDELINES1197
gene in anaplastic thyroid cancer cell lines. Problems with
gene delivery limit the clinical utility of these approaches,
which have not yet reached clinical trials in thyroid cancer.
Each of these targeted approaches holds promise for our
future ability to treat patients with life-threatening disease
unresponsive to traditional therapy. In the meantime, for
appropriate patients, entry into one of the available clinical
trials may be an attractive option.
[D8] Better understanding of the long-term risks of RAI
With the more widespread use of RAI in the management
of thyroid cancer, and the normal life expectancy of most
patients with the disease, it is imperative thatwe have a better
understanding of the long-term risks associated with its use.
Research that focuses on how to minimize the impact of RAI
on the salivary glands in order to prevent sialadenitis and
xerostomia would provide a significant benefit to patients. A
better understanding of the long-term effects of RAI on re-
productive issues in men and women is also an important
topic. Finally, while the risk of second malignancies appears
small following the usual activities of RAI used for remnant
ablation, we need better understanding of the long-term risks
for salivary gland tumors, bladder tumors, and colon cancers
when repeated doses of RAI are needed in young patients
who are potentially long-term survivors of thyroid cancer.
[D9] Clinical significance of persistent low
levels of serum Tg
After initial surgery and RAI therapy some patients will
have persistently detectable stimulated serum Tg when eval-
uated 9–12 months later. Most of these patients have stimu-
lated Tg levels in the range of 1–10ng=mL, levels typically
demonstrate a subsequent spontaneous fall in Tg over time,
others remain stable, while still others demonstrate rising Tg
levels. The optimal management of these patients is unknown.
How often should they undergo neck US or stimulated serum
Tg testing? Will sensitive Tg assays combined with neck US
replace stimulation testing? Which (if any) of these patients
should undergo chest CT, PET, or empiric RAI therapy? Can
weimprove our abilitiestopredictand monitorwhich patients
are likely to be harmed by their disease as opposed to those
who will live unaffected by theirs? Does metastatic disease in
small local lymph nodes have the potential to metastasize to
distant sites during observation while on TSH suppression
therapy? The current impetus to test and treat all of these pa-
early treatment of residual disease when treatment is more
likely to be effective, as opposed to less effective treatment
inoperable locations. However, there is no current proof that
aggressive treatment of minimal residual disease improves
about 5% of all PTC patients die of their disease, yet 15–20% of
low-risk PTC patients are likely to have persistent disease
based on persistent measurable Tg with stimulation testing.
[D10] The problem of Tg antibodies
Anti-Tg antibodies are a common clinical problem in
patients with DTC (305). The presence of these antibodies
usually interferes with serum Tg measurement and recovery
assays do not appear to accurately predict this interference
(305,428). Decreasing antibody levels are correlated with
disease (306,429). However, there are clear exceptions to this
‘‘rule.’’ These patients are therefore a challenge to manage or
study because one often can not be certain of their disease
status. This problem limits definitive investigation which, in
turn, hampers development of evidence-based guidelines
the blood may be a sensitive marker for persistent thyroid
cells even in the presence of anti-Tg antibodies (430–432), but
RNA extraction is not well standardized and some studies
question the specificity of this marker (433,434). Future
studies optimizing the measurement of Tg mRNA and per-
haps other thyroid-related substances in blood from DTC
patients with anti-Tg antibodies are needed to better monitor
this challenging subgroup of DTC patients. This goal would
also be enhanced by development of Tg assays that have
limited interference by anti-Tg antibodies and by methods to
clear anti-Tg antibodies prior to Tg measurement.
[D11] Small cervical lymph node metastases
The rates of cervical lymph node metastases generally range
rates in children or when micrometastases are considered. The
location and number of lymph node metastases is often diffi-
cult to identify before, during, or after surgery, especially mi-
crometastases. Although postoperative131I given to ablate the
the most common site of recurrence is in cervical lymph nodes,
which comprise themajority ofallrecurrences. Future research
must consider the dilemma of minimizing iatrogenic patient
harm versus preventing cancer morbidity and (perhaps) mor-
tality. Perhaps techniques will be developed to safely remove
would otherwise progress to overt, clinically significant me-
tastases. Conversely, the clinical significance of very small
(<0.5cm) nodal metastases needs to be clarified by long-term
follow-up studies. Development of a cost-effective method to
determine which metastases can be safely followed without
intervention would be of great benefit.
[D12] Improved risk stratification
Current risk stratification schemes rely almost exclusively
on clinical, pathological, and radiological data obtained dur-
ing theinitial evaluation and therapyof thepatient. However,
none of the commonly used risk stratification schemes ade-
quately incorporate the prognostic implications of the very
detailed pathological descriptions that are provided (e.g.,
various histological subtypes of thyroid cancer, frequent mi-
extension, or capsular invasion) or the molecular character-
istics of the primary tumor. Furthermore, current staging
systems are static representations of the patient at the time of
presentation and are not easily modifiable over time as new
data become available during follow-up. Therefore, a risk
stratification system that incorporates all the important in-
as new data become available would be useful in providing
1198 COOPER ET AL.
ongoing risk assessments that would optimize management
throughout the life of the patient.
The taskforce wishes to thank Ms. Bobbi Smith, Executive
Director, American Thyroid Association, and Ms. Sheri
Slaughter, Assistant to the Taskforce, for their constant help
and support. We also wish to thank Sally Carty, M.D., Quan-
Yang Duh, M.D., Gregory Randolph, M.D., David Steward,
M.D., David Terris, M.D., Ralph Tufano, M.D., and Robert
Udelsman, M.D., for their help in developing recommenda-
tions related to central neck dissection.
goal in providing support for the development of these
guidelines, that they assist in the clinical care of patients, and
share what we believe is current, rational, and optimal med-
ical practice. In some circumstances, it may be apparent that
the level of care recommended may be best provided in lim-
ited centers with specific expertise. Finally, it is not the intent
of these guidelines to replace individual decision making, the
wishes of the patient or family, or clinical judgment.
These guidelines were funded by the American Thyroid
Association without support from any commercial sources.
GMD is a consultant for MedTronic ENT. BRH has received
honoraria from Genzyme and grant=research support from
Veracyte. RTK has received grant=research support from
Genzyme, Bayer-Onyx, Eisai, and Veracyte; is a consultant for
Genzyme, Bayer-Onyx, Abbott, and Veracyte; and is on the
Speakers Bureau for Genzyme and Abbott. He has received no
honoraria for commercial speaking since November 2006 and
the ATA Board of Directors, the ATA Ethics Committee, and
has been without financial compensation. SLL has received
grant=research support from Bayer and is a consultant for
Abbott, Onyx, and Bayer. SJM has received grant=research
support from Veracyte and has been a CME speaker for Gen-
zyme. ELM is on the Speakers Bureau for Genzyme. FP has
received grant=research support from Amgen, Exelixis, and
AstraZeneca and is a consultant and on the Speakers Bureau
for Genzyme. MS has received grant=research support from
Genzyme, Amgen, AstraZeneca, Bayer, Exelixis, and Eisai; is a
is on the Speakers Bureau for Genzyme, AstraZeneca, and
Exelixis. SIS has received grant=research support from Gen-
zyme, Amgen, AstraZeneca, and Eisai; is a consultant for
AstraZeneca, Eisai, Exelixis, Plexxikon, Oxigene, Semalore,
Celgene, and Eli Lily; is on the Speakers Bureau for Genzyme;
and has received honoraria from Abbott. DLS has received
grant=research support from Veracyte, Wyeth, Astra-Zeneca,
and Gyrus. RMT is a consultant for Genzyme, Abbott, and Eli
Lily, and has received honoraria from Genzyme and Abbott.
DSC and BM report that no competing financial interests exist.
1. Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis
M, Clark F, Evans JG, Young E, Bird T, Smith PA 1977 The
spectrum of thyroid disease in a community: the Whick-
ham Survey. Clin Endocrinol (Oxf) 7:481–493.
2. Vander JB, Gaston EA, Dawber TR 1968 The significance of
nontoxic thyroid nodules. Ann Intern Med 69:537–540.
3. Tan GH, Gharib H 1997 Thyroid incidentalomas: manage-
ment approaches to nonpalpable nodules discovered inci-
dentally on thyroid imaging. Ann Intern Med 126:226–231.
4. Hegedus L 2004 Clinical practice. The thyroid nodule. N
Engl J Med 351:1764–1771.
5. Mandel SJ 2004A 64-year-old woman with a thyroid nod-
ule. JAMA 292:2632–2642.
6. Sherman SI 2003 Thyroid carcinoma. Lancet 361:501–511.
7. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ 2009
Cancer statistics, 2009. CA Cancer J Clin. Published online
before print May 27, 2009.
8. Davies L, Welch HG 2006 Increasing incidence of thyroid
cancer in the United States, 1973–2002. JAMA 295:2164–
9. Leenhardt L, Bernier MO, Boin-Pineau MH, Conte DB,
Marechaud R, Niccoli-Sire P, Nocaudie M, Orgiazzi J,
Schlumberger M, We ´meau JL, Che ´rie-Challine L, De Va-
thaire F 2004 Advances in diagnostic practices affect thyroid
cancer incidence in France. Eur J Endocrinol 150:133–139.
10. Singer PA, Cooper DS, Daniels GH, Ladenson PW,
Greenspan FS, Levy EG, Braverman LE, Clark OH,
McDougall IR, Ain KV, Dorfman SG 1996 Treatment
guidelines for patients with thyroid nodules and well-dif-
ferentiated thyroid cancer. American Thyroid Association.
Arch Intern Med 156:2165–2172.
11. American Association of Clinical Endocrinologists 2001
practice: management of thyroid carcinoma. Endocr Pract
12. British Thyroid Association and Royal College of Physi-
cians. 2007 Guidelines for the management of thyroid
cancer, 2ndEdition. www.british-thyroid-association.org.
13. National Comprehensive Cancer Network. 2009 Thyroid
PDF=thyroid.pdf. Accessed January 28, 2009.
14. Pacini F, Schlumberger M, Dralle H, Elisei R, Smit JW,
Wiersinga W 2006 European consensus for the manage-
ment of patients with differentiated thyroid carcinoma of
the follicular epithelium. Eur J Endocrinol 154:787–803.
15. Luster M, Clarke SE, Dietlein M, Lassmann M, Lind P,
Oyen WJ, Tennvall J, Bombardieri E 2008 Guidelines for
radioiodine therapy of differentiated thyroid cancer. Eur J
Nucl Med Mol Imaging 35:1941–1959.
16. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL,
Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM
2006 The American Thyroid Association Guidelines Task-
force. Management guidelines for patients with thyroid nod-
ules and differentiated thyroid cancer. Thyroid 16:109–142.
17. U.S. Preventive Services Task Force Ratings: Strength of
Recommendations and Quality of Evidence. Guide to
Clinical Preventive Services, Third Edition: Periodic Up-
dates, 2000–2003. Agency for Healthcare Research and
Quality, Rockville, MD.
18. Marqusee E, Benson CB, Frates MC, Doubilet PM, Larsen
PR, Cibas ES, Mandel SJ 2000 Usefulness of ultrasonogra-
phy in the management of nodular thyroid disease. Ann
Intern Med 1339:696–700.
19. Hagag P, Strauss S, Weiss M 1998 Role of ultrasound-
guided fine-needle aspiration biopsy in evaluation of non-
palpable thyroid nodules. Thyroid 8:989–995.
REVISED ATA THYROID CANCER GUIDELINES 1199
20. Are C, Hsu JF, Ghossein RA, Schoder H, Shah JP, Shaha AR
2007 Histological aggressiveness of fluorodeoxyglucose
positron-emission tomogram (FDG-PET)-detected inciden-
tal thyroid carcinomas. Ann Surg Oncol 14:3210–3215.
21. Bogsrud TV, Karantanis D, Nathan MA, Mullan BP, Wi-
seman GA, Collins DA, Kasperbauer JL, Strome SE, Read-
ing CC, Hay ID, Lowe VJ 2007 The value of quantifying
18F-FDG uptake in thyroid nodules found incidentally on
whole-body PET-CT. Nucl Med Commun 28:373–381.
22. Kang KW, Kim SK, Kang HS, Lee ES, Sim JS, Lee IG, Jeong
SY, Kim SW 2003 Prevalence and risk of cancer of focal
yglucose positron emission tomography for metastasis
evaluation and cancer screening in healthy subjects. J Clin
Endocrinol Metab 88:4100–4104.
23. Choi JY, Lee KS, Kim HJ, Shim YM, Kwon OJ, Park K, Baek
CH, Chung JH, Lee KH, Kim BT 2006 Focal thyroid lesions
incidentally identified by integrated 18F-FDG PET=CT:
clinical significance and improved characterization. J Nucl
24. Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie ´ G,
Travis LB, Horowitz MM, Witherspoon RP, Hoover RN,
Sobocinski KA, Fraumeni JF, Boice JD, Schoch HG, Sale GE,
Storb R, Travis WD, Kolb HJ, Gale RP, Passweg JR 1997
Solid cancers after bone marrow transplantation. N Engl J
25. Pacini F, Vorontsova T, Demidchik E, Molinaro E, Agate, L,
Romei C, Shavrova E, Cherstvoy ED, Ivashkevitch Y, Ku-
chinskaya E, Schlumberger M, Ronga G, Filesi M, Pinchera
A 1997 Post-Chernobyl thyroid carcinoma in Belarus chil-
dren and adolescents: comparison with naturally occurring
thyroid carcinoma in Italy and France. J Clin Endocrinol
26. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard
MC, Franklyn JA 2006 Serum thyrotropin concentration as
a novel predictor of malignancy in thyroid nodules inves-
tigated by fine-needle aspiration. J Clin Endo Metab
27. Hall TL, Layfield LJ, Philippe A, Rosenthal D 1989 Sources
of diagnostic error in fine needle aspiration of the thyroid.
28. Alexander EK, Heering JP, Benson CB, Frates MC, Doubilet
PM, Cibas ES, Marqusee E 2002 Assessment of non-
diagnostic ultrasound-guided fine needle aspiration of
thyroid nodules. J Clin Endocrinol Metab 87:4924–4927.
29. Brander A, Viikinkoski P, Tuuhea J, Voutilainen L, Kivi-
saari L 1992 Clinical versus ultrasound examination of the
thyroid gland in common clinical practice. J Clin Ultra-
30. Tan GH, Gharib H, Reading CC 1995 Solitary thyroid
nodule. Arch Intern Med 155:2418–2423.
31. Singh B, Shaha AR, Trivedi H, Carew JF, Poluri A, Shah JP
1999 Coexistent Hashimoto’s thyroiditis with papillary
thyroid carcinoma: impact on presentation, management,
and outcome. Surgery 126:1070–1077.
32. Repplinger D, Bargren A, Zhang YW, Adler JT, Haymart
M, Chen H 2008 Is Hashimoto’s thyroiditis a risk factor for
papillary thyroid cancer? J Surg Res 150:49–52.
33. Pacini F, Pinchera A, Giani C, Grasso L, Doveri F, Baschieri
L 1980. Serum thyroglobulin in thyroid carcinoma and
other thyroid disorders. J Endocrinol Invest 3:283–292.
34. Elisei R, Bottici V, Luchetti F, Di Coscio G, Romei C, Grasso
L, Miccoli P, Iacconi P, Basolo F, Pinchera A, Pacini F 2004
Impact of routine measurement of serum calcitonin on the
diagnosis and outcome of medullary thyroid cancer: ex-
perience in 10,864 patients with nodular thyroid disorders.
J Clin Endocrinol Metab 89:163–168.
