Clinical Review & Education

JAMA | Review

The Diagnosis and Management of Thyroid Nodules

A Review
Cosimo Durante, MD, PhD; Giorgio Grani, MD; Livia Lamartina, MD; Sebastiano Filetti, MD;
Susan J. Mandel, MD, MPH; David S. Cooper, MD

CME Quiz at
IMPORTANCE Thyroid nodules are common, being detected in up to 65% of the general jamanetwork.com/learning
population. This is likely due to the increased use of diagnostic imaging for purposes
unrelated to the thyroid. Most thyroid nodules are benign, clinically insignificant,
and safely managed with a surveillance program. The main goal of initial and long-term
follow-up is identification of the small subgroup of nodules that harbor a clinically
significant cancer (≈10%), cause compressive symptoms (≈5%), or progress to
functional disease (≈5%).

OBSERVATIONS Thyroid function testing and ultrasonographic characteristics guide

the initial management of thyroid nodules. Certain ultrasound features, such as
a cystic or spongiform appearance, suggest a benign process that does not require Author Affiliations: Dipartimento
additional testing. Suspicious sonographic patterns including solid composition, di Medicina Interna e Specialità
Mediche, Università di Roma
hypoechogenicity, irregular margins, and microcalcifications should prompt cytological
“Sapienza,” Roma, Italy (Durante,
evaluation. Additional diagnostic procedures, such as molecular testing, are indicated Grani, Lamartina, Filetti); Division of
only in selected cases, such as indeterminate cytology (≈20%-30% of all biopsies). Endocrinology, Diabetes and
The initial risk estimate, derived from ultrasound and, if performed, cytology report, Metabolism, Perelman School of
Medicine, University of Pennsylvania,
should determine the need for treatment and the type, frequency, and length of Philadelphia (Mandel); Division of
subsequent follow-up. Management includes simple observation, local treatments, Endocrinology, Diabetes and
and surgery and should be based on the estimated risk of malignancy and the Metabolism, The Johns Hopkins
University School of Medicine,
presence and severity of compressive symptoms.
Baltimore, Maryland (Cooper).
Corresponding Author: David S.
CONCLUSIONS AND RELEVANCE Most thyroid nodules are benign. A diagnostic approach Cooper, MD, Division of
that uses ultrasound and, when indicated, fine-needle aspiration biopsy and molecular Endocrinology, Diabetes, and
testing, facilitates a personalized, risk-based protocol that promotes high-quality care Metabolism, 1830 E Monument St,
Ste 333, Baltimore, MD 21287
and minimizes cost and unnecessary testing.
(dscooper@jhmi.edu).
Section Editors: Edward Livingston,
JAMA. 2018;319(9):914-924. doi:10.1001/jama.2018.0898 MD, Deputy Editor, and Mary McGrae
McDermott, MD, Senior Editor.

T
hyroid nodules are defined as discrete lesions with-
in the thyroid gland, radiologically distinct from sur-
rounding thyroid parenchyma. 1 Their diagnosis is in-
creasingly common in clinical practice. Among the large number
of nodules found in the general population (about 16 million
of individuals in the United States are estimated to have a pal-
pable nodule; up to 219 million have an ultrasound-detectable
nodule), the main goal should be the identification of nodules
that are clinically relevant. These include the subgroup harbor-
ing a significant cancer (approximately 10%), and those causing
(or are at risk of causing) compressive symptoms (5%), or thy-
roid dysfunction (5%). Approximately 90% of thyroid nodules
are benign and 95% are asymptomatic and remain so during
follow-up. These nodules can be safely managed with a less
intensive follow-up protocol. This review provides an evidence-
based summary of the optimal approach to the management of
thyroid nodules.
Methods
PubMed and Scopus databases were searched to identify high-
quality studies, systematic reviews and meta-analyses, and clin-
ical practice guidelines published in the last 3 years regarding
thyroid nodule evaluation and treatment. We identified articles
that focused on clinically important questions about thyroid
nodule management and reviewed the reference list of the
selected articles.
Epidemiology
With physical examination (neck palpation), thyroid nodule
prevalence in iodine-sufficient populations is approximately
5%, depending on age and sex.2 However, clinicians encounter
a much higher proportion of patients harboring occult thy-
roid nodules, reaching up to 68% of the general population.3

