T h y ro i d N o d u l e s

a,b a,
Geanina Popoveniuc, MD , Jacqueline Jonklaas, MD, PhD *

KEYWORDS
 Thyroid nodule  TSH  Ultrasonography  FNA biopsy
 Elastography  Molecular markers  Indeterminate cytology
 Malignancy

INTRODUCTION

Thyroid nodules are common entities, frequently discovered in clinical practice, either
during physical examination, but also incidentally, during various imaging procedures.
They are clinically important primarily due to their malignant potential. For this reason
the initial evaluation should always include a history and physical examination
focusing on features suggestive of malignancy. Serum thyrotropin (TSH) and thyroid
ultrasonography (US) are pivotal in the evaluation of thyroid nodules, as they provide
important information regarding thyroid nodule functionality and the presence of
features suspicious for malignancy, respectively. Fine needle aspiration (FNA) biopsy
is the most accurate and reliable tool for diagnosing thyroid malignancy and selecting
candidates for surgery, particularly if performed under ultrasound guidance. The
cytology findings from FNA biopsies will fall into an indeterminate category in approx-
imately 25% of the cases, in which case malignancy cannot be safely excluded. The
recent use of panels of gene mutations and molecular markers, when combined with
the cytologic diagnosis, show promising results in improving the preoperative diag-
nosis of indeterminate thyroid nodules, thus reducing the number of unnecessary
surgeries. Other tools for predicting the malignant potential of thyroid nodules still
under investigation include elastography and 18F-fluorodeoxyglucose positron emis-
sion tomography (18FDG-PET) scanning. An approach to the initial evaluation and
management of single nodules, functioning nodules, multinodular glands, incidental
nodules, and cysts are discussed. Therapeutic interventions for benign nodules,
when needed, may include surgery, radioiodine (131-I) therapy, or percutaneous

J.J. is supported by grant 1UL1RR031975 from the National Center for Research Resources,
National Institutes of Health. Funding for publication of the figures in this article was provided
by the Graduate Medical Education office at Washington Hospital Center.
Disclosure Summary: The authors have nothing to disclose.
a
Division of Endocrinology, Georgetown University Medical Center, 4000 Reservoir Road, NW,
Washington, DC 20007, USA
b
Section of Endocrinology, Washington Hospital Center, 110 Irving Street, NW, Washington,
DC 20010, USA
* Corresponding author. Division of Endocrinology, Georgetown University Medical Center,
Suite 230, Building D, 4000 Reservoir Road, NW, Washington, DC 20007.
E-mail address: jonklaaj@georgetown.edu

Med Clin N Am 96 (2012) 329–349

doi:10.1016/j.mcna.2012.02.002 medical.theclinics.com
0025-7125/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.
330 Popoveniuc & Jonklaas

ethanol injection (PEI), as indicated. Levothyroxine (T4) suppressive therapy is

currently controversial and usually not recommended. The evaluation of thyroid
nodules discovered during pregnancy is generally the same as for non-pregnant
patients, except for the contraindication to radionuclide scanning. Thyroid cancer
discovered during pregnancy may be safely managed by thyroidectomy after delivery
in most of the cases, but if aggressive features are present, surgery should be ideally
performed during the second trimester.

DEFINITION, CLINICAL IMPORTANCE, EPIDEMIOLOGY

 Thyroid nodules are most common in women and older populations

 The purpose of thyroid nodule evaluation is to determine which nodules are
malignant or require surgical attention
Thyroid nodules have been defined by the American Thyroid Association (ATA)
as “discrete lesions within the thyroid gland, radiologically distinct from sur-
rounding thyroid parenchyma.”1 They may be discovered by palpation during a
general physical examination or with radiographic studies performed for medical
evaluations, such as carotid duplex ultrasound (US), computed tomography (CT)
scans, magnetic resonance imaging (MRI) studies, or 18FDG-PET scanning. The
latter entities are called “thyroid incidentalomas” and they generally do not corre-
spond to palpable thyroid lesions. Conversely, clinicians may identify palpable
thyroid lesions that do not correspond to distinct radiological entities, and therefore
would not be defined as thyroid nodules.2
Thyroid nodules are common, their prevalence being largely dependent on the iden-
tification method. The estimated prevalence by palpation alone ranges from 4% to
7%,3,4 whereas US detects nodules in 20% to 76% of the adult population,4–6 partic-
ularly with the current use of high-resolution US techniques.7 The reported frequencies
detected by US correlate with the prevalence reported at surgery and autopsy with
ranges between 50% and 65%.8
The estimated annual incidence of thyroid nodules in the United States is approxi-
mately 0.1% per year, conferring a 10% lifetime probability for developing a thyroid
nodule.6 Thyroid nodules are 4 times more common in women than men and their
frequency increases with age and low iodine intake.4 The gender disparity is perhaps
explained by the hormonal influences of both estrogen and progesterone, as in-
creasing nodule size and new nodule development have been demonstrated to be
related to pregnancy and multiparity.9,10 Exposure to ionizing radiation, either during
childhood, or as an occupational exposure, will cause a rate of development of thyroid
nodules of 2% per year, reaching a peak incidence in 15 to 25 years.11,12
Thyroid nodules are clinically important for several reasons. They may cause thyroid
dysfunction and, rarely, compressive symptoms, but they are primarily important
because of the need to exclude thyroid cancer. The reported prevalence of malig-
nancy in thyroid nodules evaluated by biopsy ranges from 4.0% to 6.5% and is largely
independent of the nodule size.13,14 Despite this, papillary microcarcinomas (smaller
than 1 cm) incidentally found at the time of surgery are much more common (up to
36%),15,16 but it is controversial whether or not a survival benefit exists with the diag-
nosis and treatment of such entities, given their generally benign course.17,18 Impor-
tantly, the incidence of thyroid nodules discovered incidentally during 18FDG-PET
imaging is small (1%–2%), but the risk of malignancy may be as high as 27%, thus
such nodules require immediate evaluation.19
 Thyroid Nodules 331