35. Hahm JR, Lee MS, Min YK, Lee MK, Kim KW, Nam SJ,
Yang JH, Chung JH 2001 Routine measurement of serum
calcitonin is useful for early detection of medullary thyroid
carcinoma in patients with nodular thyroid diseases.
36. Niccoli P, Wion-Barbot N, Caron P, Henry JF, de Micco C,
Saint Andre JP, Bigorgne JC, Modigliani E, Conte-Devolx B
1997 Interest of routine measurement of serum calcitonin:
study in a large series of thyroidectomized patients. The
French Medullary Study Group. J Clin Endocrinol Metab
37. Costante G, Meringolo D, Durante C, Bianchi D, Nocera M,
Tumino S Crocetti U, Attard M, Maranghi M, Torlontano
M, Filetti S 2007 Predictive value of serum calcitonin levels
for preoperative diagnosis of medullary thyroid carcinoma
in a cohort of 5817 consecutive patients with thyroid nod-
ules. J Clin Endocrinol Metab 92:450–455.
38. Cheung K, Roman SA, Wang TS, Walker HD, Sosa JA 2008
Calcitonin measurement in the evaluation of thyroid nod-
ules in the United States: a cost-effectiveness and decision
analysis. J Clin Endocrinol Metab 93:2173–2180.
39. Gagel RF, Hoff AO, Cote GJ 2005 Medullary thyroid car-
cinoma. In Werner and Ingbar’s The Thyroid. Lippincott
Williams and Wilkins, Philadelphia, pp 967–988.
40. Danese D, Sciacchitano S, Farsetti A, Andreoli M, Ponte-
corvi A 1998 Diagnostic accuracy of conventional versus
sonography-guided fine-needle aspiration biopsy of thy-
roid nodules. Thyroid 8:15–21.
41. Carmeci C, Jeffrey RB, McDougall IR, Nowels KW, Weigel
RJ 1998 Ultrasound-guided fine-needle aspiration biopsy of
thyroid masses. Thyroid 8:283–289.
42. Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Ran-
dolph G, Vielh P, DeMay RM, Sidawy MK, Frable WJ 2008
Diagnostic terminology and morphologic criteria for cyto-
logic diagnosis of thyroid lesions: a synopsis of the National
Cancer Institute Thyroid Fine-Needle Aspiration State of the
Science Conference. Diagn Cytopathol 36:425–437.
43. Leenhardt L, Hejblum G, Franc B, Fediaevsky LD, Delbot T,
Le Guillouzic D, Me ´ne ´gaux F, Guillausseau C, Hoang C,
Turpin G, Aurengo A 1999 Indications and limits of ultra-
sound-guided cytology in the management of nonpalpable
thyroid nodules. J Clin Endocrinol Metab 84:24–28.
44. Papini E, Guglielmi R, Bianchini A, Crescenzi A, Taccogna
S, Nardi F, Panunzi C, Rinaldi R, Toscano V, Pacella CM
2002 Risk of malignancy in nonpalpable thyroid nodules:
predictive value of ultrasound and color-Doppler features.
J Clin Endocrinol Metab 87:1941–1946.
45. Nam-Goong IS, Kim HY, Gong G, Lee HK, Hong SJ, Kim
WB, Shong YK 2004 Ultrasonography-guided fine-needle
aspiration of thyroid incidentaloma: correlation with
pathological findings. Clin Endocrinol (Oxf) 60:21–28.
46. Cappelli C, Castellano M, Pirola I, Cumetti D, Agosti B,
Gandossi E, Agabiti Rosei E 2007 The predictive value of
ultrasound findings in the management of thyroid nodules.
47. Frates MC, Benson CB, Doubilet PM, Kunreuther E, Con-
treras M, Cibas ES, Orcutt J, Moore FD Jr, Larsen PR,
Marqusee E, Alexander EK 2006 Prevalence and distribu-
tion of carcinoma in patients with solitary and multiple
thyroid nodules on sonography. J Clin Endocrinol Metab
1200 COOPER ET AL.
48. Moon WJ, Jung SL, Lee JH, Na DG, Baek JH, Lee YH, Kim J,
Kim HS, Byun JS, Lee DH; Thyroid Study Group, Korean
Society of Neuro- and Head and Neck Radiology 2008 Be-
nign and malignant thyroid nodules: US differentiation—
multicenter retrospective study. Radiology 247:762–770.
49. Jeh SK, Jung SL, Kim BS, Lee YS 2007 Evaluating the degree
of conformity of papillary carcinoma and follicular carci-
noma to the reported ultrasonographic findings of malig-
nant thyroid tumor. Korean J Radiol 8:192–197.
50. Machens A, Holzhausen HJ, Dralle H 2005 The prognostic
value of primary tumor size in papillary and follicular
thyroid carcinoma. Cancer 103:2269–2273.
51. Moon WJ, Kwag HJ, Na DG 2009 Are there any specific
ultrasound findings of nodular hyperplasia (‘‘leave me
alone’’ lesion) to differentiate it from follicular adenoma?
Acta Radiologica 50:383–388.
52. Bonavita JA, Mayo J, Babb J, Bennett G, Oweity T, Macari
M, Yee J 2009 Pattern recognition of benign nodules at ul-
trasound of the thyroid: which nodules can be left alone?
AJR Am J Roentgenol 193:207–213.
53. Rago T, Santini F, Scutari M, Pinchera A, Vitti P 2007
Elastography: new developments in ultrasound for pre-
dicting malignancy in thyroid nodules. J Clin Endocrinol
54. Noguchi S, Yamashita H, Uchino S, Watanabe S 2008 Pa-
pillary microcarcinoma. World J Surg 32:747–753.
55. Wada N, Duh QY, Sugino K, Iwasaki H, Kameyama K,
Mimura T, Ito K, Takami H, Takanashi Y 2003 Lymph
node metastasis from 259 papillary thyroid microcarci-
nomas: frequency, pattern of occurrence and recurrence,
and optimal strategy for neck dissection. Ann Surg 237:
56. Ito Y, Tomoda C, Uruno T, Takamura Y, Miya A, Ko-
bayashi K, Matsuzuka F, Kuma K, Miyauchi A 2004 Pre-
operative ultrasonographic examination for lymph node
metastasis: usefulness when designing lymph node dis-
section for papillary microcarcinoma of the thyroid. World
J Surg 28:498–501.
57. Hemminki K, Eng C, Chen B 2005 Familial risks for non-
medullary thyroid cancer. J Clin Endocrinol Metab
58. Schneider AB, Ron E, Lubin J, Stovall M, Gierlowski TC
1993 Dose-response relationships for radiation-induced
thyroid cancer and thyroid nodules: evidence for the pro-
longed effects of radiation on the thyroid. J Clin Endocrinol
59. Shibata Y, Yamashita S, Masyakin VB, Panasyuk GD, Na-
gataki S 2001 15 years after Chernobyl: new evidence of
thyroid cancer. Lancet 358:1965–1966.
60. Braga M, Cavalcanti TC, Collaco LM, Graf H 2001 Efficacy
of ultrasound-guided fine-needle aspiration biopsy in the
diagnosis of complex thyroid nodules. J Clin Endocrinol
61. Redman R, Zalaznick H, Mazzaferri EL, Massoll NA 2006
The impact of assessing specimen adequacy and number of
needle passes for fine-needle aspiration biopsy of thyroid
nodules. Thyroid 16:55–60.
62. Baloch ZW, Tam D, Langer J, Mandel S, LiVolsi VA, Gupta
PK 2000 Ultrasound-guided fine-needle aspiration biopsy
of the thyroid: role of on-site assessment and multiple cy-
tologic preparations. Diagn Cytopathol 23:425–429.
63. de los Santos ET, Keyhani-Rofagha S, Cunningham JJ,
Mazzaferri EL 1990 Cystic thyroid nodules. The dilemma of
malignant lesions. Arch Intern Med 150:1422–1427.
64. Yeh MW, Demircan O, Ituarte P, Clark OH 2004 False-
negative fine-needle aspiration cytology results delay
treatment and adversely affect outcome in patients with
thyroid carcinoma. Thyroid 14:207–215.
65. Gharib H, Goellner JR, Johnson DA 1993 Fine-needle as-
piration cytology of the thyroid. A 12-year experience with
11,000 biopsies. Clin Lab Med 13:699–709.
66. Tuttle RM, Lemar H, Burch HB 1998 Clinical features as-
sociated with an increased risk of thyroid malignancy in
patients with follicular neoplasia by fine-needle aspiration.
67. Tyler DS, Winchester DJ, Caraway NP, Hickey RC, Evans
DB 1994 Indeterminate fine-needle aspiration biopsy of the
thyroid: identification of subgroups at high risk for inva-
sive carcinoma. Surgery 116:1054–1060.
68. Kelman AS, Rathan A, Leibowitz J, Burstein DE, Haber RS
2001 Thyroid cytology and the risk of malignancy in thy-
roid nodules: importance of nuclear atypia in indetermi-
nate specimens. Thyroid 11:271–277.
69. Bartolazzi A, Orlandi F, Saggiorato E, Volante M, Arecco F,
Rossetto R, Palestini N, Ghigo E, Papotti M, Bussolati G,
Martegani MP, Pantellini F, Carpi A, Giovagnoli MR,
Monti S, Toscano V, Sciacchitano S, Pennelli GM, Mian C,
Pelizzo MR, Rugge M, Troncone G, Palombini L, Chiap-
petta G, Botti G, Vecchione A, Bellocco R; Italian Thyroid
Cancer Study Group (ITCSG) 2008 Galectin-3-expression
analysis in the surgical selection of follicular thyroid nod-
ules with indeterminate fine-needle aspiration cytology: a
prospective multicentre study. Lancet Oncol 9:543–549.
70. Segev DL, Clark DP, Zeiger MA, Umbricht C 2003 Beyond
the suspicious thyroid fine needle aspirate. A review. Acta
71. Haugen BR, Woodmansee WW, McDermott MT 2002
Towards improving the utility of fine-needle aspiration
biopsy for the diagnosis of thyroid tumors. Clin Endo 56:
72. Sapio MR, Posca D, Raggioli A, Guerra A, Marotta V,
Deandrea M, Motta M, Limone PP, Troncone G, Caleo A,
Rossi G, Fenzi G, Vitale M 2007 Detection of RET=PTC,
TRK and BRAF mutations in preoperative diagnosis of
thyroid nodules with indeterminate cytological findings.
Clin Endocrinol (Oxf) 66:678–683.
73. Nikiforov YE, Nikiforov YE, Steward DL, Robinson-Smith
TM, Haugen BR, Klopper JP, Zhu Z, Fagin JA, Falciglia M,
Weber K, Nikiforova MN 2009 Molecular testing for mu-
tations in improving the fine-needle aspiration diagnosis of
thyroid nodules. J Clin Endocrinol Metab 94:2092–2098.
74. Franco C, Martı ´nez V, Allamand JP, Medina F, Glasinovic
A, Osorio M, Schachter D 2009 Molecular markers in thy-
roid fine-needle aspiration biopsy: a prospective study.
Appl Immunohistochem Mol Morphol 17:211–215.
75. Mitchell JC, Grant F, Evenson AR, Parker JA, Hasselgren
PO, Parangi S 2005. Preoperative evaluation of thyroid
nodules with 18FDG-PET=CT. Surgery 138:1166–1174;
76. de Geus-Oei LF, Pieters GF, Bonenkamp JJ, Mudde AH,
Bleeker-Rovers CP, Corstens FH, Oyen WJ 2006 18F-FDG
PET reduces unnecessary hemithyroidectomies for thyroid
nodules with inconclusive cytologic results. J Nucl Med
77. Kim JM, Ryu JS, Kim TY, Kim WB, Kwon GY, Gong G,
Moon DH, Kim SC, Hong SJ, Shong YK 2007 18F-
fluorodeoxyglucose positron emission tomography does
not predict malignancy in thyroid nodules cytologically
REVISED ATA THYROID CANCER GUIDELINES1201
diagnosed as follicular neoplasm. J Clin Endocrinol Metab
78. Sebastianes FM, Cerci JJ, Zanoni PH, Soares J Jr, Chibana
LK, Tomimori EK, de Camargo RY, Izaki M, Giorgi MC,
Eluf-Neto J, Meneghetti JC, Pereira MA 2007 Role of 18F-
fluorodeoxyglucose positron emission tomography in pre-
operative assessment of cytologically indeterminate thyroid
nodules. J Clin Endocrinol Metab 92:4485–4488.
79. Hales NW, Krempl GA, Medina JE 2008 Is there a role
for fluorodeoxyglucose positron emission tomography=
computed tomography in cytologically indeterminate thy-
roid nodules? Am J Otolaryngol 29:113–118.
80. Ylagan LR, Farkas T, Dehner LP 2004 Fine needle aspira-
tion of the thyroid: a cytohistologic correlation and study of
discrepant cases. Thyroid 14:35–41.
81. McCoy KL, Jabbour N, Ogilvie JB, Ohori NP, Carty SE, Yim
JH 2007 The incidence of cancer and rate of false-negative
cytology in thyroid nodules greater than or equal to 4cm in
size. Surgery 142:837–844.
82. Alexander EK, Hurwitz S, Heering JP, Benson CB, Frates
MC, Doubilet PM, Cibas ES, Larsen PR, Marqusee E 2003
Natural history of benign solid and cystic thyroid nodules.
Ann Int Med 138:315–318.
83. Asanuma K, Kobayashi S, Shingu K, Hama Y, Yokoyama S,
Fujimori M, Amano J 2001 The rate of tumour growth does
not distinguish between malignant and benign thyroid
nodules. Eur J Surg 167:102–105.
84. Erdogan MF, Kamel N, Aras D, Akdogan A, Baskal N,
Erdogan G 1998 Value of re-aspirations in benign nodular
thyroid disease. Thyroid 8:1087–1090.
85. Orlandi A, Puscar A, Capriata E, Fideleff H 2005 Repeated
fine-needle aspiration of the thyroid in benign nodular
thyroid disease: critical evaluation of long-term follow-up.
86. Papini E, Petrucci L, Guglielmi R, Panunzi C, Rinaldi R,
Bacci V, Crescenzi A, Nardi F, Fabbrini R, Pacella CM 1998
Long-term changes in nodular goiter: a 5-year prospective
randomized trial of levothyroxine suppressive therapy for
benign cold thyroid nodules. J Clin Endocrinol Metab
87. Brauer VF, Eder P, Miehle K, Wiesner TD, Hasenclever H,
Paschke R 2005 Interobserver variation for ultrasound deter-
mination of thyroid nodule volumes. Thyroid 15:1169–1175.
88. Brander AE, Viikinkoski VP, Nickels JI, Kivisaari LM 2000
Importance of thyroid abnormalities detected at US
screening: a 5-year follow-up. Radiology 215:801–806.
89. Oertel YC, Miyahara-Felipe L, Mendoza MG, Yu K 2007
Value of repeated fine needle aspirations of the thyroid: an
analysis of over ten thousand FNAs. Thyroid 17:1061–1066.
90. Bennedbaek FN, Hegedu ¨s L 2003 Treatment of recurrent
thyroid cysts with ethanol: a randomized double-blind
controlled trial. J Clin Endocrinol Metab 88:5773–5777.
91. Valcavi R, Frasoldati A 2004 Ultrasound-guided percuta-
neous ethanol injection therapy in thyroid cystic nodules.
Endocr Pract 10:269–275.
92. Antonelli A, Campatelli A, Di Vito A, Alberti B, Baldi V,
Salvioni G, Fallahi P, Baschieri L 1994 Comparison between
ethanol sclerotherapy and emptying with injection of saline
in treatment of thyroid cysts. Clin Investig 72:971–974.