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 Diagnosis and Management of Thyroid Nodules
This discrepancy is largely due to incidental discovery of asymp-
tomatic nodules, generally small, due to the increased use of diag-
nostic imaging for purposes unrelated to the thyroid (the
so-called thyroid incidentaloma). The reported prevalence is
about 65% with ultrasonography, 15% with computed tomogra-
phy (CT) or magnetic resonance imaging (MRI), and 1% to 2%
with 18fluorodeoxyglucose positron emission tomography (PET).4
Nodules are solitary in about the half of the patients.5 The preva-
lence of thyroid nodules and the rate of multinodularity increase
with age,6 female sex, and body mass index.3
Approximately 10% of patients who present with thyroid
nodules are at risk of malignancy,7 the rate of which ranges from
between 5% and 13% of patients with ultrasound-, CT-, or MRI-
detected incidentalomas. In case of focal uptake on the PET scan
and an increased maximum standardized uptake value, the risk of
malignancy may increase to 55%.8 Risk factors for malignancy
include childhood irradiation (mainly head and neck and whole
body radiation),9,10 exposure to ionizing radiation from fallout in
childhood or adolescence,11 family history of thyroid cancer or
hereditary syndromes that include thyroid cancer (eg, multiple
endocrine neoplasia syndrome type 2, familial adenomatous
polyposis), rapid nodule growth, or hoarseness. 1 Insufficient
evidence is available for other factors proposed to be associ-
ated with nodule formation or malignancy, such as serum levels
of thyrotropin,12 thyroid autoantibodies,13 obesity,14 and meta-
bolic syndrome.15
The US Preventive Services Task Force (USPSTF), which
reviews the effectiveness of screening programs in asymptomatic
individuals, recommended against screening for thyroid cancer in
adults without signs or symptoms of the disease.16 The panel con-
cluded that the potential harms likely outweigh any potential
benefits. The USPSTF recommendation does not apply to
patients with risk factors.16 Screening individuals with previous
neck irradiation or familial nonmedullary thyroid cancer (family
with ⱖ3 affected relatives, or genetic syndromes such as Cowden
disease, familial adenomatous polyposis, Carney complex) may
lead to an earlier diagnosis of cancer, but there is insufficient evi-
dence that this would reduce morbidity or mortality.1 For this rea-
son, there is no evidence to support ultrasound screening in these
contexts. Genetic counseling and testing for rearranging during
transfection (RET) germline mutations should be offered to first-
degree relatives of patients with proven hereditary medullary
thyroid cancer.17
Clinical Evaluation
Most patients are asymptomatic. Symptoms from a thyroid nodule
or thyroid enlargement include: globus sensation (sensation of a
lump or foreign body in the throat); dysphagia or swallowing com-
plaints (stasis, choking, odynophagia); dyspnea; dysphonia or hoarse-
ness; and pain (due to acute increase of nodule size, as in case of
bleeding into the nodule).
The presence of symptoms from a thyroid nodule depends
on its size and location. In particular, a globus sensation is more
likely to be associated with a nodule size of more than 3 cm and a
position close to the trachea (isthmic nodules more than paraisth-
mic nodules).18 Swallowing complaints are reported in 67% of the
patients with either hypothyroidism or thyroid nodules. However,
if attributable to nodular thyroid disease, the lesion is typically
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Review Clinical Review & Education
Box. Differential Diagnoses of Anterior Neck Masses
Congenital conditions (lateral neck: brachial anomalies,
cystic hygroma; central neck: thyroglossal duct cysts)
Inflammatory/infectious diseases (lymphadenopathy,
sialadenitis, neck abscess, tuberculosis, cat-scratch disease
[Bartonella lymphadenitis])
Trauma
Thyroid nodule
Malignancy
located in the left lobe with posterior extension, such that it may
cause extrinsic compression of the cervical esophagus.19
Physical examination of the thyroid should include inspection
for visible lumps and palpation of the thyroid and cervical lymph
nodes, searching for firm or fixed nodes or a tender mass. The dif-
ferential diagnosis of a palpable anterior neck mass is summarized
in Box.20,21 Firm, fixed, matted, or rapidly growing masses require
prompt evaluation.20 Physical examination is frequently normal be-
cause many thyroid nodules are not palpable because of their small
size, posterior location within the gland, or a consistency similar to
the thyroid gland.22
Laboratory Testing
Thyrotropin and Thyroid Hormones
Serum thyrotropin should be measured during the initial evalua-
tion of all patients with a thyroid nodule.1 The goal is to exclude the
small number of hyperfunctioning nodules (ⱕ5% of all nodules)23:
if the serum thyrotropin is subnormal, free thyroxine plus total or
free triiodothyronine should be measured22 and a radionuclide scan
performed, looking for focal uptake.1,22 If the serum thyrotropin level
is higher than the reference range, the free thyroxine and antithy-
roid peroxidase antibody should be measured to quantify the de-
gree of thyroid hypofunction and to evaluate for autoimmune
(Hashimoto) thyroiditis.22
Thyroglobulin
Routine measurement of serum thyroglobulin in evaluation of nod-
ules is not recommended.1 Even if some evidence suggests that very
high thyroglobulin levels may predict malignancy,24 thyroglobulin
can also be elevated in many benign thyroid diseases (eg, multi-
nodular goiter, thyroiditis). Therefore, this test has inadequate speci-
ficity for thyroid cancer diagnosis.
Calcitonin
Calcitonin is produced by the parafollicular C cells of the thyroid
and is a serum marker for medullary thyroid cancer. Recent guide-
lines included no recommendation regarding the measurement of
serum calcitonin to evaluate thyroid nodules.1 Although routine cal-
citonin evaluation may detect medullary thyroid cancer at an earlier
stage, there is insufficient evidence that early diagnosis reduces
medullary thyroid cancer–specific mortality.1 Furthermore, assay
performance, specificity and cost-effectiveness are suboptimal.25
If measured, basal calcitonin levels of more than 100 pg/mL sug-
gest a diagnosis of medullary thyroid cancer (sensitivity, 60%;
specificity, 100%).26(To convert calcitonin from pg/mL to pmol/L,
multiply by 0.292.)
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Table 1. Standardized Sonographic Scoring Systems Proposed or Endorsed by Practice Guidelines for Risk-Based Fine-Needle Aspiration Biopsy Guidance for Thyroid Nodules

