Meei J. Yeung and Jonathan W. Serpell
Management of the Solitary Thyroid Nodule
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Management of the Solitary Thyroid Nodule
MEEI J. YEUNG, JONATHAN W. SERPELL
The Alfred Hospital, Monash University Endocrine Surgery Unit, Melbourne, Victoria, Australia
Key Words. Thyroid • Thyroid nodule • Thyroid cancer • Fine needle aspiration biopsy • Thyroid ultrasound
Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.
After completing this course, the reader will be able to:
1. Describe the investigations used for a solitary thyroid nodule.
2. Explain the importance of thyroid ultrasound and fine-needle aspiration biopsy results.
3. Discuss how thyroid nodules are managed surgically.
Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™at CME.TheOncologist.com
Thyroid nodules are common, with up to 8% of the
adult population having palpable nodules. With the use
of ultrasound, up to 10 times more nodules are likely to
be detected. Increasing numbers of nodules are being
detected serendipitously because of the rising use of im-
aging to investigate unrelated conditions. The primary
aim in investigating a thyroid nodule is to exclude the
possibility of malignancy, which occurs in about 5% of
nodules. This begins with a thorough history, including
thyroid cancer or other endocrine diseases. Clinical ex-
amination of the neck should focus on the thyroid nod-
ule and the gland itself, but also the presence of any
cervical lymphadenopathy. Biochemical assessment of
the thyroid needs to be followed by thyroid ultrasound,
which may demonstrate features that are associated
with a higher chance of the nodule being malignant.
Fine-needle aspiration biopsy is crucial in the investiga-
tion of a thyroid nodule. It provides highly accurate cy-
tologic information about the nodule from which a
definitive management plan can be formulated. The
challenge remains in the management of nodules that
fall under the “indeterminate” category. These may be
subject to more surgical intervention than is required
because histological examination is the only way in
which a malignancy can be excluded. Surgery followed
by radioactive iodine ablation is the mainstay of treat-
ment for differentiated thyroid cancers, and the major-
ity of patients can expect high cure rates. TheOncologist
Thyroid nodules are a common problem. They are found in
4%–8% of adults by palpation and in 13%–67% when ul-
trasound detection is used. In autopsy studies, they have a
prevalence of approximately 50% [1, 2]. The prevalence of
thyroid nodules increases with age and women have a
Correspondence: Meei Yeung, B. Med. Sci., M.B.B.S., F.R.A.C.S, 304/122 Ormond Road, Elwood 3184, Melbourne, Australia. Tele-
phone: 61412925015; Fax: 61395256536; e-mail: firstname.lastname@example.org Received October 30, 2007; accepted for publication De-
cember 4, 2007. ©AlphaMed Press 1083-7159/2008/$30.00/0 doi: 10.1634/theoncologist.2007-0212
by on April 1, 2008
higher prevalence than men. The natural history of benign
nodules is unclear, but most palpable nodules probably re-
duce in size, with up to 38% disappearing altogether [3, 4].
The concern with thyroid nodules is the possibility of ma-
lignancy. Thyroid cancers are rare, accounting for only
cer deaths . Nonetheless, thyroid cancers occur in ap-
proximately 5% of all thyroid nodules independent of their
size. With thyroid nodules being so prevalent in the general
ing nodules and determining which of these will require
surgery or can be managed conservatively.
As with all assessments, a thorough history and examina-
tion is required in patients who present with a thyroid nod-
ule. Most nodules are asymptomatic and are often
discovered serendipitously by the patient or their primary
medical practitioner when being examined for another
thyroid nodules are not infrequently detected as an inciden-
tal finding on ultrasounds and computed tomography (CT)
History and Examination
Regardless of the way in which thyroid nodules are discov-
ered, a detailed patient history is requisite. Information that
a change in nodule size, previous head/neck radiation ex-
posure, and a family history of thyroid or endocrine dis-
eases. The patient may report a history of pain, which may
follow hemorrhage into a colloid nodule, or a sudden in-
of malignancy. Voice change or hoarseness may also be a
progressive symptom associated with an invasive tumor.
Symptoms of dysphagia, coughing, choking, and dyspnea
should be asked about.
Exposure of the thyroid gland to ionizing radiation is
known to contribute to a higher incidence of both benign
and malignant thyroid nodules, with malignancy rates in a
palpable nodule in a previously irradiated thyroid in the
range of 20%–50% [7, 8].
Thyroid carcinomas are classified according to the cell
type from which they develop. The majority are nonmedul-
mors and are divided into four histologic subtypes: papil-
lary (85%), follicular (11%), Hu ¨rthle cell (3%), and
anaplastic (1%). Of these, 95% are sporadic tumors and the
rest are thought to represent a familial origin, that is, famil-
ial nonmedullary thyroid cancer (FNMTC).
