The Diagnosis and Management of Thyroid Nodules A Review 2018

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
IMPORTANCE Thyroid nodules are common, being detected in up to 65% of the general
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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
additional testing. Suspicious sonographic patterns including solid composition,
hypoechogenicity, irregular margins, and microcalcifications should prompt cytological
evaluation. Additional diagnostic procedures, such as molecular testing, are indicated
only in selected cases, such as indeterminate cytology (≈20%-30% of all biopsies).
The initial risk estimate, derived from ultrasound and, if performed, cytology report,
should determine the need for treatment and the type, frequency, and length of
subsequent follow-up. Management includes simple observation, local treatments,
and surgery and should be based on the estimated risk of malignancy and the
presence and severity of compressive symptoms.
CONCLUSIONS AND RELEVANCE 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 unnecessary testing.
T
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Methods
PubMed and Scopus databases were searched to identify highquality studies, systematic reviews and meta-analyses, and clinical 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 thyroid nodules, reaching up to 68% of the general population.3
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Corresponding Author: David S.
Cooper, MD, Division of
Endocrinology, Diabetes, and
Metabolism, 1830 E Monument St,
Ste 333, Baltimore, MD 21287
(dscooper@jhmi.edu).
Section Editors: Edward Livingston,
MD, Deputy Editor, and Mary McGrae
McDermott, MD, Senior Editor.
JAMA. 2018;319(9):914-924. doi:10.1001/jama.2018.0898
hyroid nodules are defined as discrete lesions within the thyroid gland, radiologically distinct from surrounding thyroid parenchyma. 1 Their diagnosis is increasingly 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 palpable 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 harboring a significant cancer (approximately 10%), and those causing
(or are at risk of causing) compressive symptoms (5%), or thyroid 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 evidencebased summary of the optimal approach to the management of
thyroid nodules.
Author Affiliations: Dipartimento
di Medicina Interna e Specialità
Mediche, Università di Roma
“Sapienza,” Roma, Italy (Durante,
Grani, Lamartina, Filetti); Division of
Endocrinology, Diabetes and
Metabolism, Perelman School of
Medicine, University of Pennsylvania,
Philadelphia (Mandel); Division of
Endocrinology, Diabetes and
Metabolism, The Johns Hopkins
University School of Medicine,
Baltimore, Maryland (Cooper).
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Diagnosis and Management of Thyroid Nodules
This discrepancy is largely due to incidental discovery of asymptomatic nodules, generally small, due to the increased use of diagnostic imaging for purposes unrelated to the thyroid (the
so-called thyroid incidentaloma). The reported prevalence is
about 65% with ultrasonography, 15% with computed tomography (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 prevalence 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 MRIdetected 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 associated with nodule formation or malignancy, such as serum levels
of thyrotropin,12 thyroid autoantibodies,13 obesity,14 and metabolic 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 concluded 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 !3 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 evidence that this would reduce morbidity or mortality.1 For this reason, 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 firstdegree relatives of patients with proven hereditary medullary
thyroid cancer.17
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 differential 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 because 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 evaluation of all patients with a thyroid nodule.1 The goal is to exclude the
small number of hyperfunctioning nodules ("5% 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 antithyroid peroxidase antibody should be measured to quantify the degree of thyroid hypofunction and to evaluate for autoimmune
(Hashimoto) thyroiditis.22
Thyroglobulin
Routine measurement of serum thyroglobulin in evaluation of nodules 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, multinodular goiter, thyroiditis). Therefore, this test has inadequate specificity for thyroid cancer diagnosis.