HISTORY AND PHYSICAL EXAMINATION

 History and physical examination should focus on detecting features particularly

suggestive of malignancy
The spectrum of disorders associated with thyroid nodules ranges from benign
etiologies to malignant conditions that may either have an indolent course or a very
aggressive behavior (Box 1). Therefore, clinical evaluation is best tailored to identifica-
tion of clues suggestive of malignant disease. A careful history and physical examina-
tion should include information regarding previous radiation treatment of the head and
neck area; growth of a neck mass; location, size, and consistency of the thyroid
nodule; cervical lymphadenopathy; associated local symptoms such as pain, hoarse-
ness, dysphagia, dysphonia, and dyspnea; and symptoms of hypothyroidism or
hyperthyroidism.
Family history of thyroid disorders should always be investigated. Rare but important
familial thyroid syndromes include familial medullary thyroid cancer (MTC), derived from
calcitonin-producing C-cell tumors, and familial nonmedullary thyroid cancer, which is
derived from follicular cells. History of papillary thyroid cancer (PTC) in a parent or
sibling increases the patient’s risk of developing PTC by threefold and sixfold, respec-
tively.20 Familial MTC may be a component of multiple endocrine neoplasia (MEN) IIA
(pheochromocytoma, MTC, and primary hyperparathyroidism) and IIB (pheochromocy-
toma, MTC, marfanoid habitus, and mucosal and digestive neurofibromatosis), or may
occur as the sole component. Follicular cell–derived familial thyroid cancer has been
described in several syndromes, such as Cowden disease, Carney complex, Werner

Box 1
Etiology of thyroid nodules

Benign etiology
Follicular adenoma
Hurthle cell adenoma
Colloid cyst
Simple or hemorrhagic cyst
Lymphocytic thyroiditis
Granulomatous thyroiditis
Infectious processes
Malignant etiology
Malignancy of follicular or C-cell origin
Papillary carcinoma
Follicular carcinoma
Hurthle cell carcinoma
Medullary thyroid carcinoma
Anaplastic carcinoma
Malignancy of other origin
Thyroid lymphoma
Malignancy metastatic to the thyroid
332 Popoveniuc & Jonklaas

syndrome, and familial polyposis, as well as occurring in isolation. Cowden disease is an

autosomal dominant condition, resulting from a mutation in the PTEN gene, and is char-
acterized by hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal tract,
central nervous and genitourinary systems, with breast and thyroid cancers being the
most commonly encountered malignancies.21,22 Carney complex, another autosomal
dominant condition, is characterized by cardiac and cutaneous myxomas, spotty
skin pigmentation, various endocrinopathies, and malignancies of endocrine and
nonendocrine origin.23 Less commonly, thyroid cancer can be encountered in patients
with Werner syndrome, of which the main characteristic is premature aging, and familial
polyposis, which is primarily associated with colon cancer.
A personal history of head and neck irradiation, particularly as a child, young age
(<20 years), or advanced age (>70 years), and male sex are demographic features
associated with increased likelihood of malignancy in a patient with a thyroid nodule.
Table 1 summarizes clinical features that should alert the clinician to the possibility of
thyroid carcinoma in a patient with a thyroid nodule.13 It is important to know that
symptoms, such as hoarseness, dysphagia, and cough, are rarely related to thyroid
conditions, and a thorough workup should be pursued to exclude other, more
common etiologies related to gastrointestinal and respiratory systems.