Medullary thyroid cancers (MTCs) arise from the calci-
tonin-producing parafollicular cells of the thyroid and ac-
plasia (MEN) syndromes. It is important to identify these
patients, as pheochromocytomas are associated with MEN
II and need to be excluded prior to the patient receiving an
FNMTCs are rare. Based on epidemiologic studies and
kindred analysis, this group of tumors is believed to result
from a genetic inheritance, although environmental influ-
ences cannot be excluded. Inheritance is probably autoso-
mal dominant with incomplete penetrance and variable
expressivity. The diagnosis of FNMTC is made when thy-
roid cancer occurs in two or more first-degree relatives .
Clinically, FNMTCs can be divided into two groups. The
first group includes familial tumor syndromes character-
ized by a preponderance of nonthyroidal tumors. These
cancer syndromes include familial adenosis polyposis
(Gardner syndrome), familial hamartoma syndrome (Cow-
den syndrome), and the Carney complex type 1. In the sec-
ond group, NMTC predominates . Compared with
rence [11, 12].
Clinical examination of the thyroid should focus on
goiter. The characteristics of the nodule, including size,
consistency (e.g., soft, firm, woody, or hard), and involve-
ment with adjacent structures, should also be defined. Ex-
amination of the cervical lymph nodes, including the
central compartment (level VI) and the lateral neck (levels
I–V), should also be performed (Fig. 1). Suggestion of in-
volvement of lateral neck lymph nodes will change the ex-
Investigation of thyroid nodules should begin with assess-
ment of the functional status of the thyroid. Tests include
serum thyroid-stimulating hormone (TSH), free thyroxine,
and free tri-iodothyronine. Measurement of TSH is the
most useful initial step. With the availability of highly sen-
function with this test alone . If the TSH is abnormal,
free thyroid hormones and thyroid antibodies should be the
oxidase and antithyroglobulin antibodies are found in most
patients with Graves’ disease or Hashimoto’s thyroiditis.
Solitary Thyroid Nodule Management
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TSH receptor autoantibodies are detectable in the majority
the major constituent of colloid and precursor of thyroid
hormones. Serum Tg can be elevated in most thyroid dis-
eases and is therefore not recommended as a routine initial
assessment of thyroid nodules .
Calcitonin is produced from the parafollicular cells of
the thyroid. Serum levels are usually elevated in patients
with MTCs. The calcitonin assay as a screening test is not
cost-effective; however, in patients with a history sugges-
tive of MEN, it may aid in the diagnosis of MTC.
Thyroid scintigraphy has a limited role in the evaluation of
a solitary thyroid nodule. It has been relied upon in the past
to assist in risk stratification of nodules as being benign or
ing on the pattern of uptake, nodules are classified as hy-
perfunctioning (hot), hypofunctioning (cold), or normal
functioning (warm). Hot nodules are seen in about 5% of
80%–85% of nodules are cold and 10%–15% of these are
malignant . The incidence of malignancy in warm nod-
ules is reported to be 9%. This information on its own is
unlikely to change the subsequent management of the nod-
ule and further decision making . Thyroid scintigraphy
does have a place in the investigation of a thyroid nodule
determine if the nodule is an autonomously toxic nodule, if
it is part of a toxic multinodular goiter or a single nodule in
a patient with Grave’s disease [18, 19].
All patients who present with a thyroid nodule should un-
dergo ultrasound evaluation of the nodule, thyroid gland,
and cervical lymph nodes, if indicated. Ultrasound is an in-
expensive, readily available, and noninvasive investiga-
tion. The superiority of ultrasound examination of the
thyroid over clinical examination has been described, with
one study showing ultrasonography leading to a change in
solitary nodule on physical examination . As has been
eloquently described, “The ultrasound machine to the en-
docrinologist evaluating a thyroid nodule is analogous to
the stethoscope of the cardiologist” .
An ultrasound examination should focus on the size of
the nodule, its composition, the presence of additional nod-
ules, and any sonographic appearance suggestive of malig-
nancy. Patients with multiple thyroid nodules have the
ules [20, 22] or even diffuse goiters , and it is recom-
mended that all patients who have a nodular thyroid
undergo ultrasound evaluation . Numerous studies
have attempted to define which ultrasound characteristics
are most predictive of malignancy. To date, no single fea-
ture carries a high sensitivity and high positive predictive
value for thyroid cancer . However, there are a number
of ultrasound qualities that, when they occur in combina-
tion, are associated with a higher risk for malignancy [24,
cancer in a thyroid nodule has been shown to be the same
regardless of the size on ultrasound [22, 24, 26]. Previous
guidelines had recommended that the decision to perform a
fine-needle aspiration biopsy (FNAB) should be based on
in nodules ?10 mm is not less frequent, and if this value is
used as a cutoff, then a significant proportion of cancers
will be missed . The prevalence of extracapsular or
metastatic growth was shown to be similar in nodules ?10
mm and ?10 mm [22, 27]. The lower size limit of a nodule
that should be biopsied is currently under debate , but
nodules ?10 mm with associated microcalcifications or a
history of neck irradiation should undergo FNAB .