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 complaints (stasis, choking, odynophagia); dyspnea; dysphonia or hoarseness; 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 paraisthmic 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
Calcitonin
Calcitonin is produced by the parafollicular C cells of the thyroid
and is a serum marker for medullary thyroid cancer. Recent guidelines included no recommendation regarding the measurement of
serum calcitonin to evaluate thyroid nodules.1 Although routine calcitonin 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 suggest 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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Intermediate-risk definition
Risk of malignancy, 5%-15%
FNAB >20 mm
Sonographic pattern
Slightly hypoechoic
(vs thyroid tissue)
or isoechoic nodules,
with ovoid-to-round shape,
smooth or ill-defined margins
May be present
Intranodular vascularization
Elevated stiffness
at elastography
Macro or continuous
rim calcifications
Indeterminate
hyperechoic spots
Intermediate or Moderately Suspicious Thyroid Nodules
Low-risk definition
Risk of malignancy, 1%
FNAB >20 mm (selective)a
Sonographic pattern
Cysts (fluid component >80%)
Mostly cystic nodules with
reverberating artifacts
and not associated with
suspicious ultrasound signs
Isoechoic spongiform nodules,
either confluent or
with regular halo
Low-Risk and Benign Thyroid Nodules
AACE, ACE, and AME, 201622
Intermediate-suspicion definition
Risk of malignancy, 10%-20%
FNAB ≥10 mm
Sonographic pattern
Hypoechoic solid nodule
with smooth margins
without microcalcifications,
extrathyroidal extension
or taller than wide shape
Intermediate-risk (EU-TIRADS 4) definition
Risk of malignancy, 6%-17%
FNAB >15 mm
Sonographic pattern
Oval shape, smooth margins,
mildly hypoechoic, without
any feature of high risk
Low-risk (EU-TIRADS 3) risk definition
Risk of malignancy, 2%-4%
FNAB >20 mm
Sonographic pattern
Oval shape, smooth margins,
isoechoic or hyperechoic,
without any feature of high risk
Very low–suspicion risk definition
Risk of malignancy, <3%
FNAB ≥20 mm or observation
Sonographic pattern
Spongiform/partially cystic nodules
without any ultrasound features
defining low-, intermediate-,
or high-suspicion patterns
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
Benign (EU-TIRADS 2) definition
Risk of malignancy, ≈0%
FNAB is not indicated
Sonographic pattern
Pure, anechoic cysts;
Entirely spongiform nodules
EU-TIRADS, 201731
Benign definition
Risk of malignancy, <1%
FNAB is not indicated
Sonographic pattern
Purely cystic nodules (no solid component)
ATA, 20151
Moderately suspicious (TR4) definition
Risk of malignancy, 5%-20%
FNAB >15 mm
Sonographic patterns
Hypoechoic solid
noncalcified nodules
with oval shape and
either smooth or irregular
or lobulated margins
Isoechoic solid or mixed
noncalcified nodules with
either nonparallel orientation
(taller than wide), lobulated
or irregular margins, or
punctate echogenic foci
Mildly suspicious (TR3) risk definition
Risk of malignancy, 5%
FNAB ≥25 mm
Sonographic pattern
Isoechoic solid or hypoechoic
cystic noncalcified nodules
with smooth margins
and oval shape
Not suspicious (TR2) definition
Risk of malignancy, 2%
FNAB is not indicated
Sonographic pattern
Mixed cystic/solid
noncalcified nodules
with smooth margins
and oval shape
Benign (TR1) definition
Risk of malignancy, 2%
FNAB is not indicated
Sonographic pattern
Spongiform
Pure cyst
ACR TIRADS, 201730
Table 1. Standardized Sonographic Scoring Systems Proposed or Endorsed by Practice Guidelines for Risk-Based Fine-Needle Aspiration Biopsy Guidance for Thyroid Nodules
(continued)
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Diagnosis and Management of Thyroid Nodules
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An FNAB is recommended for smaller nodules that are subcapsular location near the recurrent nerve or trachea;
suspicious lymph nodes or extrathyroid spread; personal or family history of thyroid cancer; history of head
and neck irradiation; coexistent suspicious clinical findings. An FNAB indicates the size above which a FNAB
cytology is recommended.
c
Growing nodule, high-risk history, before surgery or local therapies.
In accordance with the presence of 1 or more suspicious findings.
b
a
High-suspicion definiton
Risk of malignancy, >70%-90%
FNAB ≥10 mm
Sonographic pattern
Solid hypoechoic nodule or
solid hypoechoic component
of partially cystic nodule
with ≥1 of the following:
Irregular margins
(infiltrative, microlobulated)
Microcalcifications
Taller than wide shape
Rim calcifications with
small extrusive soft tissue
Extrathyroidal extension
High-risk definition
Risk of malignancy,
50%-90%b
FNAB ≥10 mm (5 mm, selective)c
Sonographic patterns
Nodules with ≥ 1 of the following:
Marked hypoechogenicity
(vs prethyroid muscles)
Spiculated or lobulated margins
Microcalcifications
Taller-than-wide shape
Extrathyroidal growth
Pathologic adenopathy
Abbreviations. AACE/ACE/AME, American Association of Clinical Endocrinologists, American College of
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
aspiration biopsy; TR, American College of Radiologists Thyroid Imaging Reporting and Data System.