93. Verde G, Papini E, Pacella CM, Gallotti C, Delpiano S,
Strada S, Fabbrini R, Bizzarri G, Rinaldi R, Panunzi C, Geili
D 1994 Ultrasound guided percutaneous ethanol injection
in the treatment of cystic thyroid nodules. Clin Endocrinol
94. Zelmanovitz F, Genro S, Gross JL 1998 Suppressive ther-
apy with levothyroxine for solitary thyroid nodules: a
double-blind controlled clinical study and cumulative
meta-analyses. J Clin Endocrinol Metab 83:3881–3885.
95. Wemeau JL, Caron P, Schvartz C, Schlienger JL, Orgiazzi J,
Cousty C, Vlaeminck-Guillem V 2002 Effects of thyroid-
stimulating hormone suppression with levothyroxine in
reducing the volume of solitary thyroid nodules and
improving extranodular nonpalpable changes: a random-
ized, double-blind, placebo-controlled trial by the French
Thyroid Research Group. J Clin Endocrinol Metab 87:4928–
96. Castro MR, Caraballo PJ, Morris JC 2002 Effectiveness of
thyroid hormone suppressive therapy in benign solitary
thyroid nodules: a meta-analysis. J Clin Endocrinol Metab
97. Rallison ML, Dobyns BM, Keating FR Jr, Rall JE, Tyler FH
1975 Thyroid nodularity in children. JAMA 233:1069–1072.
98. Raab SS, Silverman JF, Elsheikh TM, Thomas PA, Wakely
PE 1995 Pediatric thyroid nodules: disease demographics
and clinical management as determined by fine needle as-
piration biopsy. Pediatrics 95:46–49.
99. Corrias A, Einaudi S, Chiorboli E, Weber G, Crino A, An-
dreo M, Cesaretti G, de Sanctis L, Messina MF, Segni M,
Cicchetti M, Vigone M, Pasquino AM, Spera S, de Luca F,
Mussa GC, Bona G 2001 Accuracy of fine needle aspiration
biopsy of thyroid nodules in detecting malignancy in
childhood: comparison with conventional clinical, labora-
tory, and imaging approaches. J Clin Endocrinol Metab
100. Hung W 1999 Solitary thyroid nodules in 93 children and
adolescents, a 35-years experience. Horm Res 52:15–18.
101. Gharib H, Zimmerman D, Goellner JR, Bridley SM, LeBlanc
SM 1995 Fine-needle aspiration biopsy: Use in diagnosis
and management of pediatric thyroid diseases. Endo Pract
102. Arda IS, Yildirim S, Demirhan B, Firat S 2001 Fine needle
aspiration biopsy of thyroid nodules. Arch Dis Child
103. Tan GH, Gharib H, Goellner JR, van Heerden JA, Bahn RS
1996 Management of thyroid nodules in pregnancy. Arch
Intern Med 156:2317–2320.
104. Moosa M, Mazzaferri EL 1997 Outcome of differentiated
thyroid cancer diagnosed in pregnant women. J Clin En-
docrinol Metab 82:2862–2866.
105. Mestman JH, Goodwin TM, Montoro MM 1995 Thyroid
disorders of pregnancy. Endocrinol Metab Clin North Am
106. Herzon FS, Morris DM, Segal MN, Rauch G, Parnell T 1994
Coexistent thyroid cancer and pregnancy. Arch Otolar-
yngol Head Neck Surg 120:1191–1193.
107. Mazzaferri EL, Jhiang SM 1994 Long-term impact of initial
surgical and medical therapy on papillary and follicular
thyroid cancer. Am J Med 97:418–428.
108. Kuy S, Roman SA, Desai R, Sosa JA 2009 Outcomes
following thyroid and parathyroid surgery in pregnant
women. Arch Surg 144:399–406.
109. Rosen IB, Korman M, Walfish PG 1997 Thyroid nodular
disease in pregnancy: current diagnosis and management.
Clin Obstet Gynecol 40:81–89.
110. Hundahl SA, Fleming ID, Fremgen AM, Menck HR 1998 A
National Cancer Data Base report on 53,856 cases of thy-
roid carcinoma treated in the U.S., 1985–1995. Cancer
1202 COOPER ET AL.
111. Volante M, Landolfi S, Chiusa L, Palestini N, Motta M,
Codegone A, Torchio B, Papotti MG 2004 Poorly differen-
tiated carcinomas of the thyroid with trabecular, insular,
and solid patterns: a clinicopathologic study of 183 pa-
tients. Cancer 100:950–957.
112. van Heerden JA, Hay ID, Goellner JR, Salomao D, Ebersold
JR, Bergstralh EJ, Grant CS 1992 Follicular thyroid carci-
noma with capsular invasion alone: a nonthreatening ma-
lignancy. Surgery. 112:1130–6.
113. Sanders LE, Silverman M 1998 Follicular and Hu ¨rthle cell
carcinoma: predicting outcome and directing therapy.
114. Lo CY, Chan WF, Lam KY, Wan KY 2005 Follicular thyroid
carcinoma: the role of histology and staging systems in
predicting survival. Ann Surg 242:708–715.
115. D’Avanzo A, Treseler P, Ituarte PH, Wong M, Streja L,
Greenspan FS, Siperstein AE, Duh QY, Clark OH 2004.
Follicular thyroid carcinoma: histology and prognosis.
116. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS
1993 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; discus-
117. Shah MD, Hall FT, Eski SJ, Witterick IJ, Walfish PG, Free-
man JL 2003 Clinical course of thyroid carcinoma after neck
dissection. Laryngoscope 113:2102–2107.
118. Wang TS, Dubner S, Sznyter LA, Heller KS 2004 Incidence
of metastatic well-differentiated thyroid cancer in cervical
lymph nodes. Arch Otolaryngol Head Neck Surg 130:110–
119. Sosa JA, Bowman HM, Tielsch JM, Powe NR, Gordon TA,
Udelsman R 1998 The importance of surgeon experience for
clinical and economic outcomes from thyroidectomy. Ann
120. Friedman M, Pacella BL, Jr 1990 Total versus subtotal
thyroidectomy. Arguments, approaches, and recommen-
dations. Otolaryngol Clin North Am 23:413–427.
121. Brierley JD, Panzarella T, Tsang RW, Gospodarowicz MK,
O’Sullivan B 1997 A comparison of different staging sys-
tems predictability of patient outcome. Thyroid carcinoma
as an example. Cancer 79:2414–2423.
122. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak
CE, Gorman CA, Maurer MS, McIver B, Mullan BP, Oberg
AL, Powell CC, van Heerden JA, Goellner JR 2002 Papillary
thyroid carcinoma managed at the Mayo Clinic during six
decades (1940–1999): temporal trends in initial therapy and
long-term outcome in 2444 consecutively treated patients.
World J Surg 26:879–885.
123. Lin JD, Chao TC, Huang MJ, Weng HF, Tzen KY 1998 Use
of radioactive iodine for thyroid remnant ablation in well-
differentiated thyroid carcinoma to replace thyroid re-
operation. Am J Clin Oncol 21:77–81.
124. Esnaola NF, Cantor SB, Sherman SI, Lee JE, Evans DB 2001
Optimal treatment strategy in patients with papillary thy-
roid cancer: a decision analysis. Surgery 130:921–930.
125. Mazzaferri EL 1999 An overview of the management of
126. Mazzaferri EL 2000 Long-term outcome of patients with
differentiated thyroid carcinoma: effect of therapy. Endocr
127. Cooper DS, Specker B, Ho M, Sperling M, Ladenson PW,
Ross DS, Ain KB, Bigos ST, Brierley JD, Haugen BR, Klein I,
Robbins J, Sherman SI, Taylor T, Maxon HR 3rd 1998
Thyrotropin suppression and disease progression in pa-
tients with differentiated thyroid cancer: results from the
National Thyroid Cancer Treatment Cooperative Registry.
128. Kim TH, Yang DS, Jung KY, Kim CY, Choi MS 2003 Value
of external irradiation for locally advanced papillary thy-
roid cancer. Int J Radiat Oncol Biol Phys 55:1006–1012.
129. Grebe SK, Hay ID 1996 Thyroid cancer nodal metastases:
biologic significance and therapeutic considerations. Surg
Oncol Clin N Am 5:43–63.
130. Scheumann GF, Gimm O, Wegener G, Hundeshagen H,
Dralle H 1994 Prognostic significance and surgical man-
agement of locoregional lymph node metastases in papil-
lary thyroid cancer. World J Surg 18:559–568.
131. Ito Y, Uruno T, Nakano K, Takamura Y, Miya A, Kobayashi
E, Matsuura N, Kuma K, Miyauchi A 2003 An observation
trial without surgical treatment in patients with papillary
microcarcinoma of the thyroid. Thyroid 13:381–387.
132. Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH 2003
Papillary microcarcinoma of the thyroid-Prognostic signif-
icance of lymph node metastasis and multifocality. Cancer
133. Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold
JR, Bergstralh EJ 1992 Papillary thyroid microcarcinoma: a
study of 535 cases observed in a 50-year period. Surgery
112:1139–1146; discussion 1146–1147.
134. Qubain SW, Nakano S, Baba M, Takao S, Aikou T 2002
Distribution of lymph node micrometastasis in pN0 well-
differentiated thyroid carcinoma. Surgery 131:249–256.
135. Arturi F, Russo D, Giuffrida D, Ippolito A, Perrotti N,
Vigneri R, Filetti S 1997 Early diagnosis by genetic analysis
of differentiated thyroid cancer metastases in small lymph
nodes. J Clin Endocrinol Metab 82:1638–1641.
136. Solorzano CC, Carneiro DM, Ramirez M, Lee TM, Irvin
GL3rd 2004 Surgeon-performed ultrasound in the man-
agement of thyroid malignancy. Am Surg 70:576–580; dis-
137. Shimamoto K, Satake H, Sawaki A, Ishigaki T, Funahashi
H, Imai T 1998 Preoperative staging of thyroid papillary
carcinoma with ultrasonography. Eur J Radiol 29:4–10.
138. Stulak JM, Grant CS, Farley DR, Thompson GB, van
Heerden JA, Hay ID, Reading CC, Charboneau JW 2006
Value of preoperative ultrasonography in the surgical
management of initial and reoperative papillary thyroid
cancer. Arch Surg 141:489–494.
139. Kouvaraki MA, Shapiro SE, Fornage BD, Edeiken-Monro
BS, Sherman SI, Vassilopoulou-Sellin R, Lee JE, Evans DB
2003 Role of preoperative ultrasonography in the surgical
management of patients with thyroid cancer. Surgery
134:946–954; discussion 954–955.
140. Leboulleux S, Girard E, Rose M, Travagli JP, Sabbah N,
Caillou B, Hartl DM, Lassau N, Baudin E, Schlumberger M
2007 Ultrasound criteria of malignancy for cervical lymph
nodes in patients followed up for differentiated thyroid
cancer. J Clin Endocrinol Metab 92:3590–3594.
141. Frasoldati A, Valcavi R 2004 Challenges in neck ultraso-
nography: lymphadenopathy and parathyroid glands. En-
docr Pract 10:261–268.
142. Kuna SK, Bracic I, Tesic V, Kuna K, Herceg GH, Dodig D
2006 Ultrasonographic differentiation of benign from ma-
lignant neck lymphadenopathy in thyroid cancer. J Ultra-
sound Med 25:1531–1537.
REVISED ATA THYROID CANCER GUIDELINES 1203
143. Frasoldati A, Pesenti M, Gallo M, Caroggio A, Salvo D,
Valcavi R 2003 Diagnosis of neck recurrences in patients
with differentiated thyroid carcinoma. Cancer 97:90–96.
144. Boi F, Baghino G, Atzeni F, Lai ML, Faa G, Mariotti S 2006
The diagnostic value for differentiated thyroid carcinoma
metastases of thyroglobulin (Tg) measurement in washout
fluid from fine-needle aspiration biopsy of neck lymph
nodes is maintained in the presence of circulating anti-Tg
antibodies. J Clin Endocrinol Metab 91:1364–1369.
145. Stephenson BM, Wheeler MH, Clark OH 1994 The role of
total thyroidectomy in the management of differentiated
thyroid cancer. Curr Opin Gen Surg 53–59.
146. Jeong HS, Baek CH, Son YI, Choi JY, Kim HJ, Ko YH,
Chung JH, Baek HJ 2006 Integrated 18F-FDG PET=CT for
the initial evaluation of cervical node level of patients with
papillary thyroid carcinoma: comparison with ultrasound
and contrast-enhanced CT. Clin Endocrinol (Oxf) 65:
147. Kresnik E, Gallowitsch HJ, Mikosch P, Stettner H,
Igerc I, Gomez I, Kumnig G, Lind P 2003 Fluorine-18-
fluorodeoxyglucose positron emission tomography in the
preoperative assessment of thyroid nodules in an endemic
goiter area. Surgery 133:294–299.
148. Zbaren P, Becker M, Lang H 1997 Pretherapeutic staging of
hypopharyngeal carcinoma. Clinical findings, computed
tomography, and magnetic resonance imaging compared
with histopathologic evaluation. Arch Otolaryngol Head
Neck Surg 123:908–913.
149. Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S, Lo-
Presti JS 2005 Clinical impact of thyroglobulin (Tg) and Tg
autoantibody method differences on the management of
patients with differentiated thyroid carcinomas. J Clin En-
docrinol Metab 90:5566–5575.
150. Duren M, Yavuz N, Bukey Y, Ozyegin MA, Gundogdu S,
Ac ¸bay O, Hatemi H, Uslu I, Onsel C, Aksoy F, Oz F,
Unal G, Duren E 2000 Impact of initial surgical treatment
on survival of patients with differentiated thyroid cancer:
experience of an endocrine surgery center in an iodine-
deficient region. World J Surg 24:1290–1294.
151. Gharib H, Goellner JR, Zinsmeister AR, Grant CS, Van
Heerden JA 1984. Fine-needle aspiration biopsy of the
thyroid. The problem of suspicious cytologic findings. Ann
Intern Med 101:25–28.
152. Baloch ZW, Fleisher S, LiVolsi VA, Gupta PK 2002 Diag-
nosis of ‘‘follicular neoplasm’’: a gray zone in thyroid fine-
needle aspiration cytology. Diagn Cytopathol 26:41–44.
153. Sclabas GM, Staerkel GA, Shapiro SE, Fornage BD, Sher-
man SI, Vassillopoulou-Sellin R, Lee JE, Evans DB 2003
Fine-needle aspiration of the thyroid and correlation with
histopathology in a contemporary series of 240 patients.
Am J Surg 186:702–709; discussion 709–710.
154. Goldstein RE, Netterville JL, Burkey B, Johnson JE 2002
Implications of follicular neoplasms, atypia, and lesions
suspicious for malignancy diagnosed by fine-needle aspi-
ration of thyroid nodules. Ann Surg 235:656–662.
155. Schlinkert RT, van Heerden JA, Goellner JR, Gharib H,
Smith SL, Rosales RF, Weaver AL 1997 Factors that predict
malignant thyroid lesions when fine-needle aspiration
is ‘‘suspicious for follicular neoplasm’’. Mayo Clin Proc
156. Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester
DP, Talamonti MS, Sturgeon C 2007 Extent of surgery af-
fects survival for papillary thyroid cancer. Ann Surg
157. Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C,
Couette JE, Dondon MG, Abbas MT, Langlois C, Schlum-
berger M 2003 Second primary malignancies in thyroid
cancer patients. Br J Cancer 89:1638–1644.
158. Mazzaferri EL, Young RL 1981 Papillary thyroid carcino-
ma: a 10 year follow-up report of the impact of therapy in
576 patients. Am J Med 70:511–518.