DIAGNOSTIC STUDIES

A spectrum of diagnostic studies is available to aid in the evaluation of a thyroid nodule

(Fig. 1). These include serum markers, such as serum thyrotropin (TSH) and calcitonin.
Fine-needle aspiration (FNA) cytology is the cornerstone of thyroid nodule evaluation.
Genetic markers of thyroid cancer risk, such as the BRAF mutation, can also be deter-
mined using cytology samples. In addition, immunohistochemical markers, such as
galectin-3, cyclooxygenase 2, and cyclin D2, may have potential use. Ultrasonography
plays a pivotal role in the evaluation of thyroid nodules, and elastography may prove to

Table 1
Features suggestive of increased potential for thyroid carcinoma in a patient with thyroid
nodule

Patient History or Findings on Physical

Characteristics Examination Findings Seen on Imaging
Family history of MEN, MTC, Firm nodule Suspicious ultrasound features
and PTC
History of head and neck Nodule fixed to adjacent Lymphadenopathy
irradiation structures
History of Hodgkin and Growth of nodule, especially
non-Hodgkin lymphoma during therapy to suppress
serum TSH
Age <20 Abnormal cervical
lymphadenopathy
Age >70 Paralysis of the vocal cords
Male sex
Symptoms of compression:
hoarseness, dysphagia,
dysphonia, dyspnea, cough

Abbreviations: MEN, multiple endocrine neoplasia; MTC, medullary thyroid cancer; PTC, papillary
thyroid cancer; TSH, serum thyrotropin.
 Thyroid Nodules 333

Fig. 1. Diagnostic studies available for evaluating thyroid nodules. (Modified from figure
provided by Dr BR Haugen, University of Colorado at Denver and Health Sciences Center,
Aurora, CO; with permission.)

be a valuable addition. Other imaging studies, including MRI, CT, and 18FDG-PET
scans may be helpful in certain circumstances.

Serum Markers

 The risk of malignancy in thyroid nodules increases as the serum TSH increases
TSH measurement should be part of the initial workup in every patient with a thyroid
nodule and be used as a guide for further management (Fig. 2).1,24,25 A normal or
high TSH level should raise concerns for possible malignant potential of a nodule,
whereas a low TSH is an indicator of benignity in most cases. Therefore, the next
step in the evaluation of a patient with a low TSH would be an iodine-123 (123-I) or
pertechnetate scintigraphy scan, to explore the possibility of an autonomously func-
tioning nodule. Hyperfunctioning thyroid nodules are almost always benign and gener-
ally do not require further cytologic investigation,26,27 but a nonfunctioning or “cold”
nodule in a patient with low TSH may indicate malignant potential. Recent studies
have investigated the relationship between serum TSH concentration and thyroid
cancer. TSH was found to be an independent predictor of malignancy in thyroid
nodules.28 The risk of malignancy rises in parallel with serum TSH, even within the
normal range, and higher TSH levels were found to be associated with advanced-
stage thyroid cancer.26,29–31
Calcitonin is a sensitive marker for detection of C-cell hyperplasia and MTC, as well
as for surveillance and prognosis of MTC.32 Calcitonin levels of more than 10 pg/mL
were found to have high sensitivity for the detection of MTC,33 with the specificity being
enhanced by pentagastrin stimulation, when calcitonin levels exceed 100 pg/mL.
Even though calcitonin screening was proved to be cost-effective and a useful tool
in the evaluation algorithm for thyroid nodules,34 it is not widely recognized in US,1
partly because of the low prevalence of medullary thyroid cancer and lack of
pentagastrin availability.
Serum thyroglobulin measurement is neither sensitive nor specific for the diagnosis
of thyroid cancer in nodular thyroid disease, being more influenced by iodine intake
and thyroid gland size.35 Therefore, it is not recommended to be routinely measured
in the initial evaluation of a thyroid nodule.1
334 Popoveniuc & Jonklaas

Fig. 2. Algorithm for initial evaluation of a patient with thyroid nodule. (Modified from Cooper
DS. Revised American Thyroid Association management guidelines for patients with thyroid
nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–214; with permission.)

Thyroid Ultrasonography

 Thyroid US allows targeting of nodules with suspicious appearance for biopsy

Thyroid US is an important technique widely used in the detection and evaluation of

thyroid nodules. It is a noninvasive, inexpensive procedure that provides information
with regard to nodule dimensions, structure, and thyroid parenchymal changes.
Nowadays, the use of brightness-mode US and high-frequency transducers may
detect lesions as small as 2 to 3 mm, which raises the question of which thyroid
nodules are clinically relevant for further evaluation.
Previous studies have investigated the ability of thyroid US to differentiate between
benign and malignant lesions to avoid the unnecessary use of invasive proce-
dures.36–39 As a result, several US features have been found to be indicative of malig-
nant potential. Microcalcifications (Fig. 3), irregular or microlobulated margins,
hypoechogenicity, taller-than-wide shape, and increased intranodular vascularity
(Fig. 4) were found to be independent risk factors for malignancy.38,40,41 Even though
these suspicious features are characterized by high specificity, their positive predic-
tive value is lowered by their relatively low sensitivity (Table 2). It is important to
know that none of these US features alone is sufficient to differentiate benign from
 Thyroid Nodules 335