AACE, ACE, and AME, 201622 ATA, 20151 EU-TIRADS, 201731 ACR TIRADS, 201730
Low-Risk and Benign Thyroid Nodules
Low-risk definition Benign definition Benign (EU-TIRADS 2) definition Benign (TR1) definition
Risk of malignancy, 1% Risk of malignancy, <1% Risk of malignancy, ≈0% Risk of malignancy, 2%
FNAB >20 mm (selective)a FNAB is not indicated FNAB is not indicated FNAB is not indicated
Sonographic pattern Sonographic pattern Sonographic pattern Sonographic pattern
Cysts (fluid component >80%) Purely cystic nodules (no solid component) Pure, anechoic cysts; Spongiform
Mostly cystic nodules with Entirely spongiform nodules Pure cyst
reverberating artifacts
Not suspicious (TR2) definition
and not associated with
Risk of malignancy, 2%
Clinical Review & Education Review

suspicious ultrasound signs

FNAB is not indicated
Isoechoic spongiform nodules,
Sonographic pattern
either confluent or
Mixed cystic/solid
with regular halo
noncalcified nodules
with smooth margins
and oval shape
Very low–suspicion risk definition Low-risk (EU-TIRADS 3) risk definition Mildly suspicious (TR3) risk definition
Risk of malignancy, <3% Risk of malignancy, 2%-4% Risk of malignancy, 5%

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FNAB ≥20 mm or observation FNAB >20 mm FNAB ≥25 mm
Sonographic pattern Sonographic pattern Sonographic pattern

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Spongiform/partially cystic nodules Oval shape, smooth margins, Isoechoic solid or hypoechoic
without any ultrasound features isoechoic or hyperechoic, cystic noncalcified nodules
defining low-, intermediate-, without any feature of high risk with smooth margins
or high-suspicion patterns and oval shape
Low suspicion–risk definitions
Risk of malignancy, 5%-10%
FNAB ≥15 mm
Sonographic pattern
Isoechoic/hyperechoic solid
or partially cystic nodule
with eccentric solid area
without microcalcifications,
irregular margin,
extrathyroidal extension,
taller than wide shape
Intermediate or Moderately Suspicious Thyroid Nodules
Intermediate-risk definition Intermediate-suspicion definition Intermediate-risk (EU-TIRADS 4) definition Moderately suspicious (TR4) definition
Risk of malignancy, 5%-15% Risk of malignancy, 10%-20% Risk of malignancy, 6%-17% Risk of malignancy, 5%-20%
FNAB >20 mm FNAB ≥10 mm FNAB >15 mm FNAB >15 mm

© 2018 American Medical Association. All rights reserved.

Sonographic pattern Sonographic pattern Sonographic pattern Sonographic patterns
Slightly hypoechoic Hypoechoic solid nodule Oval shape, smooth margins, Hypoechoic solid
(vs thyroid tissue) with smooth margins mildly hypoechoic, without noncalcified nodules
or isoechoic nodules, without microcalcifications, any feature of high risk with oval shape and
with ovoid-to-round shape, extrathyroidal extension either smooth or irregular
smooth or ill-defined margins or taller than wide shape or lobulated margins
May be present Isoechoic solid or mixed
Intranodular vascularization noncalcified nodules with
Elevated stiffness either nonparallel orientation
at elastography (taller than wide), lobulated
Macro or continuous or irregular margins, or
rim calcifications punctate echogenic foci
Indeterminate
hyperechoic spots

(continued)

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Diagnosis and Management of Thyroid Nodules
 Diagnosis and Management of Thyroid Nodules Review Clinical Review & Education

Ultrasound, Cytology, and Molecular Testing

An FNAB is recommended for smaller nodules that are subcapsular location near the recurrent nerve or trachea;
Thyroid Ultrasonography

and neck irradiation; coexistent suspicious clinical findings. An FNAB indicates the size above which a FNAB
suspicious lymph nodes or extrathyroid spread; personal or family history of thyroid cancer; history of head
Sonography is the primary tool used for initial cancer risk stratifica-
tion of thyroid nodules and subsequently deciding whether to
order a fine-needle aspiration biopsy. Because the thyroid is super-
ficially located in the neck, with its posterior border generally situ-

irregular or lobulated margins

ated less than 4 cm from the skin, high-resolution (ⱖ12 MHz)
Hypoechoic solid nodule with

Isoechoic solid nodule with

punctate echogenic foci

probes provide excellent image definition. Ultrasound is indicated
Table 1. Standardized Sonographic Scoring Systems Proposed or Endorsed by Practice Guidelines for Risk-Based Fine-Needle Aspiration Biopsy Guidance for Thyroid Nodules (continued)

Risk of malignancy, ≥20%

Extrathyroidal extension
Suspicious (TR5) definition

Punctate echogenic foci

and either peripheral

Nonparallel orientation
any of the following

rim calcifications or
when either the thyroid gland is palpably abnormal or a thyroid
(taller than wide)
ACR TIRADS, 201730

nodule is incidentally detected on another radiological study.