159. DeGroot LJ, Kaplan EL, McCormick M, Straus FH 1990
Natural history, treatment, and course of papillary thyroid
carcinoma. J Clin Endocrinol Metab 71:414–424.
160. Samaan NA, Schultz PN, Hickey RC, Goepfert H, Haynie
TP, Johnston DA, Ordonez NG 1992 The results of various
modalities of treatment of well differentiated thyroid car-
cinomas: a retrospective review of 1599 patients. J Clin
Endocrinol Metab 75:714–720.
161. Shaha AR, Shah JP, Loree TR 1997 Differentiated thyroid
cancer presenting initially with distant metastasis. Am J
162. Sanders LE, Cady B 1998 Differentiated thyroid cancer:
reexamination of risk groups and outcome of treatment.
Arch Surg 133:419–425.
163. Podnos YD, Smith D, Wagman LD, Ellenhorn JD 2005 The
implication of lymph node metastasis on survival in pa-
tients with well-differentiated thyroid cancer. Am Surg
164. Zaydfudim V, Feurer ID, Griffin MR, Phay JE 2008 The
impact of lymph node involvement on survival in patients
with papillary and follicular thyroid carcinoma. Surgery
144:1070–1077; discussion 1077–1078.
165. Leboulleux S, Rubino C, Baudin E, Caillou B, Hartl DM,
Bidart JM, Travagli JP, Schlumberger M 2005 Prognostic
factors for persistent or recurrent disease of papillary thy-
roid carcinoma with neck lymph node metastases and=or
tumor extension beyond the thyroid capsule at initial di-
agnosis. J Clin Endocrinol Metab 90:5723–5729.
166. Robbins KT, Shaha AR, Medina JE, Califano JA, Wolf GT,
Ferlito A, Som PM, Day TA; Committee for Neck Dissec-
tion Classification, American Head and Neck Society 2008
Consensus statement on the classification and terminology
of neck dissection. Arch Otolaryngol Head Neck Surg
167. Olson JA, Jr., DeBenedetti MK, Baumann DS, Wells SA, Jr
1996 Parathyroid autotransplantation during thyroidec-
tomy. Results of long-term follow-up. Ann Surg 223:472–
478; discussion 478–480.
168. Gimm O, Rath FW, Dralle H 1998 Pattern of lymph node
metastases in papillary thyroid carcinoma. Br J Surg
169. Henry JF, Gramatica L, Denizot A, Kvachenyuk A, Puccini
M, Defechereux T 1998 Morbidity of prophylactic lymph
node dissection in the central neck area in patients with
papillary thyroid carcinoma. Langenbecks Arch Surg
170. Cheah WK, Arici C, Ituarte PH, Siperstein AE, Duh QY,
Clark OH 2002 Complications of neck dissection for thy-
roid cancer. World J Surg 26:1013–1016.
171. White ML, Gauger PG, Doherty GM 2007 Central lymph
node dissection in differentiated thyroid cancer. World J
172. Bonnet S, Hartl D, Leboulleux S, Baudin E, Lumbroso JD,
Al Ghuzlan A, Chami L, Schlumberger M, Travagli JP 2009
Prophylactic lymph node dissection for papillary thyroid
cancer less than 2cm: implications for radioiodine treat-
ment. J Clin Endocrinol Metab 94:1162–1167.
1204 COOPER ET AL.
173. The ATA Surgery Working Group 2009 Consensus State-
ment on the Terminology and Classification of Central
Neck Dissection for Thyroid Cancer. Thyroid 19:1153–
174. Tisell LE, Nilsson B, Molne J, Hansson G, Fja ¨lling M,
Jansson S, Wingren U 1996 Improved survival of patients
with papillary thyroid cancer after surgical microdissec-
tion. World J Surg 20:854–859.
175. Sywak M, Cornford L, Roach P, Stalberg P, Sidhu S, Del-
bridge L 2006 Routine ipsilateral level VI lymphade-
nectomy reduces postoperative thyroglobulin levels in
papillary thyroid cancer. Surgery 140:1000–1007.
176. Roh JL, Park JY, Park CI 2007 Total thyroidectomy plus
neck dissection in differentiated papillary thyroid carci-
noma patients: pattern of nodal metastasis, morbidity, re-
currence, and postoperative levels of serum parathyroid
hormone. Ann Surg 245:604–610.
177. Cavicchi O, Piccin O, Caliceti U, De Cataldis A, Pasquali R,
Ceroni AR 2007 Transient hypoparathyroidism following
thyroidectomy: a prospective study and multivariate
analysis of 604 consecutive patients. Otolaryngol Head
Neck Surg 137:654–658.
178. Lee YS, Kim SW, Kim SW, Kim SK, Kang HS, Lee ES,
Chung KW 2007 Extent of routine central lymph node
dissection with small papillary thyroid carcinoma. World J
179. Kozak OV, Muzichenko LV, Trembach AM, Voit NU,
Turicina VV 2006 First treatment activity and outcome of
radioiodine therapy in thyroid cancer patients with me-
tastases in lymph nodes: mathematical correlation and
clinical implications. Exp Oncol 28:75–79.
180. Machens A, Hinze R, Thomusch O, Dralle H 2002 Pattern
of nodal metastasis for primary and reoperative thyroid
cancer. World J Surg 26:22–28.
181. Gemsenjager E, Perren A, Seifert B, Schuler G, Schweizer I,
Heitz PU 2003 Lymph node surgery in papillary thyroid
carcinoma. J Am Coll Surg 197:182–190.
182. Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber
RS 2004 Patterns of lateral neck metastasis in papillary
thyroid carcinoma. Arch Otolaryngol Head Neck Surg
183. Kupferman ME, Patterson DM, Mandel SJ, LiVolsi V, Weber
RS 2004 Safety of modified radical neck dissection for dif-
ferentiated thyroid carcinoma. Laryngoscope 114:403–406.
184. Goropoulos A, Karamoshos K, Christodoulou A, Ntitsias T,
Paulou K, Samaras A, Xirou P, Efstratiou I 2004 Value of
the cervical compartments in the surgical treatment of
papillary thyroid carcinoma. World J Surg 28:1275–1281.
185. Pacini F, Elisei R, Capezzone M, Miccoli P, Molinaro E,
Basolo F, Agate L, Bottici V, Raffaelli M, Pinchera A 2001
Contralateral papillary thyroid cancer is frequent at com-
pletion thyroidectomy with no difference in low- and high-
risk patients. Thyroid 11:877–881.
186. Pasieka JL, Thompson NW, McLeod MK, Burney RE, Ma-
cha M 1992 The incidence of bilateral well-differentiated
thyroid cancer found at completion thyroidectomy. World J
Surg 16:711–716; discussion 716–717.
187. Kim ES, Kim TY, Koh JM, Kim YI, Hong SJ, Kim WB,
Shong YK 2004 Completion thyroidectomy in patients with
thyroid cancer who initially underwent unilateral opera-
tion. Clin Endocrinol (Oxf) 61:145–148.
188. Erdem E, Gulcelik MA, Kuru B, Alagol H 2003 Comparison
of completion thyroidectomy and primary surgery for dif-
ferentiated thyroid carcinoma. Eur J Surg Oncol 29:747–749.
189. Randolph GW, Daniels GH 2002 Radioactive iodine lobe
ablation as an alternative to completion thyroidectomy for
follicular carcinoma of the thyroid. Thyroid 12:989–996.
190. Loh KC, Greenspan FS, Gee L, Miller TR, Yeo PP 1997
Pathological tumor-node-metastasis (pTNM) staging for
papillary and follicular thyroid carcinomas: a retrospective
analysis of 700 patients. J Clin Endocrinol Metab 82:3553–
191. Wittekind C, Compton CC, Greene FL, Sobin LH 2002
192. Byar DP, Green SB, Dor P, Williams ED, Colon J, van Gilse
HA, Mayer M, Sylvester RJ, van Glabbeke M 1979 A
prognostic index for thyroid carcinoma. A study of the
E.O.R.T.C. Thyroid Cancer Cooperative Group. Eur J
193. Cady B, Rossi R 1988 An expanded view of risk-group
definition in differentiated thyroid carcinoma. Surgery
194. Shaha AR, Loree TR, Shah JP 1995 Prognostic factors and
risk group analysis in follicular carcinoma of the thyroid.
Surgery 118:1131–1136; discussion 1136–1138.
195. Sherman SI, Brierley JD, Sperling M, Ain KB, Bigos ST,
Cooper DS, Haugen BR, Ho M, Klein I, Ladenson PW,
Robbins J, Ross DS, Specker B, Taylor T, Maxon HR 3rd
1998 Prospective multicenter study of thyroid carcinoma
treatment: initial analysis of staging and outcome. National
Thyroid Cancer Treatment Cooperative Study Registry
Group. Cancer 83:1012–1021.
196. Eustatia-Rutten CF, Corssmit EP, Biermasz NR, Pereira
AM, Romijn JA, Smit JW 2006 Survival and death causes in
differentiated thyroid carcinoma. J Clin Endocrinol Metab
197. Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F,
Jarzab B, Limbert E, Lind P, Pacini F, Reiners C, Sa ´nchez
Franco F, Toft A, Wiersinga WM 2004 Follow-up of low-
risk patients with differentiated thyroid carcinoma: a Eu-
ropean perspective. Eur J Endocrinol 150:105–112.
198. Toubeau M, Touzery C, Arveux P, Chaplain G, Vaillant G,
Berriolo A, Riedinger JM, Boichot C, Cochet A, Brunotte F
2004 Predictive value for disease progression of serum
thyroglobulin levels measured in the postoperative period
and after (131)I ablation therapy in patients with differen-
tiated thyroid cancer. J Nucl Med 45:988–994.
199. Rouxel A, Hejblum G, Bernier MO, Boelle PY, Menegaux F,
Mansour G, Hoang C, Aurengo A, Leenhardt L 2004
Prognostic factors associated with the survival of patients
developing loco-regional recurrences of differentiated
thyroid carcinomas. J Clin Endocrinol Metab 89:5362–
200. Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumber-
ger M 2000 Is diagnostic iodine-131 scanning useful after
total thyroid ablation for differentiated thyroid cancer? J
Clin Endocrinol Metab 85:175–178.
201. Bachelot A, Cailleux AF, Klain M, Baudin E, Ricard M,
Bellon N, Caillou B, Travagli JP, Schlumberger M 2002
Relationship between tumor burden and serum thyro-
globulin level in patients with papillary and follicular
thyroid carcinoma. Thyroid 12:707–711.
202. Wenig BM, Thompson LD, Adair CF, Shmookler B, Heffess
CS 1998 Thyroid papillary carcinoma of columnar cell type:
a clinicopathologic study of 16 cases. Cancer 82:740–753.
203. Prendiville S, Burman KD, Ringel MD, Shmookler BM,
Deeb ZE, Wolfe K, Azumi N, Wartofsky L, Sessions RB
REVISED ATA THYROID CANCER GUIDELINES1205
2000 Tall cell variant: an aggressive form of papillary thy-
roid carcinoma. Otolaryngol Head Neck Surg 122:352–357.
204. Akslen LA, Livolsi VA 2000 Prognostic significance of
histologic grading compared with subclassification of
papillary thyroid carcinoma. Cancer 88:1902–1908.
205. Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC, Hong
SJ, Shong YK 2005 Serum thyroglobulin levels at the time of
131I remnant ablation just after thyroidectomy are useful
for early prediction of clinical recurrence in low-risk pa-
tients with differentiated thyroid carcinoma. J Clin En-
docrinol Metab 90:1440–1445.
206. Tuttle RM, Leboeuf R 2008 Follow up approaches in thy-
roid cancer: a risk adapted paradigm. Endocrinol Metab
Clin North Am 37:419–435.
207. Mazzaferri EL, Jhiang SM 1994 Differentiated thyroid
cancer long-term impact of initial therapy. Trans Am Clin
Climatol Assoc 106:151–168; discussion 168–170.
208. Taylor T, Specker B, Robbins J, Sperling M, Ho M, Ain K,
Bigos ST, Brierley J, Cooper D, Haugen B, Hay I, Hertzberg
V, Klein I, Klein H, Ladenson P, Nishiyama R, Ross D,
Sherman S, Maxon HR 1998 Outcome after treatment of
high-risk papillary and non-Hu ¨rthle-cell follicular thyroid
carcinoma. Ann Intern Med 129:622–627.
209. Sawka AM, Brierley JD, Tsang RW, Thabane L, Rotstein L,
Gafni A, Straus S, Goldstein DP 2008 An updated
systematic review and commentary examining the effec-
tiveness of radioactive iodine remnant ablation in well-
differentiated thyroid cancer. Endocrinol Metab Clin North
210. Kim S, Wei JP, Braveman JM, Brams DM 2004 Predicting
outcome and directing therapy for papillary thyroid carci-
noma. Arch Surg 139:390–394; discussion 393–394.
211. Sugitani I, Fujimoto Y 1999 Symptomatic versus asymp-
tomatic papillary thyroid microcarcinoma: a retrospective
analysis of surgical outcome and prognostic factors. Endocr
212. Lundgren CI, Hall P, Dickman PW, Zedenius J 2007 In-
fluence of surgical and postoperative treatment on survival
in differentiated thyroid cancer. Br J Surg 94:571–577.
213. Mazzaferri EL1997 Thyroid remnant 131I ablation for
papillary and follicular thyroid carcinoma. Thyroid 7:265–
214. Jonklaas J, Sarlis NJ, Litofsky D, Ain KB, Bigos ST, Brierley
JD, Cooper DS, Haugen BR, Ladenson PW, Magner J,
Robbins J, Ross DS, Skarulis M, Maxon HR, Sherman SI
2006 Outcomes of patients with differentiated thyroid car-
cinoma following initial therapy. Thyroid 16:1229–1242.
215. Jung TS, Kim TY, Kim KW, Oh YL, Park do J, Cho BY,
Shong YK, Kim WB, Park YJ, Jung JH, Chung JH 2007
Clinical features and prognostic factors for survival in pa-
tients with poorly differentiated thyroid carcinoma and
comparison to the patients with the aggressive variants of
papillary thyroid carcinoma. Endocr J. 54:265–274.
216. Hay ID, Hutchinson ME, Gonzalez-Losada T, McIver B,
Reinalda ME, Grant CS, Thompson GB, Sebo TJ, Goellner
JR 2009 Papillary thyroid microcarcinoma: a study of 900
cases observed in a 60-year period. Surgery 144:980–987.
217. Ross DS, Litofsky D, Ain KB, Brierley JD, Cooper DS,
Haugen BR, Jonklaas J, Ladenson PW, Magner J, Robbins J,
Skarulis MC, Steward DL, Maxon HR, Sherman SI 2009
Recurrence after treatment of micropapillary thyroid can-
cer. Thyroid 19:1043–1048.
218. Edmonds CJ, Hayes S, Kermode JC., Thompson BD 1977
Measurement of serum TSH and thyroid hormones in the
management of treatment of thyroid carcinoma with
radioiodine. Br J Radiol 50:799–807.
219. Torres MS, Ramirez L, Simkin PH, Braverman LE, Emerson
CH 2001 Effect of various doses of recombinant human
thyrotropin on the thyroid radioactive iodine uptake and
serum levels of thyroid hormones and thyroglobulin in
normal subjects. J Clin Endocrinol Metab 86:1660–1664.
220. Hershman JM, Edwards CL 1972 Serum thyrotropin (TSH)
levels after thyroid ablation compared with TSH levels af-
ter exogenous bovine TSH: implications for 131-I treatment
of thyroid carcinoma. J Clin Endocrinol Metab 34:814–818.