Fig. 3. US image of a thyroid nodule (arrowheads) containing multiple fine punctuate echo-
genicities (arrow) with no comet-tail artifact, indicating high suspicion for malignancy. FNA
and surgery confirmed PTC. (Reproduced from Frates MC. Management of thyroid nodules
detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radi-
ology 2005;237:794–800; with permission.)

malignant tumors, but a combination of at least 2 of them better succeeds in pointing

out a subset of lesions at high risk for malignancy.42,43 Papini and colleagues38
demonstrated that nodules with a hypoechoic appearance and one of the other suspi-
cious US characteristics successfully identifies thyroid lesions that need to undergo
further cytologic examination. For example, a predominantly solid nodule with micro-
calcifications has a 31.6% likelihood of malignancy, whereas a predominantly cystic

Fig. 4. Color Doppler US of a thyroid nodule showing marked internal vascularity, indicating
increased likelihood of malignancy. Histology demonstrated PTC. (Reproduced from Frates
MC. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound
consensus conference statement. Radiology 2005;237:794–800; with permission.)
336 Popoveniuc & Jonklaas

Table 2
Ultrasound characteristics of thyroid nodules predictive of malignancy

Positive Predictive Negative Predictive

Ultrasound Feature Sensitivity, % Specificity, % Value, % Value, %
Microcalcifications 26.1–59.1 85.8–95.0 24.3–70.7 41.8–94.2
Hypoechogenicity 26.5–87.1 43.4–94.3 11.4–68.4 73.5–93.8
Irregular margins 17.4–77.5 38.9–85.0 9.3–60.0 38.9–97.8
or no halo
Solid 69.0–75.0 52.5–55.9 15.6–27.0 88.0–92.1
Intranodule 54.3–74.2 78.6–80.8 24.0–41.9 85.7–97.4
vascularity
More tall than wide 32.7 92.5 66.7 74.8

Reproduced from Frates MC. Management of thyroid nodules detected at US: Society of Radiolo-
gists in Ultrasound consensus conference statement. Radiology 2005;237(3):794–800; with
permission.

lesion (Fig. 5) with no microcalcifications lowers the probability for being cancer to
1.0%.44 US findings such as isoechogenicity and spongiform appearance (defined
as aggregations of multiple microcysts in more than 50% of the nodule) are features
highly suggestive of benignity.41
The number of nodules and their size are not predictive of malignancy, as a nodule
smaller than 1 cm is as likely as a larger nodule to harbor neoplastic cells in the pres-
ence of suspicious US features.44,45 Choosing an arbitrary size as cutoff for the likeli-
hood of cancer or stratifying the risk in a multinodular goiter based on the “dominant”
nodule has fallen into disfavor.38
US identification of cervical lymph nodes demonstrating microcalcifications,
increased vascularity, cystic changes, and rounded shape, along with coexisting ipsi-
lateral thyroid nodules, are also very important clues for malignant etiology.42
Evidence of extracapsular growth, which may range from invasion of the thyroid
capsule to perithyroidal muscle infiltration and recurrent laryngeal nerve extension,
is another strong indicator of malignancy.42,43

Fig. 5. US image of a cystic thyroid nodule (arrowheads). (Reproduced from Frates MC.
Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound
consensus conference statement. Radiology 2005;237:794–800; with permission.)
 Thyroid Nodules 337

Screening for thyroid nodules by US, or by any other types of imaging studies, is not
recommended in the general population because of the minimal aggressiveness and
indolent course of most of the thyroid cancers. Current ATA guidelines1 recommend
diagnostic thyroid sonography to be performed only in patients with known or sus-
pected thyroid nodules, or in the presence of risk factors.24,46
Other diagnostic imaging techniques, such as MRI and CT scans, are not indicated
for routine thyroid nodule evaluation, but they may be helpful for the assessment of
nodule size, substernal extension of a nodular goiter, and airway compression.25

Elastography

 Elastography is a promising tool for predicting the malignant potential of thyroid

nodules
A recent advancement in the diagnosis of thyroid nodules has been brought by the use
of elastography. This is a dynamic technique that assesses the hardness of the tissue
as an indicator of malignancy.47 This technique was demonstrated to be highly
specific (96%–100%) and sensitive (82%–97%) in the diagnostic evaluation of thyroid
nodules, independent of nodule size, or location within the thyroid gland.48,49 It was
also found to be reliable in the diagnostic evaluation of indeterminate/follicular lesions,
but this aspect of its use still needs to be confirmed.50 The diagnostic yield of elastog-
raphy is impaired in nodules with a calcified shell, cystic lesions, and multinodular
goiter with coalescent nodules, because the margins need to be well demarcated
for proper interpretation.51 It is not suitable for diagnosis of follicular carcinoma and
its use is restricted to high-end US devices. Although more data from larger prospec-
tive studies is needed to establish the accuracy of this diagnostic technique, it remains
a promising tool in selecting nodules for FNA.