Sonographic pattern
FNAB >10 mm

Nonspecific symptoms or abnormal laboratory test results (such

as fatigue, increased serum thyrotropin levels, or autoimmune

In accordance with the presence of 1 or more suspicious findings.

thyroiditis) are not indications for sonography. However, ultra-
sound is necessary to differentiate between asymmetric involve-
ment of the thyroid gland by lymphocytic thyroiditis vs a superim-
posed thyroid nodule, for which further evaluation may be
required. A diagnostic ultrasound report should include descrip-
tion of the background thyroid parenchyma, nodule location, size
(in 3 dimensions), sonographic features (Table 1), and survey of
the cervical lymph nodes.27
Nodules with ≥ 1 of the following:
High-risk (EU-TIRADS 5) definition

Certain sonographic characteristics are associated with thyroid

Risk of malignancy, 26%-87%

cancer while others are more likely to indicate a benign nature.

cytology is recommended.
Marked hypoechogenicity

Ultrasound characteristics associated with malignancy include solid

composition, hypoechogenicity (nodule is darker than normal thy-
Microcalcifications
Sonographic pattern

Irregular margins
EU-TIRADS, 201731

roid tissue), margins that appear infiltrative or irregular, and pres-

Nonoval shape
FNAB >10 mm

ence of microcalcifications. In addition, a nodule surrounded by

interrupted rim calcifications with evidence of soft tissue extrusion
is likely to be an infiltrative cancer.28 Conversely, pure cysts and
b

nodules with a “spongiform” consistency, defined when more than

c

half of nodule volume is composed of microcystic spaces, are

unlikely to be malignant (<2%). Cancer risk is low (<5%-10%) for
Endocrinology, and Associazione Medici Endocrinologi; ACR, American College of Radiologists; ATA, American
Thyroid Association; EU-TIRADS, European Thyroid Imaging Reporting and Data System; FNAB, fine-needle

solid noncalcified smoothly marginated nodules that are either

isoechoic or hyperechoic (same or lighter gray scale imaging com-
Abbreviations. AACE/ACE/AME, American Association of Clinical Endocrinologists, American College of

aspiration biopsy; TR, American College of Radiologists Thyroid Imaging Reporting and Data System.

pared with normal thyroid).29

(infiltrative, microlobulated)

small extrusive soft tissue

The American Thyroid Association1 and other professional

solid hypoechoic component
Risk of malignancy, >70%-90%

Extrathyroidal extension

groups22,30-32 have devised similar but not identically tiered sys-

Rim calcifications with
with ≥1 of the following:

Taller than wide shape

of partially cystic nodule
Solid hypoechoic nodule or

tems to classify nodules by constellations of sonographic features

Microcalcifications
Irregular margins
High-suspicion definiton

that convey cancer risk and to recommend size cutoffs for fine-
Sonographic pattern

needle aspiration biopsy (Table 1, Figure 1, and Figure 2). Guidelines

FNAB ≥10 mm

from endocrinology societies have focused on nodule pattern

identification,1,22,31 accompanied by figures illustrating these pat-
ATA, 20151

Growing nodule, high-risk history, before surgery or local therapies.

terns. Guidelines correlate each pattern to an estimated cancer risk.

Recently, the American College of Radiology30 recommended a
point system for systematic assessment of imaging for thyroid nod-
ules (Thyroid Imaging Reporting and Data System); this mirrors the
American College of Radiology approach to imaging other organs
(eg, the breast). Points are assigned based on 5 ultrasound features
and the sum determines the Thyroid Imaging Reporting and Data
High-Risk or Suspicious Thyroid Nodules

System classification of the nodule, its estimated cancer risk, and

Nodules with ≥ 1 of the following:
FNAB ≥10 mm (5 mm, selective)c

Spiculated or lobulated margins

recommendations for either fine-needle aspiration biopsy or sur-

AACE, ACE, and AME, 201622

veillance. Malignancy risk estimates based on sonographic appear-

(vs prethyroid muscles)
Marked hypoechogenicity

Taller-than-wide shape

Pathologic adenopathy

ance are similar across all 4 classification systems; however, fine-

Extrathyroidal growth
Risk of malignancy,

Microcalcifications
Sonographic patterns

needle aspiration biopsy recommended cutoff sizes differ (Table 1,

High-risk definition

Figure 1, and Figure 2).

50%-90%b

Fine-needle aspiration biopsy is not recommended for pure

cysts, unless it is for fluid aspiration for symptomatic relief. If fine-
needle aspiration biopsy is to be performed for spongiform nod-
ules, the size cutoff is larger than 2 cm, with some guidelines not
a