221. Martin ND 1978 Endogenous serum TSH levels and met-
astatic survey scans in thyroid cancer patients using triio-
dothyronine withdrawal. Clin Nucl Med 3:401–403.
222. Hilts SV, Hellman D, Anderson J, Woolfenden J, Van An-
twerp J, Patton D 1979 Serial TSH determination after T3
withdrawal or thyroidectomy in the therapy of thyroid
carcinoma. J Nucl Med 20:928–932.
223. Goldman JM, Line BR, Aamodt RL, Robbins J 1980 Influ-
ence of triiodothyronine withdrawal time on 131I uptake
postthyroidectomy for thyroid cancer. J Clin Endocrinol
224. Schneider AB, Line B, Goldman JM, Robbins J 1981 Se-
quential serum thyroglobulin determinations, 131I scans,
and 131I uptakes after triiodothyronine withdrawal in
patients with thyroid cancer. J Clin Endocrinol Metab
225. Maxon HR, Thomas SR, Hertzberg VS, Kereiakes JG, Chen
IW, Sperling MI, Saenger EL 1983 Relation between effec-
tive radiation dose and outcome of radioiodine therapy for
thyroid cancer. N Engl J Med 309:937–941.
226. Liel Y 2002 Preparation for radioactive iodine administra-
tion in differentiated thyroid cancer patients. Clin En-
227. Sanchez R, Espinosa-de-los-Monteros AL, Mendoza V, Brea
E, Hernandez I, Sosa E, Mercado M 2002 Adequate thyroid-
stimulating hormone levels after levothyroxine discontin-
uation in the follow-up of patients with well-differentiated
thyroid carcinoma. Arch Med Res 33:478–481.
228. Grigsby PW, Siegel BA, Bekker S, Clutter WE, Moley JF
2004 Preparation of patients with thyroid cancer for 131I
scintigraphy or therapy by 1–3 weeks of thyroxine dis-
continuation. J Nucl Med 45:567–570.
229. Serhal DI, Nasrallah MP, Arafah BM 2004 Rapid rise in
serum thyrotropin concentrations after thyroidectomy or
withdrawal of suppressive thyroxine therapy in prepara-
tion for radioactive iodine administration to patients with
differentiated thyroid cancer. J Clin Endocrinol Metab
230. Leboeuf R, Perron P, Carpentier AC, Verreault J, Langlois
MF 2007 L-T3 preparation for whole-body scintigraphy: a
randomized-controlled trial. Clin Endocrinol (Oxf) 67:839–
231. Guimaraes V, DeGroot LJ 1996 Moderate hypothyroidism
in preparation for whole body 131I scintiscans and thyro-
globulin testing. Thyroid 6:69–73.
232. Maxon HR 1999 Detection of residual and recurrent thyroid
cancer by radionuclide imaging. Thyroid 9:443–446.
233. Kuijt WJ, Huang SA 2005 Children with differentiated
thyroid cancer achieve adequate hyperthyrotropinemia
within 14 days of levothyroxine withdrawal. J Clin En-
docrinol Metab 90:6123–6125.
234. Heemstra KA, Liu YY, Stokkel M, Kievit J, Corssmit E,
Pereira AM, Romijn JA, Smit JW 2007 Serum thyroglobulin
1206 COOPER ET AL.
concentrations predict disease-free remission and death in
differentiated thyroid carcinoma. Clin Endocrinol (Oxf)
235. Robbins RJ, Larson SM, Sinha N, Shaha A, Divgi C, Pen-
tlow KS, Ghossein R, Tuttle RM 2002 A retrospective re-
view of the effectiveness of recombinant human TSH as a
preparation for radioiodine thyroid remnant ablation. J
Nucl Med 43:1482–1488.
236. Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C,
Agate L, Elisei R, Pinchera A 2002 Ablation of thyroid
residues with 30mCi (131)I: a comparison in thyroid cancer
patients prepared with recombinant human TSH or thyroid
hormone withdrawal. J Clin Endocrinol Metab 87:4063–
237. Pacini F, Ladenson PW, Schlumberger M, Driedger A,
Luster M, Kloos RT, Sherman S, Haugen B, Corone C,
Molinaro E, Elisei R, Ceccarelli C, Pinchera A, Wahl RL,
Leboulleux S, Ricard M, Yoo J, Busaidy NL, Delpassand E,
Hanscheid H, Felbinger R, Lassmann M, Reiners C 2006
Radioiodine ablation of thyroid remnants after preparation
with recombinant human thyrotropin in differentiated
thyroid carcinoma: results of an international, randomized,
controlled study. J Clin Endocrinol Metab 91:926–932.
238. Pilli T, Brianzoni E, Capoccetti F, Castagna MG, Fattori S,
Poggiu A, Rossi G, Ferretti F, Guarino E, Burroni L,
Vattimo A, Cipri C, Pacini F 2007 A comparison of 1850
(50mCi) and 3700MBq (100mCi) 131-iodine administered
doses for recombinant thyrotropin-stimulated postopera-
tive thyroid remnant ablation in differentiated thyroid
cancer. J Clin Endocrinol Metab 92:3542–3546.
239. Chianelli M, Todino V, Graziano F, Panunzi C, Pace D,
Guglielmi R, Signore A, Papini E 2009 Low dose (2.0GBq;
54mCi) radioiodine postsurgical remnant ablation in thy-
roid cancer: comparison between hormone withdrawal and
use of rhTSH in low risk patients. Eur J Endocrinol 160:
240. Tuttle RM, Brokhin M, Omry G, Martorella AJ, Larson SM,
Grewal RK, Fleisher M, Robbins RJ 2008. Recombinant
human TSH-assisted radioactive iodine remnant ablation
achieves short-term clinical recurrence rates similar to those
of traditional thyroid hormone withdrawal. J Nucl Med
241. Carril JM, Quirce R, Serrano J, Banzo I, Jime ´nez-Bonilla JF,
Tabuenca O, Barquı ´n RG 1997 Total-body scintigraphy
with thallium-201 and iodine-131 in the follow-up of dif-
ferentiated thyroid cancer. J Nucl Med 38:686–692.
242. Muratet JP, Giraud P, Daver A, Minier JF, Gamelin E, Larra
F 1997 Predicting the efficacy of first iodine-131 treatment
in differentiated thyroid carcinoma. J Nucl Med 38:1362–
243. Leger AF, Pellan M, Dagousset F, Chevalier A, Keller I,
Clerc J 2005 A case of stunning of lung and bone metastases
of papillary thyroid cancer after a therapeutic dose
(3.7GBq) of 131I and review of the literature: implications
for sequential treatments. Br J Radiol 78:428–432.
244. Park HM, Park YH, Zhou XH 1997 Detection of thyroid
remnant=metastasis without stunning: an ongoing di-
lemma. Thyroid 7:277–280.
245. Hilditch TE, Dempsey MF, Bolster AA, McMenemin RM,
Reed NS 2002 Self-stunning in thyroid ablation: evidence
from comparative studies of diagnostic 131I and 123I. Eur J
Nucl Med Mol Imaging 29:783–788.
246. Morris LF, Waxman AD, Braunstein GD 2001 The nonim-
pact of thyroid stunning: remnant ablation rates in 131I-
scanned and nonscanned individuals. J Clin Endocrinol
247. Lassmann M, Luster M, Hanscheid H, Reiners C 2004 Im-
pact of (131)I diagnostic activities on the biokinetics of
thyroid remnants. J Nucl Med 45:619–625.
248. Anderson GS, Fish S, Nakhoda K, Zhuang H, Alava A,
Mandel SJ 2003 Comparison of I-123 and I-131 for whole-
body imaging after stimulation by recombinant human
thyrotropin: a preliminary report. Clin Nucl Med 28:93–96.
249. Gerard SK, Cavalieri RR 2002 I-123 diagnostic thyroid tu-
mor whole-body scanning with imaging at 6, 24, and 48
hours. Clin Nucl Med 27:1–8.
250. Silberstein EB 2007 Comparison of outcomes after (123)I
versus (131)I pre-ablation imaging before radioiodine ab-
lation in differentiated thyroid carcinoma. J Nucl Med
251. Rosario PW, Reis JS, Barroso AL, Rezende LL, Padrao EL,
Fagundes TA 2004 Efficacy of low and high 131I doses for
thyroid remnant ablation in patients with differentiated
thyroid carcinoma based on post-operative cervical uptake.
Nucl Med Commun 25:1077–1081.
252. Bal C, Padhy AK, Jana S, Pant GS, Basu AK 1996 Pro-
spective randomized clinical trial to evaluate the optimal
dose of 131 I for remnant ablation in patients with differ-
entiated thyroid carcinoma. Cancer 77:2574–2580.
253. Creutzig H 1987 High or low dose radioiodine ablation of
thyroid remnants? Eur J Nucl Med 12:500–502.
254. Johansen K, Woodhouse NJ, Odugbesan O1991 Compar-
ison of 1073MBq and 3700MBq iodine-131 in postoperative
ablation of residual thyroid tissue in patients with differ-
entiated thyroid cancer. J Nucl Med 32:252–254.
255. Doi SA, Woodhouse NJ 2000 Ablation of the thyroid rem-
nant and 131I dose in differentiated thyroid cancer. Clin
Endocrinol (Oxf) 52:765–773.
256. Hackshaw A, Harmer C, Mallick U, Haq M, Franklyn JA
2007 131I activity for remnant ablation in patients with
differentiated thyroid cancer: a systematic review. J Clin
Endocrinol Metab 92:28–38.
257. Maenpaa HO, Heikkonen J, Vaalavirta L, Tenhunen M,
Joensuu H 2008 Low vs. high radioiodine activity to ablate
the thyroid after thyroidectomy for cancer: a randomized
study. PLoS ONE 3:e1885.
258. Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P,
Pasquini C, Piazza F, Caciagli M, Mariani G 2003 Radio-
iodine treatment with 30mCi after recombinant human
thyrotropin stimulation in thyroid cancer: effectiveness for
postsurgical remnants ablation and possible role of iodine
content in L-thyroxine in the outcome of ablation. J Clin
Endocrinol Metab 88:4110–4115.
259. Franzius C, Dietlein M, Biermann M, Fru ¨hwald M, Linden
T, Bucsky P, Reiners C, Schober O 2007 Procedure guide-
line for radioiodine therapy and 131iodine whole-body
scintigraphy in paediatric patients with differentiated thy-
roid cancer. Nuklearmedizin 46:224–231.
260. Jarzab B, Handkiewicz-Junak D, Wloch J 2005 Juvenile
differentiated thyroid carcinoma and the role of radio-
iodine in its treatment: a qualitative review. Endocr Relat
261. Maxon HR, Thomas SR, Boehringer A, Drilling J, Sperling
MI, Sparks JC, Chen IW 1983 Low iodine diet in I-131 ab-
lation of thyroid remnants. Clin Nucl Med 8:123–126.
262. Goslings BM 1975 Proceedings: Effect of a low iodine diet
on 131-I therapy in follicular thyroid carcinomata. J En-
REVISED ATA THYROID CANCER GUIDELINES1207
263. Pluijmen MJ, Eustatia-Rutten C, Goslings BM, Stokkel MP,
Arias AM, Diamant M, Romijn JA, Smit JW 2003 Effects of
low-iodide diet on postsurgical radioiodide ablation ther-
apy in patients with differentiated thyroid carcinoma. Clin
Endocrinol (Oxf) 58:428–435.
264. Fatourechi V, Hay ID, Mullan BP, Wiseman GA, Eghbali-
Fatourechi GZ, Thorson LM, Gorman CA 2000 Are post-
therapy radioiodine scans informative and do they
influence subsequent therapy of patients with differenti-
ated thyroid cancer? Thyroid 10:573–577.
265. Sherman SI, Tielens ET, Sostre S, Wharam MD Jr, Ladenson
PW 1994 Clinical utility of posttreatment radioiodine scans
in the management of patients with thyroid carcinoma. J
Clin Endocrinol Metab 78:629–634.
266. Souza Rosario PW, Barroso AL, Rezende LL, Padrao EL,
Fagundes TA, Penna GC, Purisch S 2004 Post I-131 therapy
scanning in patients with thyroid carcinoma metastases: an
unnecessary cost or a relevant contribution? Clin Nucl Med
267. Wong KK, Zarzhevsky N, Cahill JM, Frey KA, Avram AM
2008 Incremental value of diagnostic 131I SPECT=CT fu-
sion imaging in the evaluation of differentiated thyroid
carcinoma. AJR Am J Roentgenol 191:1785–1794.
268. Brabant G 2008 Thyrotropin suppressive therapy in thyroid
carcinoma: what are the targets? J Clin Endocrinol Metab
269. McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F,
Sarlis NJ 2002 Effects of thyroid hormone suppression
therapy on adverse clinical outcomes in thyroid cancer.
Ann Med 34:554–564.
270. Pujol P, Daures JP, Nsakala N, Baldet L, Bringer J, Jaffiol C
1996 Degree of thyrotropin suppression as a prognostic
determinant in differentiated thyroid cancer. J Clin En-
docrinol Metab 81:4318–4323.
271. Hovens GC, Stokkel MP, Kievit J, Corssmit EP, Pereira AM,
Romijn JA, Smit JW 2007 Associations of serum thyrotropin
concentrations with recurrence and death in differentiated
thyroid cancer. J Clin Endocrinol Metab 92:2610–2615.
272. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Ba-
charach P, Wilson PW, Benjamin EJ, D’Agostino RB 1994
Low serum thyrotropin concentrations as a risk factor for
atrial fibrillation in older persons. N Engl J Med 33:1249–
273. Toft AD 2001 Clinical practice. Subclinical hyperthyroid-
ism. N Engl J Med 345:512–516.
274. Wilson PC, Millar BM, Brierley JD 2004 The management of
advanced thyroid cancer. Clin Oncol (R Coll Radiol).
275. Ford D, Giridharan S, McConkey C, Hartley A, Brammer C,
Watkinson JC, Glaholm J 2003 External beam radiotherapy
in the management of differentiated thyroid cancer. Clin
Oncol (R Coll Radiol). 15:337–341.
Tuttle RM, Wolden SL, Zelefsky MJ, Wong RJ, Patel SG,
Pfister DG, Shaha AR, Lee NY 2008 Role of external beam
radiotherapy in patients with advanced or recurrent non-
Cancer Center experience. Int J Radiat Oncol Biol Phys
277. Brierley J, Tsang R, Panzarella T, Bana N 2005 Prognostic
factors and the effect of treatment with radioactive iodine
and external beam radiation on patients with differentiated
thyroid cancer seen at a single institution over 40 years.
Clin Endocrinol (Oxf) 63:418–427.
278. Sanders EM Jr, LiVolsi VA, Brierley J, Shin J, Randolph GW
2007 An evidence-based review of poorly differentiated
thyroid cancer. World J Surg 31:934–945.
279. Kim JH, Leeper RD 1987 Treatment of locally advanced
thyroid carcinoma with combination doxorubicin and ra-
diation therapy. Cancer 60:2372–2375.
280. Links TP, van Tol KM, Jager PL, Plukker JT, Piers DA,
Boezen HM, Dullaart RP, de Vries EG, Sluiter WJ 2005 Life
expectancy in differentiated thyroid cancer: a novel ap-
proach to survival analysis. Endocr Relat Cancer 12:273–
281. Brown AP, Chen J, Hitchcock YJ, Szabo A, Schrieve DC,
Tward JD 2008 The risk of second primary malignancies up
to three decades after the treatment of differentiated thy-
roid cancer. J Clin Endocrinol Metab 93:504–515.