FNA Biopsy

 FNA, in conjunction with US, forms the cornerstone of thyroid nodule evaluation

Thyroid FNA biopsy is the most reliable, safe, and cost-effective diagnostic tool used
in the evaluation of thyroid nodules.52,53 FNA under US guidance is preferred over the
palpation-guided approach because of lower rates of false-negative and nondiagnos-
tic cytology.54 This is particularly true for nodules that are nonpalpable, located deeply
in the thyroid bed, or have a predominantly cystic component.1
The decision to pursue FNA sampling should be based on a risk-stratifying
approach that includes history, US characteristics, and nodule size (Table 3). Sub-
centimeter nodules should be biopsied only if there is more than 1 suspicious US char-
acteristic, extracapsular growth, abnormal cervical lymph nodes, or high-risk history
(see Table 1). Otherwise, a cutoff size of 1 cm can be used for solid nodules that
have only 1 suspicious sonographic feature, such as microcalcifications or hypoe-
choic appearance. Mixed cystic-solid nodules should undergo biopsy if they are
more than 1.5 cm in size and the solid component should be targeted for biopsy.
Purely cystic and spongiform lesions are considered to have low risk for malignancy;
therefore, they could be either monitored or biopsied if larger than 2 cm (see Table 3).
Cytologic diagnosis

 FNA based on an adequate sample is 95% accurate for diagnosing thyroid cancer

Almost 20% of FNA results are nondiagnostic, because of sampling error or poor
preparation technique.55 In such cases, it is recommended that a repeat FNA be
338 Popoveniuc & Jonklaas

Table 3
Sonographic and clinical features of thyroid nodules and recommendations for FNA

Recommendeda Nodule Threshold Size

Nodule Sonographic or Clinical Features for FNA
High-risk history
Nodule with suspicious sonographic features >5 mm Recommendation A
Nodule without suspicious sonographic features >5 mm Recommendation I
Abnormal cervical lymph nodes All Recommendation A
Microcalcifications present in nodule 1 cm Recommendation B
Solid nodule
And hypoechoic >1 cm Recommendation B
And iso- or hyperechoic 1–1.5 cm Recommendation C
Mixed cystic-solid nodule
With any suspicious ultrasound features 1.5–2.0 cm Recommendation B
Without suspicious ultrasound features 2.0 cm Recommendation C
Spongiform nodule 2.0 cmb Recommendation C
Purely cystic nodule FNA not indicatedc Recommendation E

Abbreviation: FNA, fine-needle aspiration.

a
Explanation of Recommendations: A, strongly recommends based on good evidence; B, recom-
mends, based on fair evidence; C, recommends based on expert opinion; E, recommends against
based on fair evidence; I, recommends neither for nor against, evidence insufficient.
b
Sonographic monitoring without biopsy may be an acceptable alternative.
c
Unless indicated as therapeutic modality.
Modified from Cooper D. Revised American Thyroid Association management guidelines for
patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19(11):1167–214;
with permission.

performed under US guidance, and if available, on-site cytologic examination for

better cytologic adequacy.56,57 Approximately 7% of the nodules will still yield unsat-
isfactory cytologic results on repeated biopsies. In this situation, surgery is strongly
recommended for solid nodules and close observation or surgery for partially cystic
lesions, as they may harbor neoplastic potential.1,58
Diagnostic FNA results are divided into 5 categories, based on the recent Bethesda
System for Reporting Thyroid Cytopathology59: benign (70%), malignant (5%), suspicious
for malignancy, follicular or Hurthle cell neoplasm, and follicular lesions of undetermined
significance or atypia. The last 3 cytologic diagnoses, which represent 25% of the total
cases, have been previously classified as indeterminate lesions. They have a predicted
probability for cancer of 50% to 75%, 20% to 30%, and 5% to 10%, respectively.59
The most common benign lesions include colloid nodule, macrofollicular adenoma,
and lymphocytic thyroiditis, among others.24 The most prevalent malignant lesions by
far are represented by PTC, followed by follicular thyroid cancer (FTC), MTC,
anaplastic carcinoma, and high-grade metastatic neoplasms.60 Suspicious lesions
may represent PTC that lacks definitive diagnostic criteria, follicular neoplasm, Hurthle
cell neoplasm, lymphoma, or PTC-follicular variant.
Surgery, with lobectomy or total thyroidectomy is the treatment of choice for malig-
nant and suspicious lesions.1 The same is true for follicular lesions, unless the nodule
is found to be autonomous on a 123-I scan in the setting of low-normal TSH.1 Thyroid
nodules larger than 3 cm with mixed cystic/solid components should be strongly
considered for surgery for diagnostic purposes, as FNA yields a high rate of false-
negative results in these lesions.61
 Thyroid Nodules 339

