Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.
ABSTRACT 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 management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines.
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.
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.
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 patients with these disorders.
- [Show abstract] [Hide abstract]
ABSTRACT: A novel approach to the development of a precise method of intraoperative diagnostics of thyroid cancer has been proposed on the basis of fundamental study of proteasomes in malignant tumors of mammals and human. The method is based on estimation of proteasome activity in small fragments of the tumor and adjacent tissues.Biology Bulletin 07/2014; 41(4):318-323. · 0.24 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Context and Objective: Oncocytic thyroid carcinoma, also known as Hürthle cell thyroid carcinoma, accounts for only a small percentage of all thyroid cancers. However, this malignancy often presents at an advanced stage and poses unique challenges to patients and clinicians. Surgical resection of the tumor accompanied in some cases by radioactive iodine treatment, radiation and chemotherapy are the established modes of therapy. Knowledge of the perturbed oncogenic pathways can provide better understanding of the mechanism of disease and thus opportunities for more effective clinical management. Design and Patients: Initially, two oncocytic thyroid carcinomas and their matched normal tissues were profiled using whole genome sequencing. Subsequently, 72 oncocytic thyroid carcinomas, one cell line and 5 Hürthle cell adenomas were examined by targeted sequencing for the presence of mutations in the multiple endocrine neoplasia I (MEN1) gene. Results: Here we report the identification of MEN1 loss-of-function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma. Whole genome sequence data also revealed large regions of copy number variation encompassing nearly the entire genomes of these tumors. Conclusion: Menin, a ubiquitously expressed nuclear protein, is a well-characterized tumor suppressor whose loss is the cause of multiple endocrine neoplasia type 1 syndrome. Menin is involved in several major cellular pathways such as regulation of transcription, control of cell cycle, apoptosis and DNA damage repair pathways. Mutations of this gene in a subset of Hürthle cell tumors point to a potential role for this protein and its associated pathways in thyroid tumorigenesis.The Journal of clinical endocrinology and metabolism. 01/2015;
- [Show abstract] [Hide abstract]
ABSTRACT: Lymph node metastases at the time of diagnosis have a major impact on both therapeutic strategy and tumor recurrence for patients with papillary thyroid microcarcinoma (PTMC). Our objective was to evaluate the usefulness of PTMC characteristics on ultrasonography for predicting central compartment lymph node metastases (CCLNM) of PTMC. One hundred twenty seven patients who underwent surgery for PTMC were enrolled in this study. The relationship between the CCLNM and the characteristics on conventional US, elastographic, and contrast enhanced ultrasound (CEUS) were investigated. Univariate analysis indicated that PTMCs with CCLNM were more often nodule irregular shape, microcalcifications, hyperenhancing or isoenhancing parametric maps, and peak index ≥1 at preoperative US and CEUS than those without CCLNM (P< 0.01, 0.05, 0.01 and 0.05 respectively). Multivariate analysis showed that microcalcification (OR:2.378, 95% CI: 1.096-5.158) and hyperenhancement or isoenhancement (OR:2.8, 95% CI: 1.287-6.094) were predictive for the presence of CCLNM. Elastography score was not significantly different between the groups. Our study indicated that preoperative thyroid nodule characteristics on conventional US and CEUS may serve as a useful tool to predict central compartment lymph node metastases in PTMC.Scientific reports. 01/2015; 5:7748.
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)
Sections and subsectionsItemb
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 GUIDELINES 1171
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:
1176COOPER 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 GUIDELINES 1177
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
1178COOPER 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-
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).
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