Suspicious (TR5) definition
Risk of malignancy, ≥20%
FNAB >10 mm
Sonographic pattern
Hypoechoic solid nodule with
any of the following
Nonparallel orientation
(taller than wide)
Extrathyroidal extension
Punctate echogenic foci
Isoechoic solid nodule with
irregular or lobulated margins
and either peripheral
rim calcifications or
punctate echogenic foci
High-risk (EU-TIRADS 5) definition
Risk of malignancy, 26%-87%
FNAB >10 mm
Sonographic pattern
Nodules with ≥ 1 of the following:
Nonoval shape
Irregular margins
Microcalcifications
Marked hypoechogenicity
ACR TIRADS, 201730
EU-TIRADS, 201731
ATA, 20151
High-Risk or Suspicious Thyroid Nodules
AACE, ACE, and AME, 201622
Table 1. Standardized Sonographic Scoring Systems Proposed or Endorsed by Practice Guidelines for Risk-Based Fine-Needle Aspiration Biopsy Guidance for Thyroid Nodules (continued)
Diagnosis and Management of Thyroid Nodules
Ultrasound, Cytology, and Molecular Testing
Thyroid Ultrasonography
Sonography is the primary tool used for initial cancer risk stratification of thyroid nodules and subsequently deciding whether to
order a fine-needle aspiration biopsy. Because the thyroid is superficially located in the neck, with its posterior border generally situated less than 4 cm from the skin, high-resolution (!12 MHz)
probes provide excellent image definition. Ultrasound is indicated
when either the thyroid gland is palpably abnormal or a thyroid
nodule is incidentally detected on another radiological study.
Nonspecific symptoms or abnormal laboratory test results (such
as fatigue, increased serum thyrotropin levels, or autoimmune
thyroiditis) are not indications for sonography. However, ultrasound is necessary to differentiate between asymmetric involvement of the thyroid gland by lymphocytic thyroiditis vs a superimposed thyroid nodule, for which further evaluation may be
required. A diagnostic ultrasound report should include description of the background thyroid parenchyma, nodule location, size
(in 3 dimensions), sonographic features (Table 1), and survey of
the cervical lymph nodes.27
Certain sonographic characteristics are associated with thyroid
cancer while others are more likely to indicate a benign nature.
Ultrasound characteristics associated with malignancy include solid
composition, hypoechogenicity (nodule is darker than normal thyroid tissue), margins that appear infiltrative or irregular, and presence 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
nodules with a “spongiform” consistency, defined when more than
half of nodule volume is composed of microcystic spaces, are
unlikely to be malignant (<2%). Cancer risk is low (<5%-10%) for
solid noncalcified smoothly marginated nodules that are either
isoechoic or hyperechoic (same or lighter gray scale imaging compared with normal thyroid).29
The American Thyroid Association1 and other professional
groups22,30-32 have devised similar but not identically tiered systems to classify nodules by constellations of sonographic features
that convey cancer risk and to recommend size cutoffs for fineneedle aspiration biopsy (Table 1, Figure 1, and Figure 2). Guidelines
from endocrinology societies have focused on nodule pattern
identification,1,22,31 accompanied by figures illustrating these patterns. 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 nodules (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
System classification of the nodule, its estimated cancer risk, and
recommendations for either fine-needle aspiration biopsy or surveillance. Malignancy risk estimates based on sonographic appearance are similar across all 4 classification systems; however, fineneedle aspiration biopsy recommended cutoff sizes differ (Table 1,
Figure 1, and Figure 2).
Fine-needle aspiration biopsy is not recommended for pure
cysts, unless it is for fluid aspiration for symptomatic relief. If fineneedle aspiration biopsy is to be performed for spongiform nodules, the size cutoff is larger than 2 cm, with some guidelines not
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Figure 1. Ultrasonographic Features of Thyroid Nodules Suspicious for Malignancy
A
B
C
D
E
F
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
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.
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 systems 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.
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 nonaggressive. 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 follicular thyroid cancer is low (≈20% of malignant cases).47 The new
Bethesda system adjusts the risk of malignancy of the indeterminate diagnostic categories and their management recommendations 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 invasive 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 similar to that used for a low-risk thyroid cancer.50
Cytology
Fine-needle aspiration biopsy provides the most definitive diagnostic 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 performed under ultrasound guidance. In the United States and
much of the world, thyroid cytological results reporting is stratified 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 values (75.2%, category 5; 98.6%, category 6) for accurate clinical
decision making. 42 However, categories 3 and 4, comprising
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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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Figure 2. Imaging Features of Indeterminate and Low Suspicion Thyroid Nodules
Imaging features of indeterminate thyroid nodules
A
B
C
Ultrasonographic features of low or very low suspicion thyroid nodules
D
E
F
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.