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 Clinical Review & Education Review
Figure 1. Ultrasonographic Features of Thyroid Nodules Suspicious for Malignancy
A B
D E
A, Markedly hypoechoic nodule (similar echogenicity as the surrounding strap
muscles) with irregular margins. B, Taller-than-wide hypoechoic nodule.
C, Markedly hypoechoic nodule with regular margins. D, Hypoechoic nodule
with infiltrative margins and suspicious extrathyroidal extension (indicated by a
blue arrowhead). E, Multiple interruptions in calcific rim with evidence of
recommending fine-needle aspiration biopsy.30,31 There is wide
variability in the description of single ultrasonographic features
(Cohen κ range, 0.4-0.6 for most variables); the classification sys-
tems may improve interobserver agreement (κ range, 0.61-0.82).33
No evidence is available to guide which system is best. Long-term
prospective studies are needed.
Cytology
Fine-needle aspiration biopsy provides the most definitive diag-
nostic information for evaluating thyroid nodules.1 Fine-needle
aspiration biopsy is simple, safe, and reliable. If the nodule is not
easily palpable or cystic, fine-needle aspiration biopsy is best per-
formed under ultrasound guidance. In the United States and
much of the world, thyroid cytological results reporting is strati-
fied using the 2017 updated Bethesda classification system,34
which provides 6 diagnostic categories (Table 2).35-44 Category 1
is defined as nondiagnostic or insufficient; category 2, benign, and
categories 5 and 6, suspicious for malignancy and malignant,
respectively. Despite interobserver differences in cytological
interpretation,34 Bethesda categories 2, 5, and 6 provide high
enough negative (96.3%, category 2) and positive predictive val-
ues (75.2%, category 5; 98.6%, category 6) for accurate clinical
decision making. 42 However, categories 3 and 4, comprising
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Diagnosis and Management of Thyroid Nodules
C
F
extrusive tissue (indicated by blue arrowheads). Echogenicity is difficult to
interpret because of acoustic shadowing of the calcific rim). F, hypoechoic solid
nodule with microcalcifications and irregular margins. The yellow arrowheads
indicate the thyroid nodule in each panel. The gray scale graphically represents
the shades of gray that can be provided by the ultrasound equipment.
about 20% to 30% of all biopsies, are indeterminate readings and
usually require additional evaluation, having a risk of malignancy
of 10% to 30% and 25% to 40%, respectively.34 In the United
States, the most common approach is the avoidance of surgery
because the majority of nodules in these 2 categories are
benign,42,45 and, when cancer is identified, it is usually nonag-
gressive. In fact, these indeterminate categories rarely include
aggressive variants of papillary thyroid cancer because more than
90% are reported in categories 5 and 6,46 and the rate of follicu-
lar thyroid cancer is low (≈20% of malignant cases).47 The new
Bethesda system adjusts the risk of malignancy of the indetermi-
nate diagnostic categories and their management recommenda-
tions due to the recent recognition of the noninvasive follicular
thyroid neoplasm with papillar y-like nuclear feature s
(NIFTP).34,48 This is thought to represent an early stage of inva-
sive encapsulated follicular variant of papillary cancer, with an
extremely low malignant potential. 49 However, surgery is
required for a definitive diagnosis, and initial management is simi-
lar to that used for a low-risk thyroid cancer.50
Molecular Testing
Molecular testing of fine-needle aspiration biopsy specimens has
gained acceptance in the United States as a popular51 and poten-
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 Diagnosis and Management of Thyroid Nodules
Figure 2. Imaging Features of Indeterminate and Low Suspicion Thyroid Nodules
Imaging features of indeterminate thyroid nodules
A B
Ultrasonographic features of low or very low suspicion thyroid nodules
D E
A, Elevated stiffness at elastography (red indicates soft tissues; blue, hard
tissues; and green, intermediate values of stiffness). B, Complete rim
calcification. C, Slightly hypoechoic nodule with intranodular vascularization.
Flow velocity is converted into a color scale. Flow toward the transducer is
represented in red; away from the transducer is depicted in blue. D, pure cyst.
tially practice-changing approach52,53 to diagnosing indetermi-
nate thyroid nodules. Mutations occur principally in genes coding
for proteins in the mitogen-activated protein kinase (MAPK or
MAP kinase) pathway that regulates cellular proliferation and dif-
ferentiation. A mutation in the BRAF gene (V600E) is found in
approximately 40% of papillary thyroid cancers, as well as in
some poorly differentiated (33%) and anaplastic cancers (45%)
that likely arise from papillary cancers.54 Mutations in the RAS
gene family are found in some papillary cancers (13%, generally
the encapsulated follicular variant), follicular thyroid cancers
(40%-50%), benign follicular adenomas (20%-40%),54 as well as
in NIFTP (30%).49 Fusion genes, hybrid genes formed from 2 pre-
viously separate genes—in which the RET gene that codes for a
cell surface receptor protein not normally expressed by thyroid
follicular cells is fused with a second unrelated gene, called
a RET/PTC oncogene—has been associated with radiation-related
papillary thyroid cancers. Another fusion gene between the gene
coding for the thyroid transcription factor PAX8 and the peroxi-
some proliferator-activated receptor, gamma isoform (PPARG)
gene (PAX8/PPARG) is seen in some follicular thyroid cancers
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Review Clinical Review & Education
C
F
E, Spongiform nodule with more than 50% of the nodule volume composed of
microcystic spaces. F, solid hyperechoic nodule. The arrowheads indicate the
thyroid nodule in each panel. The gray scale graphically represents the shades
of gray that can be provided by the ultrasound equipment.
(30%-35%), the follicular variant of papillary thyroid cancer
(38%), and in some follicular adenomas (2%-13%). Mutations in
the telomerase reverse transcriptase (TERT) and TP53 tumor sup-
pressor genes have also been observed in some thyroid cancers.
In particular, TERT has been reported in less than 10% of papillary
thyroid cancer and more than 70% of anaplastic thyroid cancer;