282. Berthe E, Henry-Amar M, Michels JJ, Rame JP, Berthet P,
Babin E, Icard P, Samama G, Galateau-Salle ´ F, Mahoudeau
J, Bardet S 2004 Risk of second primary cancer following
differentiated thyroid cancer. Eur J Nucl Med Mol Imaging
283. Biondi B, Filetti S, Schlumberger M 2005 Thyroid-hormone
therapy and thyroid cancer: a reassessment. Nat Clin Pract
Endocrinol Metab 1:32–40.
284. Eustatia-Rutten CF, Smit JW, Romijn JA, van der Kleij-
Corssmit EP, Pereira AM, Stokkel MP, Kievit J 2004 Diag-
nostic value of serum thyroglobulin measurements in the
follow-up of differentiated thyroid carcinoma, a structured
meta-analysis. Clin Endocrinol (Oxf) 61:61–74.
285. Mazzaferri EL, Robbins RJ, Braverman LE, Pacini F, Hau-
gen B, Wartofsky L, Haugen BR, Sherman SI, Cooper DS,
Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson
PW, Pinchera A 2003 Authors’ response: a consensus report
of the role of serum thyroglobulin as a monitoring method
for low-risk patients with papillary thyroid carcinoma. J
Clin Endocrinol Metab;88:4508–4509.
286. Bachelot A, Leboulleux S, Baudin E, Hartl DM, Caillou B,
Travagli JP, Schlumberger M 2005 Neck recurrence
from thyroid carcinoma: serum thyroglobulin and high-
dose total body scan are not reliable criteria for cure
after radioiodine treatment. Clin Endocrinol (Oxf) 62:376–
287. Robbins RJ, Srivastava S, Shaha A, Ghossein R, Larson SM,
Fleisher M, Tuttle RM 2004 Factors influencing the Basal
and recombinant human thyrotropin-stimulated serum
thyroglobulin in patients with metastatic thyroid carci-
noma. J Clin Endocrinol Metab 89:6010–6016.
288. Kloos RT, Mazzaferri EL 2005 A single recombinant human
thyrotrophin-stimulated serum thyroglobulin measure-
ment predicts differentiated thyroid carcinoma metastases
three to five years later. J Clin Endocrinol Metab 90:5047–
289. Castagna MG, Brilli L, Pilli T, Montanaro A, Cipri C,
Fioravanti C, Sestini F, Capezzone M, Pacini F 2008
Limited value of repeat recombinant thyrotropin (rhTSH)-
stimulated thyroglobulin testing in differentiated thyroid
stimulated thyroglobulin and undetectable basal serum
thyroglobulin levels. J Clin Endocrinol Metab 93:76–81.
290. Torlontano M, Crocetti U, Augello G, D’Aloiso L, Bonfitto
N, Varraso A, Dicembrino F, Modoni S, Frusciante V, Di
Giorgio A, Bruno R, Filetti S, Trischitta V 2006 Comparative
evaluation of recombinant human thyrotropin-stimulated
thyroglobulin levels, 131I whole-body scintigraphy, and
neck ultrasonography in the follow-up of patients with
1208 COOPER ET AL.
papillary thyroid microcarcinoma who have not undergone
radioiodine therapy. J Clin Endocrinol Metab 91:60–63.
291. Smallridge RC, Meek SE, Morgan MA, Gates GS, Fox TP,
Grebe S, Fatourechi V 2007 Monitoring thyroglobulin in
a sensitive immunoassay has comparable sensitivity to
recombinant human TSH-stimulated thyroglobulin in
follow-up of thyroid cancer patients. J Clin Endocrinol
292. Iervasi A, Iervasi G, Ferdeghini M, Solimeo C, Bottoni A,
Rossi L, Colato C, Zucchelli GC 2007 Clinical relevance of
highly sensitive Tg assay in monitoring patients treated for
293. Schlumberger M, Hitzel A, Toubert ME, Corone C, Troalen
F, Schlageter MH, Claustrat F, Koscielny S, Taieb D, Tou-
beau M, Bonichon F, Borson-Chazot F, Leenhardt L,
Schvartz C, Dejax C, Brenot-Rossi I, Torlontano M, Te-
nenbaum F, Bardet S, Bussie `re F, Girard JJ, Morel O,
Schneegans O, Schlienger JL, Prost A, So D, Archambeaud
F, Ricard M, Benhamou E 2007 Comparison of seven serum
thyroglobulin assays in the follow-up of papillary and
follicular thyroid cancer patients. J Clin Endocrinol Metab
294. Baudin E, Do Cao C, Cailleux AF, Leboulleux S, Travagli
JP, Schlumberger M 2003 Positive predictive value of serum
thyroglobulin levels, measured during the first year of
follow-up after thyroid hormone withdrawal, in thyroid
cancer patients. J Clin Endocrinol Metab 88:1107–1111.
295. Haugen BR, Pacini F, Reiners C, Schlumberger M, La-
denson PW, Sherman SI, Cooper DS, Graham KE, Braver-
man LE, Skarulis MC, Davies TF, DeGroot LJ, Mazzaferri
EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker
DV, Maxon HR 3rd, Cavalieri RR, Spencer CA, McEllin K,
Weintraub BD, Ridgway EC 1999 A comparison of re-
combinant human thyrotropin and thyroid hormone
withdrawal for the detection of thyroid remnant or cancer. J
Clin Endocrinol Metab 84:3877–3885.
296. David A, Blotta A, Bondanelli M, Rossi R, Roti E, Braver-
man LE, Busutti L, degli Uberti EC 2001 Serum thyro-
globulin concentrations and (131)I whole-body scan results
in patients with differentiated thyroid carcinoma after ad-
ministration of recombinant human thyroid-stimulating
hormone. J Nucl Med 42:1470–1475.
297. Mazzaferri EL, Kloos RT 2002 Is diagnostic iodine-131
scanning with recombinant human TSH (rhTSH) useful in
the follow-up of differentiated thyroid cancer after thyroid
ablation? J Clin Endocrinol Metab 87:1490–1498.
298. Haugen BR, Ridgway EC, McLaughlin BA, McDermott MT
2002 Clinical comparison of whole-body radioiodine scan
and serum thyroglobulin after stimulation with recombi-
nant human thyrotropin. Thyroid 12:37–43.
299. Lima N, Cavaliere H, Tomimori E, Knobel M, Medeiros-
Neto G 2002 Prognostic value of serial serum thyroglobulin
determinations after total thyroidectomy for differentiated
thyroid cancer. J Endocrinol Invest 25:110–115.
300. Wartofsky L 2002 Management of low-risk well-differen-
tiated thyroid cancer based only on thyroglobulin mea-
surement after recombinant human thyrotropin. Thyroid
301. Schaap J, Eustatia-Rutten CF, Stokkel M, Links TP, Dia-
mant M, van der Velde EA, Romijn JA, Smit JW 2002 Does
radioiodine therapy have disadvantageous effects in non-
iodine accumulating differentiated thyroid carcinoma? Clin
Endocrinol (Oxf) 57:117–124.
302. Spencer CA, LoPresti JS, Fatemi S, Nicoloff JT 1999 Detec-
tion of residual and recurrent differentiated thyroid carci-
noma by serum thyroglobulin measurement. Thyroid
303. Hollowell JG, Staehling NW, Flanders WD, Hannon WH,
Gunter EW, Spencer CA, Braverman LE 2002 Serum TSH,
T(4), and thyroid antibodies in the United States population
(1988 to 1994): National Health and Nutrition Examination
Survey (NHANES III). J Clin Endocrinol Metab 87:489–499.
304. Spencer CA 2004 Challenges of serum thyroglobulin (thy-
roglobulin) measurement in the presence of thyroglobulin
autoantibodies. J Clin Endocrinol Metab 89:3702–3704.
305. Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Gut-
tler RB, Singer PA, Fatemi S, LoPresti JS, Nicoloff JT 1998
Serum thyroglobulin autoantibodies: prevalence, influence
on serum thyroglobulin measurement, and prognostic sig-
nificance in patients with differentiated thyroid carcinoma.
J Clin Endocrinol Metab 83:1121–1127.
306. Chiovato L, Latrofa F, Braverman LE, Pacini F, Capezzone
M, Masserini L, Grasso L, Pinchera A 2003 Disappearance
of humoral thyroid autoimmunity after complete removal
of thyroid antigens. Ann Intern Med 139:346–351.
307. Schlumberger M, Mancusi F, Baudin E, Pacini F 1997 131-I
308. Mazzaferri EL, Kloos RT 2001 Current approaches to pri-
mary therapy for papillary and follicular thyroid cancer. J
Clin Endocrinol Metab 86:1447–1463.
309. Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D,
Pinchera A 2002 Diagnostic 131-iodine whole-body scan
may be avoided in thyroid cancer patients who have un-
detectable stimulated serum thyroglobulin levels after ini-
tial treatment. J Clin Endocrinol Metab 87:1499–1501.
310. Koh JM, Kim ES, Ryu JS, Hong SJ, Kim WB, Shong YK 2003
Effects of therapeutic doses of 131I in thyroid papillary
carcinoma patients with elevated thyroglobulin level and
negative 131I whole-body scan: comparative study. Clin
Endocrinol (Oxf) 58:421–427.
311. Torlontano M, Crocetti U, D’Aloiso L, Bonfitto N, Di Giorgio
A, Modoni S, Valle G, Frusciante V, Bisceglia M, Filetti S,
Schlumberger M, Trischitta V 2003 Serum thyroglobulin and
131I whole body scan after recombinant human TSH stim-
ulation in the follow-up of low-risk patients with differen-
tiated thyroid cancer. Eur J Endocrinol 148:19–24.
312. Pacini F, Molinaro E, Castagna MG, Agate L, Elisei R,
Ceccarelli C, Lippi F, Taddei D, Grasso L, Pinchera A 2003
Recombinant human thyrotropin-stimulated serum thyro-
globulin combined with neck ultrasonography has the
highest sensitivity in monitoring differentiated thyroid
carcinoma. J Clin Endocrinol Metab 88:3668–3673.
313. Snozek CL, Chambers EP, Reading CC, Sebo TJ, Sistrunk
JW, Singh RJ, Grebe SK 2007 Serum thyroglobulin, high-
resolution ultrasound, and lymph node thyroglobulin in
diagnosis of differentiated thyroid carcinoma nodal me-
tastases. J Clin Endocrinol Metab 92:4278–4281.
314. Cunha N, Rodrigues F, Curado F, Ilhe ´u O, Cruz C, Nai-
denov P, Rasca ˜o MJ, Ganho J, Gomes I, Pereira H, Real O,
Figueiredo P, Campos B, Valido F 2007 Thyroglobulin de-
tection in fine-needle aspirates of cervical lymph nodes: a
technique for the diagnosis of metastatic differentiated
thyroid cancer. Eur J Endocrinol 157:101–107.
thyroid cancer management. Semin Roentgenol 37:169–174.
316. Leboulleux S, Schroeder PR, Busaidy NL, Auperin A,
Corone C, Jacene HA, Ewertz ME, Bournaud C, Wahl RL,
REVISED ATA THYROID CANCER GUIDELINES1209
Sherman SI, Ladenson PW, Schlumberger M 2009 Assess-
ment of the incremental value of recombinant TSH stimu-
lation before FDG PET=CT imaging to localize residual
differentiated thyroid cancer. J Clin Endocrinol Metab
317. Wang PW, Wang ST, Liu RT, Chien WY, Tung SC, Lu YC,
Chen HY, Lee CH 1999 Levothyroxine suppression of
thyroglobulin in patients with differentiated thyroid carci-
noma. J Clin Endocrinol Metab 84:4549–4553.
318. Leeper RD 1973 The effect of 131 I therapy on survival of
patients with metastatic papillary or follicular thyroid car-
cinoma. J Clin Endocrinol Metab 36:1143–1152.
319. Beierwaltes WH, Nishiyama RH, Thompson NW, Copp JE,
Kubo A 1982 Survival time and ‘‘cure’’ in papillary and
follicular thyroid carcinoma with distant metastases: sta-
tistics following University of Michigan therapy. J Nucl
320. Bernier MO, Leenhardt L, Hoang C, Aurengo A, Mary JY,
Menegaux F, Enkaoua E, Turpin G, Chiras J, Saillant G,
Hejblum G 2001 Survival and therapeutic modalities in
patients with bone metastases of differentiated thyroid
carcinomas. J Clin Endocrinol Metab 86:1568–1573.
321. Sampson E, Brierly JD, Le LW, Rotstein L, Tsang RW 2007
Clinical management and outcome of papillary and folli-
cular (differentiated) thyroid cancer presenting with distant
metastasis at diagnosis. Cancer 110:1451–1456.
322. Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D,
Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire
F, Schlumberger M 2006 Long term outcome of 444 patients
with distant metastases from papillary and follicular thy-
roid carcinoma: benefits and limits of radioiodine therapy.
J Clin Endocrinol Metab 92:450–455.
323. Dupuy DE, Monchik JM, Decrea C, Pisharodi L 2001
Radiofrequency ablation of regional recurrence from well-
differentiated thyroid malignancy. Surgery 130:971–977.
324. Lewis BD, Hay ID, Charboneau JW, McIver B, Reading CC,
Goellner JR 2002 Percutaneous ethanol injection for
treatment of cervical lymph node metastasesinpatients with
papillary thyroid carcinoma. Am J Roentgenol 178:699–704.
325. Eustatia-Rutten CF, Romijn JA, Guijt MJ, Vielvoye GJ, van
den Berg R, Corssmit EP, Pereira AM, Smit JW 2003 Out-
come of palliative embolization of bone metastases in dif-
ferentiated thyroid carcinoma. J Clin Endocrinol Metab
326. Uchino S, Noguchi S, Yamashita H, Watanabe S 2004
Modified radical neck dissection for differentiated thyroid
cancer: operative technique. World J Surg 28:1199–1203.
327. Noguchi S, Yamashita H, Murakami N, Nakayama I, Toda
M, Kawamoto H 1996 Small carcinomas of the thyroid.
A long-term follow-up of 867 patients. Arch Surg 131:
328. Marchesi M, Biffoni M, Biancari F, Berni A, Campana FP
2003 Predictors of outcome for patients with differentiated
and aggressive thyroid carcinoma. Eur J Surg Suppl 588:
329. Ge JH, Zhao RL, Hu JL, Zhou WA 2004 Surgical treatment
of advanced thyroid carcinoma with aero-digestive inva-
sion. Zhonghua Er Bi Yan Hou Ke Za Zhi 39:237–240.
330. Avenia N, Ragusa M, Monacelli M, Calzolari F, Daddi N,
Di Carlo L, Semeraro A, Puma F 2004 Locally advanced
thyroid cancer: therapeutic options. Chir Ital 56:501–508.
331. McCaffrey JC 2000 Evaluation and treatment of aero-
digestive tract invasion by well-differentiated thyroid car-
cinoma. Cancer Control 7:246–252.
332. Musholt TJ, Musholt PB, Behrend M, Raab R, Scheumann
GF, Klempnauer J 1999 Invasive differentiated thyroid car-
cinoma: tracheal resection and reconstruction procedures in
the hands of the endocrine surgeon. Surgery 126:1078–1087;
333. Czaja JM, McCaffrey TV 1997 The surgical management of
laryngotracheal invasion by well-differentiated papillary
thyroid carcinoma. Arch Otolaryngol Head Neck Surg
334. Van Nostrand D, Atkins F, Yeganeh F, Acio E, Bursaw R,
Wartofsky L 2002 Dosimetrically determined doses of
radioiodine for the treatment of metastatic thyroid carci-
noma. Thyroid 12:121–134.
335. Robbins RJ, Schlumberger MJ 2005 The evolving role of
(131)I for the treatment of differentiated thyroid carcinoma.
J Nucl Med 46:28S–37S.