Indeterminate cytology

 The cytology findings from some FNA biopsies fall into an indeterminate category
in which malignancy cannot reliably be excluded
 Panels of gene mutations may serve as markers of which patients with cytologi-
cally indeterminate nodules may safely avoid surgery
Current management for most patients with indeterminate cytology at FNA biopsy
consists of diagnostic surgery to establish a histopathological diagnosis. However,
only 10–40% of these cases will turn out to be malignant,59,62 leading to more than
60% of surgeries being unnecessary, with their associated risks and costs. The eval-
uation of genetic markers associated with thyroid carcinoma (PTC: BRAF, RAS, RET/
PTC; FTC: PAX8/PPARg1) in the cytology specimen has been shown to improve
preoperative diagnosis of thyroid nodules in large prospective studies, particularly
when used in combination with cytologic features.63,64 For example, in a Korean pop-
ulation, the combination of both cytology and BRAF mutation status increased the
specificity of testing from 36% to 95% compared with FNA cytology alone.65 The
use of molecular markers, in the form of a panel of gene mutations, in patients with
indeterminate cytology on FNA samples has been shown to increase the probability
of cancer from 24% to 89% if any mutation is identified, whereas the lack of any muta-
tion decreases the risk to 11%.66 Cost-effectiveness analysis using a molecular panel
of gene markers, coupled with classical cytologic findings, to increase the predictive
power of diagnostic interpretations shows promising results when compared with the
surgical approach, and is likely to be used in the future in clinical practice.67
Currently, there are 2 commercially available assays that provide molecular testing of
the thyroid cytologic specimens from FNA biopsy. Veracyte Afirma Gene Expression
Classifier, promoted by Genzyme (Cambridge, MA, USA), evaluates messenger RNA
(mRNA) expression levels for 142 genes. It has a negative predictive value of 96%
when evaluated in samples with indeterminate cytology, thus helping patients with
benign lesions to avoid unnecessary surgeries.68 The recent cost-effectiveness anal-
ysis by Li and colleagues67 predicts that routine application of the gene expression clas-
sifier lowers the rate of surgeries for benign nodules from 57% (with current practice) to
14%. miRInform Thyroid is another commercially available assay provided by Asuragen
(Austin, TX, USA), which analyzes a panel of 7 molecular markers most commonly
encountered in thyroid cancers (BRAF, KRAS, HRAS, NRAS, RET/PTC1, RET/PTC3,
PAX8/PPARg). In contrast to the Veracyte product, it is thus designed to improve the
preoperative cytologic diagnosis of indeterminate thyroid nodules by predicting which
nodules are most likely to be malignant. Its clinical validation still needs to be deter-
mined, but the analytical specificity was found to be 99%, and the sensitivity 95%.
In addition to genetic markers, immunohistochemical staining of cytology speci-
mens and other novel serum markers may be of use. With respect to immunohisto-
chemical markers, galectin-3 is a protein marker that was also shown to improve
preoperative diagnosis in indeterminate follicular lesions when used in combination
with conventional cytomorphological diagnostic procedures.69,70 However, recent
data have shown that galectin-3 is more useful for diagnosing PTC than FTC.71
Measurement of serum TSH receptor mRNA, which serves as an indicator of circu-
lating thyroid cancer cells, may be useful for helping determine which nodules with
indeterminate cytology are malignant. TSH receptor mRNA concentrations greater
than 1 ng/mg had a positive predictive value of greater than 90% for carcinoma.72
The use of 18FDG-PET scan in the preoperative diagnosis of thyroid nodules with
indeterminate cytology has high sensitivity, but histologic diagnosis is still required
to distinguish benign from malignant etiology in 18FDG-PET–positive nodules.73–76
340 Popoveniuc & Jonklaas

However, the use of 18FDG-PET could potentially reduce the number of unnecessary
thyroidectomies by 39% to 46%.73,74 It has limited value in selecting candidates for
surgery among patients with the cytologic diagnosis of follicular neoplasm, as the
glucose metabolic activity is similar in benign and malignant nodules with follicular
pattern cytology.45