TP53, in less than 1% of papillary thyroid cancer and more than
70% of anaplastic thyroid cancer.53
The 2 most common molecular testing strategies are muta-
tional analysis and gene expression analysis, in which genetic infor-
mation can be derived from the same material obtained in the origi-
nal fine-needle aspiration biopsy sample. Mutational analysis
involves isolating DNA from thyroid follicular cells in the specimen
and performing gene sequencing, focusing on possible mutations
in BRAF, RAS, TERT, TP53, and other relevant genes, as well for the
presence of fusion genes.55 Such mutational testing has been
termed a rule in test because if a BRAF, TERT, or TP53 mutation is
found or if a fusion gene is detected, thyroid cancer is almost
always present.56 However, while mutations in RAS genes (HRAS,
KRAS, NRAS) are present in thyroid cancers, they are also present in
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 Clinical Review & Education Review
Table 2. The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management
Diagnostic Category
Category 1: Nondiagnostic or Unsatisfactory
Cyst fluid only
Virtually acellular specimen
Obscuring blood, artifacts
Category 2: Benign
Benign follicular nodule (eg, adenomatoid nodule, colloid nodule)
Chronic lymphocytic (Hashimoto) thyroiditis
Granulomatous (subacute) thyroiditis
Category 3: Atypia of Undetermined significance or Follicular Lesion of Undetermined Significance
Focal nuclear atypia
Predominance of Hurthle cells
Microfollicular pattern in a hypocellular specimen
Category 4: Follicular Neoplasm or Suspicious for a Follicular Neoplasmf
Crowded and overlapping follicular cells some or most of which
are arranged as microfollicles
Category 5: Suspicious for Malignancy
Suspicious for papillary thyroid carcinoma
Suspicious for medullary thyroid carcinoma
Suspicious for metastatic carcinoma
Suspicious for lymphoma
Category 6: Malignant
Papillary thyroid carcinoma
Poorly differentiated carcinoma
Medullary thyroid carcinoma
Undifferentiated (anaplastic) carcinoma
Squamous cell carcinoma
Carcinoma with mixed features (to be described)
Abbreviation: FNAB, fine-needle aspiration biopsy.
a
Actual management may depend on other factors (eg, clinical, sonographic)
besides the FNA interpretation.
b
The risk of malignancy varies with the type or structure of the nodule (ie, solid
vs complex vs ⱖ50% cystic). Nondiagnostic aspirates from solid nodules are
associated with a higher risk of malignancy vs those showing cystic change of
50% or more and low-risk ultrasonographic features.
c
Estimate extrapolated from studies showing correlation between biopsied
nodule and surgical pathology follow-up.35-38 See Figure 3 for suggested timing.
d i
Estimates extrapolated from histopathologic data from large case cohorts
(including repeat atypical FNAs) and meta-analysis of the post-2007
literature.35,39-42
nonmalignant thyroid neoplasms and in NIFTP, and are therefore
less specific. Furthermore, if no mutations are found, a thyroid
malignancy with a mutation that was not assessed could still be
present (≈ 4%); therefore, mutational testing may lead to both
false-negative and false-positive results, especially if RAS mutations
are found.
In a single-institution study involving 239 patients with
Bethesda category 3 or 4 cytology, the mutational testing strat-
egy (ThyroSeq v2) yielded a negative predictive value when a
mutation was not found of about 96% and a positive predictive
value of approximately 80%. 57 In a second single-institution
study involving 182 patients with 190 Bethesda category 3 and
4 cytologies, the negative predictive value was 91% (95% CI,
82%-97%) and the positive predictive value was 42% (95% CI,
25%-61%).58
BRAF- and RAS-mutation status may provide information
beyond diagnosis: BRAF-positive malignant nodules are frequently
present in malignant or suspicious Bethesda cytology categories
and frequently show suspicious sonographic and advanced
histological features, while RAS-positive malignancies are more dif-
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Diagnosis and Management of Thyroid Nodules
Risk of Malignancy, % Usual Managementa
0-5b Repeat FNAB with ultrasound guidance
0-3c Clinical and sonographic follow-upc
≈10-30d Repeat FNAB, molecular testing, or
lobectomy
25-40e Molecular testing, lobectomy
50-75 Near total thyroidectomy or lobectomyg,h
97-99 Near total thyroidectomyh,i
e
Estimates extrapolated from histopathologic data from large case cohorts
and meta-analysis of the post-2007 literature.35,39-44
f
Includes cases of follicular neoplasm with oncocytic features (Hürthle cell
neoplasm).
g
Some studies have recommended molecular analysis to assess the type of
surgical procedure (lobectomy vs total thyroidectomy).
h
In the case of “suspicious for metastatic tumor” or a malignant interpretation
indicating metastatic tumor rather than a primary thyroid malignancy, surgery
may not be indicated.
Lobectomy is appropriate for most papillary thyroid cancers smaller than 4
cm, without other features such as gross extrathyroidal extension or clinical
or radiological lymphadenopathy.
ficult to identify by sonography, more commonly reported in lower-
risk, indeterminate cytology categories, and usually have an indo-
lent behavior.59
The second type of molecular testing, gene expression analy-
sis or gene expression classifier (GEC), uses a proprietary algo-
rithm to analyze the expression of specific genes in a 142-gene
panel. Nodules are classified as benign or suspicious rather than
as malignant. The test is designed to identify nodules that do not
require surgery. In the original multi-institutional validation study,
a benign Afirma test had a negative predictive value of approxi-
mately 95%.60 In a pooled analysis of 12 studies involving 1303
nodules, the negative predictive value was 92% (95% CI, 87%-
96%) and the malignanc y prevalence of 31% (95% CI,
29%-34%).61 The GEC has a low positive predictive value (range,
13%-23%) in the context of a suspicious GEC result when NIFTP is
factored in.62 MicroRNA analysis is a more recent method for
molecular testing for which there are limited data 63 but may
prove to be useful in diagnostic decision making. Future refine-
ment in molecular testing strategies is expected, with improved
diagnostic performance.
jama.com
 Diagnosis and Management of Thyroid Nodules Review Clinical Review & Education