336. Holst JP, Burman KD, Atkins F, Umans JG, Jonklaas J 2005
Radioiodine therapy for thyroid cancer and hyperthyroid-
ism in patients with end-stage renal disease on hemodial-
ysis. Thyroid 15:1321–1331.
337. Driedger AA, Quirk S, McDonald TJ, Ledger S, Gray D,
Wall W, Yoo J 2006 A pragmatic protocol for I-131 rhTSH-
stimulated ablation therapy in patients with renal failure.
Clin Nucl Med 31:454–457.
338. Samuel AM, Rajashekharrao B, Shah DH 1998 Pulmonary
differentiated thyroid cancer. J Nucl Med 39:1531–1536.
339. Sgouros G, Kolbert KS, Sheikh A, Pentlow KS, Mun EF,
Barth A, Robbins RJ, Larson SM 2004 Patient-specific
dosimetry for 131I thyroid cancer therapy using 124I PET
and 3-dimensional-internal dosimetry (3D-ID) software.
J Nucl Med 45:1366–1372.
340. Jentzen W, Freudenberg L, Eising EG, Sonnenschein W,
Knust J, Bockisch A 2008 Optimized 124I PET dosimetry
protocol for radioiodine therapy of differentiated thyroid
cancer. J Nucl Med 49:1017–1023.
341. Kulkarni K, Nostrand DV, Atkins F, Aiken M, Burman K,
Wartofsky L 2006 The relative frequency in which empiric
dosages of radioiodine would potentially overtreat or un-
dertreat patients who have metastatic well-differentiated
thyroid cancer. Thyroid 16:1019–1023.
342. Tuttle RM, Leboeuf R, Robbins RJ, Qualey R, Pentlow K,
Larson SM, Chan CY 2006 Empiric radioactive iodine
dosing regimens frequently exceed maximum tolerated
activity levels in elderly patients with thyroid cancer. J
Nucl Med 47:1587–1591.
343. Rudavsky AZ, Freeman LM 1997 Treatment of scan-
negative, thyroglobulin-positive metastatic thyroid cancer
using radioiodine 131I and recombinant human thyroid
stimulating hormone. J Clin Endocrinol Metab 82:11–14.
344. Ringel MD, Ladenson PW 1996 Diagnostic accuracy of 131I
scanning with recombinant human thyrotropin versus
thyroid hormone withdrawal in a patient with metastatic
thyroid carcinoma and hypopituitarism. J Clin Endocrinol
345. Luster M, Lassmann M, Haenscheid H, Michalowski U,
Incerti C, Reiners C 2000 Use of recombinant human thy-
rotropin before radioiodine therapy in patients with ad-
vanced differentiated thyroid carcinoma. J Clin Endocrinol
346. Mariani G, Ferdeghini M, Augeri C, Villa G, Taddei GZ,
Scopinaro G, Boni G, Bodei L, Rabitti C, Molinari E, Bianchi
R 2000 Clinical experience with recombinant human thy-
rotrophin (rhTSH) in the management of patients with
1210COOPER ET AL.
differentiated thyroid cancer. Cancer Biother Radiopharm
347. Perros P 1999 Recombinant human thyroid-stimulating
hormone (rhTSH) in the radioablation of well-differentiated
thyroid cancer: preliminary therapeutic experience. J En-
docrinol Invest 22:30–34.
348. Lippi F, Capezzone M, Angelini F, Taddei D, Molinaro E,
Pinchera A, Pacini F 2001 Radioiodine treatment of meta-
static differentiated thyroid cancer in patients on L-
349. Pellegriti G, Scollo C, Giuffrida D, Vigneri R, Squatrito S,
Pezzino V 2001 Usefulness of recombinant human thyro-
tropin in the radiometabolic treatment of selected patients
with thyroid cancer. Thyroid 11:1025–1030.
350. Adler ML, Macapinlac HA, Robbins RJ 1998 Radioiodine
treatment of thyroid cancer with the aid of recombinant
human thyrotropin. Endocr Pract 4:282–286.
351. Chiu AC, Delpassand ES, Sherman SI 1997 Prognosis and
treatment of brain metastases in thyroid carcinoma. J Clin
Endocrinol Metab 82:3637–3642.
352. Lau WF, Zacharin MR, Waters K, Wheeler G, Johnston V,
Hicks RJ 2006 Management of paediatric thyroid carcino-
ma: recent experience with recombinant human thyroid
stimulating hormone in preparation for radioiodine ther-
apy. Intern Med J.36:564–570.
353. Po ¨tzi C, Moameni A, Karanikas G, Preitfellner J, Becherer
A, Pirich C, Dudczak R 2006 Comparison of iodine uptake
in tumour and nontumour tissue under thyroid hormone
deprivation and with recombinant human thyrotropin in
thyroid cancer patients. Clin Endocrinol (Oxf) 65:519–523.
354. Vargas GE, Uy H, Bazan C, Guise TA, Bruder JM 1999
Hemiplegia after thyrotropin alfa in a hypothyroid patient
with thyroid carcinoma metastatic to the brain. J Clin En-
docrinol Metab 84:3867–3871.
355. Robbins RJ, Voelker E, Wang W, Macapinlac HA, Larson
SM 2000 Compassionate use of recombinant human thy-
rotropin to facilitate radioiodine therapy: case report and
review of literature. Endocr Pract 6:460–464.
356. Braga M, Ringel MD, Cooper DS 2001 Sudden enlargement
of local recurrent thyroid tumor after recombinant human
TSH administration. J Clin Endocrinol Metab 86:5148–5151.
357. Pons F, Carrio I, Estorch M, Ginjaume M, Pons J, Milian R
1987 Lithium as an adjuvant of iodine-131 uptake when
treating patients with well-differentiated thyroid carci-
noma. Clin Nucl Med 12:644–647.
358. Koong SS, Reynolds JC, Movius EG, Keenan AM, Ain KB,
Lakshmanan MC, Robbins J 1999 Lithium as a potential
adjuvant to 131I therapy of metastatic, well differentiated
thyroid carcinoma. J Clin Endocrinol Metab 84:912–916.
359. Liu YY, van der Pluijm G, Karperien M, Stokkel MP, Per-
eira AM, Morreau J, Kievit J, Romijn JA, Smit JW 2006
Lithium as adjuvant to radioiodine therapy in differenti-
ated thyroid carcinoma: clinical and in vitro studies. Clin
Endocrinol (Oxf) 64:617–624.
360. Ronga G, Filesi M, Montesano T, Di Nicola AD, Pace C,
Travascio L, Ventroni G, Antonaci A, Vestri AR 2004 Lung
metastases from differentiated thyroid carcinoma. A 40
years’ experience. Q J Nucl Med Mol Imaging 48:12–19.
361. Lin JD, Chao TC, Chou SC, Hsueh C 2004 Papillary thyroid
carcinomas with lung metastases. Thyroid 14:1091–1096.
362. Shoup M, Stojadinovic A, Nissan A, Ghossein RA, Freed-
man S, Brennan MF, Shah JP, Shaha AR 2003 Prognostic
indicators of outcomes in patients with distant metastases
from differentiated thyroid carcinoma. J Am Coll Surg
363. Zettinig G, Fueger BJ, Passler C, Kaserer K, Pirich C,
Dudczak R, Niederle B 2002 Long-term follow-up of pa-
tients with bone metastases from differentiated thyroid
carcinoma—surgery or conventional therapy? Clin En-
docrinol (Oxf) 56:377–382.
364. Pittas AG, Adler M, Fazzari M, Tickoo S, Rosai J, Larson
SM, Robbins RJ 2000 Bone metastases from thyroid carci-
noma: clinical characteristics and prognostic variables in
one hundred forty-six patients. Thyroid 10:261–268.
365. Schlumberger M, Challeton C, De Vathaire F, Travagli J-P,
Gardet P, Lumbroso J-D, Francese C, Fontaine F, Ricard M,
Parmentier C 1996 Radioactive iodine treatment and ex-
ternal radiotherapy for lung and bone metastases from
thyroid carcinoma. J Nucl Med 37:598–605.
366. Dinneen SF, Valimaki MJ, Bergstralh EJ, Goellner JR, Gor-
man CA, Hay ID 1995 Distant metastases in papillary
thyroid carcinoma: 100 cases observed at one institution
during 5 decades. J Clin Endocrinol Metab 80:2041–2045.
367. Foote RL, Brown PD, Garces YI, McIver B, Kasperbauer JL
2003 Is there a role for radiation therapy in the manage-
ment of Hu ¨rthle cell carcinoma? Int J Radiat Oncol Biol
368. Pak H, Gourgiotis L, Chang WI, Guthrie LC, Skarulis MC,
Reynolds JC, Merino MJ, Schrump DS, Libutti SK, Alex-
ander HR, Jr, Sarlis NJ 2003 Role of metastasectomy in
the management of thyroid carcinoma: the NIH experience.
J Surg Oncol 82:10–18.
369. Vitale G, Fonderico F, Martignetti A, Caraglia M, Ciccarelli
A, Nuzzo V, Abbruzzese A, Lupoli G 2001 Pamidronate
improves the quality of life and induces clinical remission
of bone metastases in patients with thyroid cancer. Br J
370. Kitamura Y, Shimizu K, Nagahama M, Sugino K, Ozaki O,
Mimura T, Ito K, Tanaka S 1999 Immediate causes of death
in thyroid carcinoma: clinicopathological analysis of 161
fatal cases. J Clin Endocrinol Metab 84:4043–4049.
371. Benua RS, Cicale NR, Sonenberg M, Rawson RW 1962 The
relation of radioiodine dosimetry to results and complica-
tions in the treatment of metastatic thyroid cancer. AJR
372. Ilgan S, Karacalioglu AO, Pabuscu Y, Atac GK, Arslan N,
Ozturk E, Gunalp B, Ozguven MA 2004 Iodine-131 treat-
ment and high-resolution CT: results in patients with lung
metastases from differentiated thyroid carcinoma. Eur J
Nucl Med Mol Imaging 3:825–830.
373. Hod N, Hagag P, Baumer M, Sandbank J, Horne T 2005
Differentiated thyroid carcinoma in children and young
adults: evaluation of response to treatment. Clin Nucl Med
374. Fatourechi V, Hay ID, Javedan H, Wiseman GA, Mullan
BP, Gorman CA 2002 Lack of impact of radioiodine therapy
in thyroglobulin-positive, diagnostic whole- body scan-
negative patients with follicular cell-derived thyroid can-
cer. J Clin Endocrinol Metab 87:1521–1526.
375. Wang W, Larson SM, Fazzari M, Tickoo SK, Kolbert K,
Sgouros G, Yeung H, Macapinlac H, Rosai J, Robbins RJ
2000 Prognostic value of [18F]fluorodeoxyglucose positron
emission tomographic scanning in patients with thyroid
cancer. J Clin Endocrinol Metab 85:1107–1113.
376. Wang W, Larson SM, Tuttle RM, Kalaigian H, Kolbert K,
Sonenberg M, Robbins RJ 2001 Resistance of [18f]-
fluorodeoxyglucose-avid metastatic thyroid cancer lesions
REVISED ATA THYROID CANCER GUIDELINES 1211
to treatment with high-dose radioactive iodine. Thyroid
377. Hooft L, Hoekstra OS, Deville W, Lips P, Teule GJ, Boers
M, van Tulder MW 2001 Diagnostic accuracy of 18F-
fluorodeoxyglucose positron emission tomography in the
follow-up of papillary or follicular thyroid cancer. J Clin
Endocrinol Metab 86:3779–3786.
378. Robbins RJ, Wan Q, Grewal RK, Reibke R, Gonen M,
Strauss HW, Tuttle RM, Drucker W, Larson SM 2006 Real-
time prognosis for metastatic thyroid carcinoma based on
2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomog-
raphy scanning. J Clin Endocrinol Metab 91:498–505.
379. Sarlis NJ 2001 Metastatic thyroid cancer unresponsive to
conventional therapies: novel management approaches
through translational clinical research. Curr Drug Targets
Immune Endocr Metabol Disord 1:103–115.
380. Gottlieb JA, Hill CS, Jr., Ibanez ML, Clark RL 1972 Che-
motherapy of thyroid cancer. An evaluation of experience
with 37 patients. Cancer 30:848–853.
381. Gottlieb JA, Hill CS, Jr 1974 Chemotherapy of thyroid
cancer with adriamycin. Experience with 30 patients. N
Engl J Med 290:93–197.
382. O’Bryan RM, Baker LH, Gottlieb JE, Rivkin SE, Balcerzak
SP, Grumet GN, Salmon SE, Moon TE, Hoogstraten B 1977
Dose response evaluation of adriamycin in human neo-
plasia. Cancer 39:1940–1948.
383. Pacini F, Vitti P, Martino E, Giani C, Bambini G, Pinchera
A, Bascheri L 1984 Treatment of refractory thyroid cancer
with adriamycin. Drugs Experimental Clinical Research
384. Haugen BR 1999 Management of the patient with pro-
gressive radioiodine non-responsive disease. Semin Surg
385. Ain KB, Egorin MJ, DeSimone PA 2000 Treatment of ana-
plastic thyroid carcinoma with paclitaxel: phase 2 trial us-
ing ninety-six-hour infusion. Collaborative Anaplastic
Thyroid Cancer Health Intervention Trials (CATCHIT)
Group. Thyroid 10:587–594.
386. Santini F, Bottici V, Elisei R, Montanelli L, Mazzeo S, Basolo
F, Pinchera A, Pacini F 2002 Cytotoxic effects of carbopla-
tinum and epirubicin in the setting of an elevated serum
thyrotropin for advanced poorly differentiated thyroid
cancer. J Clin Endocrinol Metab 87:4160–4165.
387. Ain KB, Lee C, Williams KD 2007 Phase II trial of tha-
lidomide for therapy of radioiodine-unresponsive and
rapidly progressive thyroid carcinomas. Thyroid 17:663–
388. Cohen EE, Rosen LS, Vokes EE, Kies MS, Forastiere AA,
Worden FP, Kane MA, Sherman E, Kim S, Bycott P, Tor-
torici M, Shalinsky DR, Liau KF, Cohen RB 2008 Axitinib is
an active treatment for all histologic subtypes of advanced
thyroid cancer: results from a phase II study. J Clin Oncol
389. Gupta-Abramson V, Troxel AB, Nellore A, Puttaswamy K,
Redlinger M, Ransone K, Mandel SJ, Flaherty KT, Loevner
LA, O’Dwyer PJ, Brose MS 2008 Phase II trial of sorafenib
in advanced thyroid cancer. J Clin Oncol 26:4714–4719.
390. Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L,
Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T,
Stepan DE, Schlumberger MJ 2008 Motesanib diphosphate
in progressive differentiated thyroid cancer. N Engl J Med
391. Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Ste-
vens R, Liang J, Wakely PE Jr, Vasko VV, Saji M, Ritten-
berry J, Wei L, Arbogast D, Collamore M, Wright JJ, Grever
M, Shah MH 2009 Phase II trial of sorafenib in metastatic
thyroid cancer. J Clin Oncol 27:1675–1684.
392. Luster M, Lippi F, Jarzab B, Perros P, Lassmann M, Reiners
C, Pacini F 2005 rhTSH-aided radioiodine ablation and
treatment of differentiated thyroid carcinoma: a compre-
hensive review. Endocr Relat Cancer 12:49–64.
393. Van Tol KM, Hew JM, Jager PL, Vermey A, Dullaart RP,
Links TP 2000 Embolization in combination with radio-
iodine therapy for bone metastases from differentiated
thyroid carcinoma. Clin Endocrinol (Oxf) 52:653–659.