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.
tially practice-changing approach52,53 to diagnosing indeterminate 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 differentiation. 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 previously 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 peroxisome proliferator-activated receptor, gamma isoform (PPARG)
gene (PAX8/PPARG) is seen in some follicular thyroid cancers
(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 suppressor 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 mutational analysis and gene expression analysis, in which genetic information can be derived from the same material obtained in the original 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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Table 2. The Bethesda System for Reporting Thyroid Cytopathology: Implied Risk of Malignancy and Recommended Clinical Management
Diagnostic Category
Risk of Malignancy, %
Usual Managementa
Category 1: Nondiagnostic or Unsatisfactory
Cyst fluid only
Virtually acellular specimen
Obscuring blood, artifacts
0-5b
Repeat FNAB with ultrasound guidance
0-3c
Clinical and sonographic follow-upc
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
≈10-30d
Focal nuclear atypia
Predominance of Hurthle cells
Microfollicular pattern in a hypocellular specimen
Repeat FNAB, molecular testing, or
lobectomy
Category 4: Follicular Neoplasm or Suspicious for a Follicular Neoplasmf
Crowded and overlapping follicular cells some or most of which
are arranged as microfollicles
25-40e
Molecular testing, lobectomy
50-75
Near total thyroidectomy or lobectomyg,h
97-99
Near total thyroidectomyh,i
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 !50% 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
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 strategy (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 dif920
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.
i
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 lowerrisk, indeterminate cytology categories, and usually have an indolent behavior.59
The second type of molecular testing, gene expression analysis or gene expression classifier (GEC), uses a proprietary algorithm 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 approximately 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 refinement in molecular testing strategies is expected, with improved
diagnostic performance.
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Review Clinical Review & Education
Diagnosis and Management of Thyroid Nodules
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)
Perform thyroid ultrasound
FNAB not indicated (see Table 1)
Nodule without
FNAB assessment
Cytologically benign
nodule (Bethesda class 2)
High suspicion
sonographic pattern
Intermediate to very low
suspicion sonographic pattern
High suspicion sonographic
pattern (nodule size < 1 cm)a
Repeat FNAB within
12 mo
Repeat thyroid ultrasound
Intermediate to low estimated
malignancy risk: within 12-24 mo
Very low estimated malignancy
risk: after 24 mo, if ever
Repeat thyroid ultrasound
after 6-12 mo
No change
Intermediate to low
suspicion sonographic
pattern
Very low suspicion
sonographic pattern
Repeat thyroid ultrasound
after 12-24 mo
Repeat thyroid ultrasound
after 24 mo, if everb
Nodule growthc
New suspicious
sonographic features
Perform FNAB
Repeat thyroid ultrasound
High estimated malignancy risk:
within 6-12 mo
Intermediate to low estimated
malignancy risk: within 12-24 mo
Very low estimated malignancy
risk: after 24 mo, if ever
2 Benign
(Bethesda class 2)
cytology results
Nondiagnostic
(Bethesda class 1)
cytology results
Indeterminate or malignant
(Bethesda classes 3, 4, 5, 6)
cytology results
No further FNAB
assessment
Repeat thyroid
ultrasound for growth
surveillance only
Repeat FNAB
(see Table 2)
Manage based on risk
of malignancy (see Table 2)
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
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.
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 complications 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 performance 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.
b
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.
c
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.
Management of Thyroid Nodules
Nonoperative Management of Benign Thyroid Nodules
More than 90% of detected thyroid nodules are clinically insignificant because they have no ultrasound features that suggest malignancy or because they are cytologically benign.68 In one series of
2000 consecutive nodules that were at least 1 cm, 58% were sonographically 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 sonographic 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 multivariable logistic regression analysis, nodule growth was associ(Reprinted) JAMA March 6, 2018 Volume 319, Number 9
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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 sonographic 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 biopsy, 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 falsenegative cytological results is higher: in a series of 1343 cytologically 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 nodules 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 ultrasound 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 virtually zero, irrespective of the sonographic appearance.70 For these
patients, continued follow-up may be discontinued, and a surveillance strategy aimed at nodule growth assessment may be warranted only for larger nodules that could more easily lead to compressive 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 thyroid 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
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.
922
Surgical Management of Thyroid Nodules
Thyroid lobectomy provides histological diagnosis and tumor removal with a lower risk of complications. The risks of total thyroidectomy include recurrent laryngeal nerve injury (2.5% of the procedures, rarely bilateral), hypocalcemia (8.1%), and hemorrhage.72
However, in some situations subsequent surgery for completion thyroidectomy (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 favors total thyroidectomy.
Patients with cytologically suspicious or malignant nodules
(ie, Bethesda classes 5 and 6) should generally be referred for surgery. 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 recommended 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) cytologically benign nodules should be considered if malignancy is considered possible, in the setting of new suspicious sonographic features (despite cytological findings),1,22 or compressive symptoms.
Alternative Treatments
Recently, image-guided minimally invasive techniques (percutaneous 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 hyperfunctioning nodules whose biochemical testing shows hyperthyroidism, 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 unnecessary testing.
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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