INITIAL EVALUATION OF SINGLE NODULES, FUNCTIONING NODULES, MULTINODULAR

GLANDS, INCIDENTAL NODULES, AND CYSTS

 A patient with a multinodular thyroid has the same risk of having a malignancy as
a patient with a single thyroid nodule
An algorithm for the initial evaluation of a thyroid nodule is shown in Fig. 2. Tests that
direct the evaluation along different pathways depending on their results include TSH
values, US findings, FNA results, scintigraphy findings, and results of molecular
testing. Most nodules will be found to be benign based on cytology. Such nodules
do not require immediate further diagnostic evaluation or treatment,1 but can simply
be monitored.
With respect to TSH values, a scintigraphy scan (123-I or technetium 99mTc per-
technetate) should be performed in patients with thyroid nodules and serologic
evidence of low or low-normal TSH concentration for further evaluation of nodule func-
tionality. Nodules that are interpreted as “hot” on scintigraphy represent hyperfunc-
tioning nodules and should not be considered for FNA biopsy because they are
very rarely malignant.25 The isofunctioning or nonfunctioning nodules, also named
“cold” nodules, have a risk for cancer between 5% and 15%, and therefore should
be aspirated for further evaluation. The ability to assess nodular functioning with radio-
isotope scanning is generally limited in lesions smaller than 1 cm.35
US examination, in addition to providing information about the appearance and size
of nodules, will also document the number of nodules. Of note, the prevalence of
thyroid cancer in patients with a multinodular goiter is the same as in patients with
a solitary nodule and is independent of the number of nodules. However, the likelihood
of malignancy per nodule decreases as the number of nodules increases.77 If 2 or
more nodules larger than 1 cm are present, the selection of nodules for FNA biopsy
should be made on the basis of the previously described suspicious US characteris-
tics. Otherwise, the largest nodule should be targeted for biopsy.1
Thyroid incidentalomas discovered by CT or MRI should initially undergo US evalu-
ation, with further management being guided based on the sonographic characteris-
tics, as mentioned previously. In contradistinction, incidentalomas detected by
18FDG-PET examination have a high risk of malignancy, and US evaluation, along
with FNA biopsy, should be performed.25
Totally cystic lesions are generally considered benign and, unless a solid compo-
nent is present, further diagnostic investigation is not required (see Table 3).

TREATMENT FOR BENIGN NODULES

 Surgical treatment is recommended for nodules causing compressive symptoms,

and can be considered for toxic nodular disease and thyroid cysts
 T4 suppressive therapy is controversial: it is associated with the risks of iatrogenic
hyperthyroidism, but may prevent new nodule formation

Most benign thyroid nodules do not require any specific intervention, unless there are
local compressive symptoms from significant enlargement, such as dysphagia,
 Thyroid Nodules 341

choking, shortness of breath, hoarseness, or pain, in which case thyroidectomy

should be performed.
Other indications for surgery in benign nodules include the presence of a single toxic
nodule, or a toxic multinodular goiter. Radioiodine (131-I) therapy is another option for
treatment of toxic nodular goiters, but they are usually more radioresistant than toxic
diffuse goiter and radioiodine is not the first-line therapy if compressive symptoms are
present. Treatment with 131-I for larger nodules is not preferred either, as such
nodules require high doses of 131-I with its associated side effects. Radioiodine
therapy needs to be approached with caution in individuals with uncontrolled thyro-
toxicosis. However, the only absolute contraindications to 131-I therapy are preg-
nancy and lactation.78
Aspiration is the treatment of choice in thyroid cysts, but the recurrence rates are
high (60%–90% of patients), particularly with repeated aspirations and large-volume
cysts.79,80 Percutaneous ethanol injection (PEI) has been studied in several large
randomized controlled studies, with reported success in 82–85% of the cases after
an average of 2 sessions, with a volume reduction of more than 85% from baseline
size.79,80 PEI may also be considered for hyperfunctioning nodules, particularly if
a large fluid component is present. It has a success rate ranging from 64% to
95%,81–83 with a mean volume reduction of 66%,81 but recurrences are more common
and the number of sessions required to achieve good response is higher (about 4
sessions per patient). PEI is a safe procedure, with the most common reported
adverse effects being local pain, dysphonia, flushing, dizziness, and, rarely, recurrent
laryngeal nerve damage.79,80,84 Surgery, in addition to serving as a suitable option for
treatment of single toxic nodules and toxic multinodular goiter, is also a reasonable
therapy for cystic lesions, as an alternative to the previously mentioned procedures.
Levothyroxine (T4) therapy for benign thyroid nodules has been proposed with the
aim of achieving nodule shrinkage and preventing further appearance of new nodules
through TSH suppression. Although several randomized control trials and meta-
analyses have demonstrated nodule shrinkage in patients from areas of iodine defi-
ciency,85–88 a clinically significant decrease in nodule volume is achieved only in
a minority of patients with sufficient iodine intake.85,88,89 Other predictive features of
good response to T4 treatment are recent diagnosis, small nodule size, and colloid
appearance at FNA.90
T4 suppressive therapy is not devoid of adverse effects, such as decreased bone
density, particularly in postmenopausal women, atrial fibrillation, and increased overall
morbidity and mortality from cardiovascular diseases.91 Current guidelines1 do not
recommend routine use of T4 suppressive treatment in patients with benign thyroid
nodules from areas with iodine sufficiency. A recent study conducted in Italy in individ-
uals with nontoxic goiter. However, a recent study conducted in Italy in individuals with
non-toxic goiter showed decreased goiter growth, decreased formation of new
nodules, and decreased risk of developing PTC in a population receiving T4,
compared with an untreated population.92 Thus, this management technique may
have some utility.