Figure 1. Location of cervical lymph node levels. Level I,
submental and submandibular nodes; level II, upper jugular
nodes; level III, midjugular nodes; level IV, lower jugular
nodes; level V, posterior triangle and supraclavicular nodes;
level VI, pretracheal, prelaryngeal, and paratracheal nodes;
level VII, nodes within the superior mediastinum.
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Nodules can be descriptively classified depending on their
predominant composition, for example, solid, cystic or
mixed, or complex. Papillary thyroid cancer (PTC) is iden-
tified in 87% of solid nodules, 7% of mixed composition
nodules, and 6% of predominantly cystic nodules .
have undergone cystic degeneration. The cystic component
lial portion potentially representing only a small, com-
to this solid component to rule out malignant disease.
The presence of any calcification within a nodule increases
the likelihood of malignancy. Microcalcifications are de-
fined as multiple, small intranodular punctate hyperechoic
spots, with scanty or no posterior acoustic shadowing .
They are thought to represent the superimposition of Psam-
indicative of PTC and have a specificity of up to 95% .
nodule, there is an approximately threefold higher cancer
risk, and coarse calcifications are associated with a twofold
higher risk, as compared with solid nodules without calci-
in a solitary nodule in a young patient should raise concern
for PTC .
Solitary Versus Multiple Nodules
ilar in patients with a solitary nodule and patients with mul-
tiple nodules . In glands with multiple nodules, the
recommendation of the American Thyroid Association
(ATA) is to biopsy nodules that are ?10 mm and those that
have suspicious features .
Other Ultrasound Features
as a possible predictor of thyroid malignancy. Benign nod-
ules are thought to demonstrate peripheral flow, with ma-
lignant lesions showing flow predominantly in the central
portion. Results have failed to conclusively support this.
Hypoechogenicity and the absence of a halo around the
nodule are nonspecific markers of thyroid cancers .
A nodule that is shaped more tall than wide (defined as
verse dimension) has been shown to be suggestive of ma-
Ultrasound is an accurate and sensitive imaging modality
for the detection of cervical lymph node metastasis and re-
currence . The ultrasound features associated with the
highest risk for cancer include a heterogeneous echotex-
ture, calcifications, no hilus, a rounded appearance, cystic
changes, and chaotic hypervascularity. These lymph nodes
should always be biopsied even in the absence of a malig-
nant-appearing thyroid nodule .
Other Imaging Modalities
sion tomography (PET) scanning are not recommended in
the routine workup of thyroid nodules. CT is useful in pro-
viding additional anatomical information, such as the pres-
ence of a retrosternal goiter, compressive symptoms
attributable to a posteromedially placed nodule, and the re-
lationship of a goiter to adjacent structures. MRI can do the
same, but at a greater cost.
With the advent of the increased use of PET scanning in
the staging and surveillance of various malignancies, the
becoming more prevalent. These PET-detected nodules
have been shown, in some studies, to harbor a higher ma-
lignancy risk [32–34]. Until more information is collected
on the significance of these nodules, it seems prudent to
have a low threshold for biopsying these lesions.
FNAB is the most crucial step in the evaluation of a thyroid
nodule and is the procedure of choice in the workup of thy-
roid nodules [15, 35]. It is able to provide specific informa-
tion about the cellular composition of a nodule that directs
subsequent management decisions.
FNAB can be performed by palpation or with ultra-
sound guidance. In our institution, it is performed exclu-
sively with ultrasound guidance. This technique has been
shown to decrease false negatives resulting from needle
misplacement and reduce the rate of nondiagnostic smears
from 15% to 3% [36–39]. The use of FNAB has led to a
reduction in the number of patients requiring surgery and
increased the diagnostic yield of cancers at thyroidectomy
[5, 40, 41].
For FNAB to be regarded as a useful diagnostic tool, it
must have a low false-negative rate. The false-negative rate
is reported in the literature to be in the range of 1%–11%,
with a value ?5% being acceptable [42, 43]. A number of
strategies, including aspirating multiple nodule sites, sub-
mitting cyst fluid for cytologic examination, and reviewing
slides with an experienced cytopathologist , have been
suggested to minimize false negatives.
Solitary Thyroid Nodule Management
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