Figure 3. Algorithm for the Follow-up of Cytologically Benign Thyroid Nodules or Nodules Without Indication for Fine-Needle Aspiration Cytology

Patient with suspected thyroid nodule

FNAB indicated (see Table 1) FNAB not indicated (see Table 1)

Perform thyroid ultrasound

Cytologically benign Nodule without

nodule (Bethesda class 2) FNAB assessment

High suspicion Intermediate to very low High suspicion sonographic Intermediate to low Very low suspicion
sonographic pattern suspicion sonographic pattern pattern (nodule size < 1 cm)a suspicion sonographic sonographic pattern
pattern

Repeat FNAB within Repeat thyroid ultrasound Repeat thyroid ultrasound Repeat thyroid ultrasound Repeat thyroid ultrasound
12 mo Intermediate to low estimated after 6-12 mo after 12-24 mo after 24 mo, if everb
malignancy risk: within 12-24 mo
Very low estimated malignancy
risk: after 24 mo, if ever

No change New suspicious Nodule growthc

sonographic features

Perform FNAB

2 Benign Nondiagnostic Indeterminate or malignant

(Bethesda class 2) (Bethesda class 1) (Bethesda classes 3, 4, 5, 6)
cytology results cytology results cytology results

Repeat thyroid ultrasound No further FNAB Repeat FNAB Manage based on risk
High estimated malignancy risk: assessment (see Table 2) of malignancy (see Table 2)
within 6-12 mo Repeat thyroid
Intermediate to low estimated ultrasound for growth
malignancy risk: within 12-24 mo surveillance only
Very low estimated malignancy
risk: after 24 mo, if ever

b
Sonographic suspicion in this Figure is graded according to the American
Thyroid Association Guidelines. FNAB indicates fine-needle aspiration biopsy.
a
Subcentimeter thyroid nodules harboring high-suspicion sonographic features
c
and not requiring routine biopsy include those nodules without evidence of
extrathyroidal extension or sonographically suspicious lymph nodes.
Subcapsular location near the recurrent nerve or trachea, patient age
(<40 years old being at higher risk) and preference, a strong family history of
thyroid cancer or known syndromes associated with thyroid cancer, or a
history of therapeutic head and neck or whole body radiation exposure as
children may drive decision making toward performing an FNAB.
Nodules smaller than 1 cm with a very low-suspicion pattern do not require
routine sonographic follow-up, while such nodules larger than 1 cm should be
followed up at more than 24 months intervals, if ever.
The minimal clinically significant change in nodule size should be a 20%
increase in at least 2 diameters with a minimum increase of 2 mm,
which corresponds to an increase in nodule volume of more than 50%.
Compared with a slower growth rate, nodule growth of more than 2 mm a year
vs slower growth rate predicts malignancy (relative risk, 2.5; 95% CI, 1.6-3.1;
P < .001).71 If compressive symptoms appear following thyroid nodule growth,
consider surgery.

Molecular testing is expensive, costing from between $3000
and $5000 per test in 2015, depending on the specific testing
strategy.64 Several studies suggested that molecular testing using
the GEC is cost-effective,65-67 primarily because of a decrease in
the number of diagnostic surgeries and their associated complica-
tions when the test results are negative. However, most of these
analyses are based on simulation modeling rather than on actual
patient data, and the results vary depending on the test perfor-
mance parameters, malignancy rates in the patient population,
anticipated surgical procedure, surgical complication rates, health
care setting, and other factors.56 Molecular testing results in a
decrease in number of diagnostic surgeries in the United States,
which benefits the patient, but the high cost of testing makes it
unaffordable in many parts of the world.
Management of Thyroid Nodules
Nonoperative Management of Benign Thyroid Nodules
More than 90% of detected thyroid nodules are clinically insignifi-
cant because they have no ultrasound features that suggest malig-
nancy or because they are cytologically benign.68 In one series of
2000 consecutive nodules that were at least 1 cm, 58% were sono-
graphically benign or of low suspicion.69 The rate of cytologically
benign nodules ranges from 39% to 73% in large series.42
In a 5-year prospective study involving 992 patients with
1597 apparently benign thyroid nodules on the basis of sono-
graphic appearance and cytology, most (≈85%) did not grow at
all.5 Those that grew exhibited a slow and steady growth, with a
mean 5-year largest diameter increase of about 5 mm. After mul-
tivariable logistic regression analysis, nodule growth was associ-

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 Clinical Review & Education Review Diagnosis and Management of Thyroid Nodules