FOLLOW-UP

 A 50% increase in the volume of a previously biopsied thyroid nodule is a reason-

able trigger for repeating an FNA
Benign thyroid nodules require further long-term follow-up because of the risk of false-
negative results after initial FNA, which is about 5%.93 Serial US at 6 to 18 months from
the initial FNA is the recommended investigation for the follow-up examination of
342 Popoveniuc & Jonklaas

thyroid nodules to accurately detect significant changes in size94 or discover changes

in appearance (Fig. 6).
There is no consensus definition for nodule growth and threshold size to repeat an
FNA. However, many investigators propose a cutoff value of 50% for nodule volume
growth, or more than 20% increase in at least 2 dimensions of a solid nodule, or the
solid portion of a mixed cystic-solid nodule to be reasonable and safe.95 An online
calculator to determine the change in volume of a thyroid nodule from its serial dimen-
sions is available on the ATA Web site (http://www.thyroid.org/professionals/
calculators/CINV.php). Although nodule growth is an indication for repeat biopsy,1
growth is not pathognomonic for malignancy.96 Repeated FNA biopsy is recommen-
ded to be performed under US guidance, as false-negative rates are higher with
palpation-guided FNA, compared with US-guided FNA.54 A recent retrospective anal-
ysis of value of repeated FNAs of benign thyroid nodules demonstrated high accuracy
(98%) of the initial diagnosis.97
If no significant nodule growth is observed at repeated US, a follow-up interval of
3 to 5 years may be reasonable (see Fig. 6).1

THYROID NODULES IN PREGNANCY

 If a diagnosis of thyroid cancer is made during pregnancy, surgery usually may be

delayed until after delivery

Fig. 6. Algorithm for follow-up of benign thyroid nodules.

 Thyroid Nodules 343

 In the case of aggressive or rapidly growing thyroid cancer, surgery during the
second trimester is safest
The etiology and behavior of thyroid nodules discovered during pregnancy as
compared with the general population is unknown.98 As a consequence, the evalua-
tion should be similar to that for nonpregnant patients, except for the contraindication
to radionuclide scanning. If a patient is found to have persistently suppressed serum
TSH levels after the first trimester, the radionuclide scan and possible subsequent
FNA can be safely postponed until after delivery and cessation of lactation.1 In euthy-
roid or hypothyroid pregnant women with thyroid nodules, consensus guidelines
recommend that an FNA biopsy should be performed.1 An argument can be made,
however, for deferring the FNA until after delivery unless there are worrisome clinical
features that would perhaps lead to a recommendation for a thyroidectomy during
pregnancy. If a diagnosis of malignancy results from the FNA, but postponement of
thyroidectomy until the patient is post partum is the intended plan before the FNA,
this simply exposes the patient to anxiety regarding a diagnosis about which she
can take no action.
Previous studies have demonstrated similar cancer behavior in pregnant patients
diagnosed with PTC when compared with the general population,99,100 with no differ-
ences in survival rates or recurrences in pregnant women operated for PTC during or
after delivery.100 Rates of complications after thyroid surgery are higher in pregnant
women than their nonpregnant counterparts, however.101 Because additional retro-
spective data suggest that delaying surgery for less than 1 year from the time of the
differentiated thyroid cancer diagnosis has no impact on patient outcome,102 post-
poning the surgery until after delivery seems a reasonable approach. If more advanced
or aggressive disease is present at the time of diagnosis, or a decision is made to
pursue thyroidectomy for thyroid cancer discovered early in pregnancy, surgery
should be ideally performed in the second trimester of pregnancy,103 as this may
decrease the risk of early miscarriage and premature delivery.
T4 suppressive therapy to maintain a serum TSH level between 0.1 and 1.0 mU/L is
a reasonable approach in pregnant patients diagnosed with thyroid cancer on the
basis of an FNA and who are awaiting thyroidectomy.104

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