394. Posteraro AF, Dupuy DE, Mayo-Smith WW 2004 Radio-
frequency ablation of bony metastatic disease. Clin Radiol
395. Masala S, Fiori R, Massari F, Simonetti G 2003 Vertebro-
plasty and kyphoplasty: new equipment for malignant
vertebral fractures treatment. J Exp Clin Cancer Res 22:
396. McWilliams RR, Giannini C, Hay ID, Atkinson JL, Stafford
SL, Buckner JC 2003 Management of brain metastases from
thyroid carcinoma: a study of 16 pathologically confirmed
cases over 25 years. Cancer 98:356–362.
397. Walter MA, Turtschi CP, Schindler C, Minnig P, Mu ¨ller-
Brand J, Mu ¨ller B 2007 The dental safety profile of high-
dose radioiodine therapy for thyroid cancer: long-term
results of a longitudinal cohort study. J Nucl Med 48:1620–
398. Kloos RT, Duvuuri V, Jhiang SM, Cahill KV, Foster JA,
Burns JA 2002 Nasolacrimal drainage system obstruction
from radioactive iodine therapy for thyroid carcinoma. J
Clin Endocrinol Metab 87:5817–5820.
399. Sandeep TC, Strachan MW, Reynolds RM, Brewster DH,
Sce ´lo G, Pukkala E, Hemminki K, Anderson A, Tracey E,
Friis S, McBride ML, Kee-Seng C, Pompe-Kirn V, Kliewer
EV, Tonita JM, Jonasson JG, Martos C, Boffetta P, Brennan
P 2006 Second primary cancers in thyroid cancer patients: a
multinational record linkage study. J Clin Endocrinol Me-
400. Subramanian S, Goldstein DP, Parlea L, Thabane L, Ezzat
S, Ibrahim-Zada I, Straus S, Brierley JD, Tsang RW, Gafni
A, Rotstein L, Sawka AM 2007 Second primary malignancy
risk in thyroid cancer survivors: a systematic review and
meta-analysis. Thyroid 17:1277–1288.
401. Mandel SJ, Mandel L 2003 Radioactive iodine and the sal-
ivary glands. Thyroid 13:265–271.
402. Nakada K, Ishibashi T, Takei T, Hirata K, Shinohara K,
Katoh S, Zhao S, Tamaki N, Noguchi Y, Noguchi S 2005
Does lemon candy decrease salivary gland damage after
radioiodine therapy for thyroid cancer? J Nucl Med 46:
403. Sawka AM, Thabane L, Parlea L, Ibrahim-Zada I, Tsang
RW, Brierley JD, Straus S, Ezzat S, Goldstein DP 2009
Second primary malignancy risk after radioactive iodine
treatment for thyroid cancer: a systematic review and meta-
analysis. Thyroid 19:451–457.
404. Chen AY, Levy L, Goepfert H, Brown BW, Spitz MR,
Vassilopoulou-Sellin R 2001 The development of breast
carcinoma in women with thyroid carcinoma. Cancer
405. Vini, L, Hyer S, Al-Saadi A, Pratt B, Harmer C 2002 Prog-
nosis for fertility and ovarian function after treatment with
radioiodine for thyroid cancer. Postgrad Med J 78:92.
406. Dottorini ME, Lomuscio G, Mazzucchelli L, Vignati A,
Colombo L 1995 Assessment of female fertility and carci-
1212COOPER ET AL.
nogenesis after iodine-131 therapy for differentiated thy-
roid carcinoma. J Nucl Med 36:21–27.
407. Sawka AM, Lakra DC, Lea J, Alshehri B, Tsang RW,
Brierley JD, Straus S, Thabane L, Gafni A, Ezzat S, George
SR, Goldstein DP 2008 A systematic review examining the
effects of therapeutic radioactive iodine on ovarian function
and future pregnancy in female thyroid cancer survivors.
Clin Endocrinol (Oxf) 69:479–490.
408. Schlumberger M, De Vathaire F, Ceccarelli C, Delisle MJ,
Francese C, Couette JE, Pinchera A, Parmentier C 1996
Exposure to radioactive iodine-131 for scintigraphy or
therapy does not preclude pregnancy in thyroid cancer
patients. J Nucl Med 37:606–612.
409. Garsi JP, Schlumberger M, Rubino C, Ricard M, Labbe ´ M,
Paoletti C, Ceccarelli C, Schvartz C, Henri-Amar M, Cou-
ette JE, de Vathaire F 2008 Therapeutic administration of
131I for differentiated thyroid cancer, radiation dose to
ovaries and outcome of pregnancies. J Nucl Med 49:
410. Ceccarelli C, Benicivelli W, Morciano D, Pinchera A, Pacini
F 2001 I-131 therapy for differentiated thyroid cancer leads
to an earlier onset of menopause: Results of a retrospective
study. J Clin Endocrinol Metab 86:3512.
411. Wichers M, Benz E, Palmedo H, Biersack HJ, Grunwald F,
Klingmuller D 2000 Testicular function after radioiodine
therapy for thyroid carcinoma. Eur J Nucl Med 27:503–507.
412. Hyer S, Vini L, O’Connell M, Pratt B, Harmer C 2002 Tes-
ticular dose and fertility in men following I(131) therapy for
thyroid cancer. Clin Endocrinol (Oxf) 56:755–758.
413. Lushbaugh CC, Casarett GW 1976 The effects of gonadal
irradiation in clinical radiation therapy: a review. Cancer
414. Sarkar SD, Beierwaltes WH, Gill SP, Cowley BJ 1976 Sub-
sequent fertility and birth histories of children and ado-
lescents treated with I-131 for thyroid cancer. J Nucl Med
415. Mazzaferri E 2002 Gonadal damage from 131I therapy for
thyroid cancer. Clin Endocrinol 57:313–314.
416. van Tol KM, Jager PL, de Vries EG, Piers DA, Boezen HM,
Sluiter WJ, Dullaart RP, Links TP 2003 Outcome in patients
with differentiated thyroid cancer with negative diagnostic
whole-body scanning and detectable stimulated thyro-
globulin. Eur J Endocrinol 148:589–596.
417. Pineda JD, Lee T, Ain K, Reynolds JC, Robbins J 1995
Iodine-131 therapy for thyroid cancer patients with ele-
vated thyroglobulin and negative diagnostic scan. J Clin
Endocrinol Metab 80:1488–1492.
418. Pacini F, Agate L, Elisei R, Capezzone M, Ceccarelli C,
Lippi F, Molinaro E, Pinchera A 2001 Outcome of differ-
entiated thyroid cancer with detectable serum thyroglob-
ulin and negative diagnostic (131)I whole body scan:
comparison of patients treated with high (131)I activities
versus untreated patients. J Clin Endocrinol Metab 86:4092–
419. Palmedo H, Bucerius J, Joe A, Strunk H, Hortling N, Meyka
S, Roedel R, Wolff M, Wardelmann E, Biersack HJ, Jaeger U
2006 Integrated PET=CT in differentiated thyroid cancer:
diagnostic accuracy and impact on patient management. J
Nucl Med 47:616–624.
420. Shammas A, Degirmenci B, Mountz JM, McCook BM,
Branstetter B, Bencherif B, Joyce JM, Carty SE, Kuffner HA,
Avril N 2007 18F-FDG PET=CT in patients with suspected
recurrent or metastatic well-differentiated thyroid cancer. J
Nucl Med 48:221–226.
421. Dietlein M, Scheidhauer K, Voth E, Theissen P, Schicha H
1997 Fluorine-18 fluorodeoxyglucose positron emission
tomography and iodine-131 whole-body scintigraphy in
the follow-up of differentiated thyroid cancer. Eur J Nucl
422. Schlu ¨ter B, Bohuslavizki KH, Beyer W, Plotkin M, Buchert
R, Clausen M 2001 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.
423. Kloos RT 2008 Approach to the patient with a positive se-
rum thyroglobulin and a negative radioiodine scan after
initial therapy for differentiated thyroid cancer. J Clin En-
docrinol Metab 93:1519–1525.
424. Kabasakal L, Selcuk NA, Shafipour H, Ozmen O, Onsel C,
Uslu I 2004 Treatment of iodine-negative thyroglobulin-
positive thyroid cancer: differences in outcome in patients
with macrometastases and patients with micrometastases.
Eur J Nucl Med Mol Imaging 31:1500–1504.
425. Wang W, Macapinlac H, Larson SM, Yeh SD, Akhurst T,
Finn RD, Rosai J, Robbins RJ 1999 [18F]-2-fluoro-2-deoxy-
D-glucose 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.
426. Helal BO, Merlet P, Toubert ME, Franc B, Schvartz C,
Gauthier-Koelesnikov H, Prigent A, Syrota A 2001 Clinical
impact of (18)F-FDG PET in thyroid carcinoma patients
with elevated thyroglobulin levels and negative (131)I
scanning results after therapy. J Nucl Med 42:1464–1469.
427. Nahas Z, Goldenberg D, Fakhry C, Ewertz M, Zeiger M,
Ladenson PW, Wahl R, Tufano RP 2005 The role of positron
emission tomography=computed tomography in the man-
agement of recurrent papillary thyroid carcinoma. Lar-
428. Rosario PW, Maia FF, Fagundes TA, Vasconcelos FP, Car-
doso LD, Purisch S 2004 Antithyroglobulin antibodies in
patients with differentiated thyroid carcinoma: methods of
detection, interference with serum thyroglobulin measure-
ment and clinical significance. Arq Bras Endocrinol Meta-
429. Chung JK, Park YJ, Kim TY, So Y, Kim SK, Park DJ, Lee DS,
Lee MC, Cho BY 2002 Clinical significance of elevated level
of serum antithyroglobulin antibody in patients with dif-
ferentiated thyroid cancer after thyroid ablation. Clin En-
docrinol (Oxf) 57:215–221.
430. Chinnappa P, Taguba L, Arciaga R, Faiman C, Siperstein A,
Mehta AE, Reddy SK, Nasr C, Gupta MK 2004 Detection of
thyrotropin-receptor messenger ribonucleic acid (mRNA)
and thyroglobulin mRNA transcripts in peripheral blood of
patients with thyroid disease: sensitive and specific mark-
ers for thyroid cancer. J Clin Endocrinol Metab 89:3705–
431. Li D, Butt A, Clarke S, Swaminathana R 2004 Real-time
quantitative PCR measurement of thyroglobulin mRNA in
peripheral blood of thyroid cancer patients and healthy
subjects. Ann N Y Acad Sci 1022:147–151.
432. Grammatopoulos D, Elliott Y, Smith SC, Brown I, Grieve
RJ, Hillhouse EW, Levine MA, Ringel MD 2003 Measure-
ment of thyroglobulin mRNA in peripheral blood as an
adjunctive test for monitoring thyroid cancer. Mol Pathol
433. Elisei R, Vivaldi A, Agate L, Molinaro E, Nencetti C, Grasso
L, Pinchera A, Pacini F 2004 Low specificity of blood thy-
roglobulin messenger ribonucleic acid assay prevents its
REVISED ATA THYROID CANCER GUIDELINES 1213
use in the follow-up of differentiated thyroid cancer pa-
tients. J Clin Endocrinol Metab 89:33–39.
434. Bellantone R, Lombardi CP, Bossola M, Ferrante A, Princi
P, Boscherini M, Maussier L, Salvatori M, Rufini V, Reale F,
Romano L, Tallini G, Zelano G, Pontecorvi A 2001 Validity
of thyroglobulin mRNA assay in peripheral blood of
postoperative thyroid carcinoma patients in predicting tu-
mor recurrences varies according to the histologic type:
results of a prospective study. Cancer 92:2273–2279.
435. Greene FL (ed) 2002 AJCC Cancer Staging Manual, 6th ed.
Springer-Verlag, New York.
436. Preissner CM, Dodge LA, O’Kane DJ, Singh RJ, Grebe SK
2005 Prevalence of heterophilic antibody interference in
eight automated tumor marker immunoassays. Clin Chem
437. Preissner CM, O’Kane DJ, Singh RJ, Morris JC, Grebe SK
2003 Phantoms in the assay tube: heterophile antibody in-
terferences in serum thyroglobulin assays. J Clin En-
docrinol Metab 88:3069–3074.
Address correspondence to:
David S. Cooper, M.D.
Division of Endocrinology
The Johns Hopkins University School of Medicine
1830 East Monument Street Suite 333
Baltimore, MD 21287
1214 COOPER ET AL.
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radioiodine therapy of thyroid cancer using 124I PET(/CT) imaging. European Journal of Nuclear Medicine and Molecular Imaging
28.Flavia Prodam , Loredana Pagano , Sara Belcastro , Giuliana Golisano , Arianna Busti , Mariateresa Samà , Marina Caputo ,
Simonetta Bellone , Andrea Voci , Guido Valente , Gianluca Aimaretti . 2010. Pituitary Metastases from Follicular Thyroid
CarcinomaPituitary Metastases from Follicular Thyroid Carcinoma. Thyroid 20:7, 823-830. [Abstract] [Full Text] [PDF] [PDF
29.Ralph P. Tufano , Emad Kandil . 2010. Considerations for Personalized Surgery in Patients with Papillary Thyroid
CancerConsiderations for Personalized Surgery in Patients with Papillary Thyroid Cancer. Thyroid 20:7, 771-776. [Abstract]
[Full Text] [PDF] [PDF Plus]
30.N. G. Iyer, Ashok R. Shaha, Carl E. Silver, Kenneth O. Devaney, Alessandra Rinaldo, Phillip K. Pellitteri, Alfio Ferlito. 2010.
Thyroid incidentalomas: to treat or not to treat. European Archives of Oto-Rhino-Laryngology 267:7, 1019-1026. [CrossRef]
31.S. Piana, A. Frasoldati, M. Ferrari, R. Valcavi, E. Froio, V. Barbieri, C. Pedroni, G. Gardini. 2010. Is a five-category reporting
scheme for thyroid fine needle aspiration cytology accurate? Experience of over 18 000 FNAs reported at the same institution
during 1998-2007. Cytopathology no-no. [CrossRef]
32.M. Dietlein, M. Luster, C. Reiners. 2010. Nuklearmedizinische Therapie und Nachsorge des differenzierten
Schilddrüsenkarzinoms: Status quo. Der Onkologe 16:7, 678-689. [CrossRef]
33.H. Dralle, K. Lorenz, A. Machens, M. Brauckhoff, P. Nguyen Thanh. 2010. Tumortyp- und tumorstadienorientiertes
chirurgisches Konzept bei Karzinomen der Schilddrüse. Der Onkologe 16:7, 666-677. [CrossRef]
34.W. Karges. 2010. Kalzitoninbestimmung zur Frühdiagnose des medullären Schilddrüsenkarzinoms. Der Chirurg 81:7, 620-626.
35.W. Karges, G. Brabant. 2010. Schilddrüsenkarzinom – Klinik und Diagnostik. Der Onkologe 16:7, 657-665. [CrossRef]
36.Dong Li, Zhaowei Meng, Guizhi Zhang, Tielian Yu, Jian Tan, Feng Dong. 2010. Visualization of Thyroglossal Duct Cyst in
Differentiated Thyroid Cancer Patient. Clinical Nuclear Medicine 35:7, 499-504. [CrossRef]
37.D. Vordermark, T. Pelz, F. Sieker. 2010. Die Rolle der externen Strahlentherapie bei der Behandlung des Schilddrüsenkarzinoms.
Der Onkologe 16:7, 695-700. [CrossRef]
38.M. Hermann, K. Tonninger, F. Kober, E.-M. Furtlehner, A. Schultheis, N. Neuhold. 2010. Minimal-invasives follikuläres
Schilddrüsenkarzinom. Der Chirurg 81:7, 627-635. [CrossRef]