ated with the presence of multiple, larger nodules, and younger
age. Most important, very few (0.3%) of the nodules included in
the study were found to be cancerous during the 5-year period.
Furthermore, malignancy was predicted by a change in the sono-
graphic characteristics of the nodule, not growth.
The risk of malignancy based on the sonographic pattern should
guide not only the initial indication for fine-needle aspiration bi-
opsy, but also the type, frequency, and the need for follow up. An
algorithm, based on the authors’ experience, is shown in Figure 3.
The rate of false-negative results in thyroid biopsy cytology is
very low (<3%).5,70 However, cytologically benign thyroid nodules
with highly suspicious ultrasound features warrant a repeat biopsy
within 12 months.1,22 In this subset of nodules the risk of false-
negative cytological results is higher: in a series of 1343 cytologi-
cally benign nodules, Kwak et al70 reported a 20% malignancy rate
in nodules with suspicious sonographic features vs 0.6% in nodules
that were benign based on both cytology and sonography. For nod-
ules that are benign based on sonographic and cytological results,
evaluation, if performed, should be at least 24 months later,
as an earlier ultrasound is unlikely to be informative. According to
the current guidelines, sonographic surveillance of low- to
intermediate-risk nodules should be done after 12 to 24 months,1
despite some data suggesting that this interval could be safely
extended.36 In this case, repeat biopsy should be considered in
case of nodule growth or the development of suspicious ultra-
sound features.1,22,30 The minimal clinically significant change in
nodule size should be a 20% increase in at least 2 diameters with a
minimum increase of 2 mm, corresponding to an increase in nodule
volume of more than 50%.1
After 2 benign cytology results, the risk of malignancy is virtu-
ally zero, irrespective of the sonographic appearance.70 For these
patients, continued follow-up may be discontinued, and a surveil-
lance strategy aimed at nodule growth assessment may be war-
ranted only for larger nodules that could more easily lead to com-
pressive symptoms.1,22 In the case of thyroid nodules that do not
meet the fine-needle aspiration biopsy criteria because of their
sonographic pattern or size (see the previous section), sonographic
reassessments should be performed after 6 to 12 months for high
risk nodules, 12 to 24 months for low- to intermediate-risk nodules,
and at least 24 months (if ever) for very low-risk nodules larger
than 1 cm. 1 These long-term follow-up recommendations are
mainly based on low-quality evidence or expert opinion. A study
directly comparing the growth rate of benign and malignant thy-
roid nodules showed that the latter were more likely to grow more
than 2 mm per year (relative risk, 2.5): this clinical parameter can
contribute to the assessment of thyroid cancer risk, particularly in
nodules not submitted to cytology.71
Thyrotropin-suppressive therapy with thyroid hormone is
not recommended.1,22
Surgical Management of Thyroid Nodules
Thyroid lobectomy provides histological diagnosis and tumor re-
moval with a lower risk of complications. The risks of total thyroid-
ectomy include recurrent laryngeal nerve injury (2.5% of the pro-
cedures, rarely bilateral), hypocalcemia (8.1%), and hemorrhage.72
However, in some situations subsequent surgery for completion thy-
roidectomy (ie, the removal of the remnant thyroid tissue) will be
required after lobectomy.1 The presence of large bilateral thyroid
nodules1,73 or other thyroid conditions such as Graves disease73 fa-
vors total thyroidectomy.
Patients with cytologically suspicious or malignant nodules
(ie, Bethesda classes 5 and 6) should generally be referred for sur-
gery. Small (<1 cm) intrathyroidal cancers could undergo active
ultrasound surveillance without surgery. 1,74 In patients with
smaller (< 4 cm) Bethesda Class 5 or 6 tumors, lobectomy or total
thyroidectomy are both acceptable approaches, while for patients
with large ones (> 4 cm), clinical or radiologic evidence of gross
extrathyroidal extension,1 clinical or radiologic evidence of lymph
node or distant metastases, or both, the preferred surgical
approach is total thyroidectomy. When surgery is considered for
indeterminate nodules (ie, Bethesda classes 3 and 4) lobectomy is
preferred.1,73 A bilateral procedure could be considered for those
patients in which completion thyroidectomy would be recom-
mended in order to administer radioiodine should the nodule
prove to be malignant histologically.1 When clinical, cytological, or
sonographic findings are discordant, a multidisciplinary team
approach is recommended.73 Surgery for large (> 4 cm) cytologi-
cally benign nodules should be considered if malignancy is consid-
ered possible, in the setting of new suspicious sonographic fea-
tures (despite cytological findings),1,22 or compressive symptoms.
Alternative Treatments
Recently, image-guided minimally invasive techniques (percutane-
ous ethanol ablation, radiofrequency, laser, microwave ablation, and
high-intensity focused ultrasound) have been proposed and may be
considered for treating clinically relevant benign thyroid nodules.22,75
Radioiodine therapy should be considered for patients with hyper-
functioning nodules whose biochemical testing shows hyperthy-
roidism, but surgery is also a reasonable approach in patients with
large (> 4 cm) nodules.22
Conclusions
Most thyroid nodules are benign. A diagnostic approach that uses
ultrasound and, when indicated, fine-needle aspiration biopsy and
molecular testing, facilitates a personalized, risk-based protocol
that promotes high-quality care and minimizes cost and unneces-
sary testing.

ARTICLE INFORMATION
Accepted for Publication: January 30, 2018.
Author Contributions: Dr Durante had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Durante, Filetti, Mandel,
Cooper.
Acquisition, analysis, or interpretation of data:
Grani, Lamartina, Filetti, Mandel, Cooper.
Drafting of the manuscript: Durante, Grani,
Lamartina, Mandel, Cooper.
Critical revision of the manuscript for important
intellectual content: All authors.
Administrative, technical, or material support:
Lamartina, Cooper.
Supervision: Durante, Filetti, Mandel, Cooper.
Funding/Support: Drs Grani and Lamartina
contributed to this article as recipients of the PhD
program of Biotechnologies and Clinical Medicine
of the University of Rome, Sapienza. Dr Cooper
contributed to this article as the recipient of the
Visiting Professor for Research Activities 2016 grant
at University of Rome, Sapienza (C26V157CMC).
Role of the Funder/Sponsor: The Sapienza
University of Rome had no role in the design and

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 Diagnosis and Management of Thyroid Nodules
conduct of the study; collection, management,
analysis, and interpretation of the data;
preparation, review, or approval of the manuscript;
and decision to submit the manuscript for
publication.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
Submissions: We encourage authors to submit
papers for consideration as a Review. Please
contact Edward Livingston, MD, at Edward
.livingston@jamanetwork.org or Mary McGrae
McDermott, MD, at mdm608@northwestern.edu.
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