The Patient with
a Thyroid Nodule
Matthew C. Miller, MD
As defined by the American Thyroid Association’s task force on the management of
thyroid nodules and differentiated thyroid cancer,1a thyroid nodule is ‘‘a discrete
lesion within the thyroid gland that is radiologically distinct from the surrounding
thyroid parenchyma.’’ By this definition, nodular thyroid disease is common in the
United States and throughout the world. With increased sensitivities of radiographic
studies, it is expected that the prevalence of thyroid nodules will also rise.
Although most nodules are benign and asymptomatic, there is a small but not insig-
nificant risk of carcinoma that necessitates further evaluation in many patients –
including the consideration for surgical intervention. This article familiarizes the reader
with a number of the current concepts pertaining to nodular thyroid disease and
provides a framework for appropriate diagnostic evaluation and referral to an endo-
crine or head and neck surgeon.
RISK FACTORS FOR THE DEVELOPMENT OF THYROID NODULES
Several authors have attempted to establish risk factors for the development of soli-
tary nodules and nonendemic multinodular disease. The most comprehensive and
systematic evaluation of these was published by Knudsen and colleagues2in 2002.
Their cohort of 4649 Danish patients was evaluated in the context of other large series
and a set of risk factors for both goiter and thyroid nodules was proposed. In Knud-
sen’s and other similar papers, the strongest of these were female gender, tobacco
smoking, and advanced age.2–4Interestingly, subset analysis found that most of the
age-related prevalence differences were attributable to the presence of multinodular
disease.2Other individual studies have pointed to radiation exposure as a risk factor
for nodules. Although radiation-induced thyroid disease is generally thought to be
associated with childhood exposure,5relative risk rates may also be as high as eight
times in occupationally exposed adults.6As indicated by the gender disparity in
thyroid nodule risk, hormonal influences may also be at play. Pregnancy and multipar-
ity are associated with an increase in the size of pre-existing nodules and with the
Department of Otolaryngology-Head and Neck Surgery, University of Rochester Medical
Center, Box 629, 601 Elmwood Avenue, Rochester, NY 14642, USA
E-mail address: Matthew_miller@urmc.rochester.edu
? Thyroid nodule ? Fine-needle aspiration ? Incidentaloma
Med Clin N Am 94 (2010) 1003–1015
0025-7125/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
development of new nodules.7,8The gestational effects are most pronounced in the
third trimester and in the first 3 months postpartum7and are likely secondary to the
effects of estrogens and progesterone. These hormones may also be responsible
for the observed association between uterine fibroids and thyroid nodules.9
EPIDEMIOLOGY OF THYROID NODULES
The point prevalence of thyroid nodules is variably reported throughout the literature.
This rate has been dependent on the population studied, the detection method, and
the definition used. Among large and heterogeneous populations, palpable nodules
are present in 0.2% to 21% and may be more common in women and older
patients.3,10–14Palpation is generally considered to be the least sensitive and specific
means of detection and is thought to be unreliable for nodules smaller than 1 cm.11
Physical examination of the thyroid, however, is inexpensive, is not technically
demanding, and is easily performed in just about any clinical setting. Consequently,
it is advised that any head and neck examination include palpation of the gland to eval-
uate for nodules or thyromegaly. The presence of a palpable thyroid nodule should
lead the clinician to obtain follow-up testing, which typically includes thyroid
Ultrasound has the benefit of being a more sensitive test than physical examination
for the detection of thyroid nodules. It is estimated that palpation alone fails to detect
up to two thirds of sonographically identifiable nodules.3,11Not surprisingly, preva-
lence rates for thyroid nodules are significantly higher when ultrasound is used as
the screening modality. Among large series of asymptomatic patients, 19% to 35%
have solitary or multiple nodules on ultrasound.3,10–13With high-resolution (ie, 13
MHz) techniques, this number approaches 70%.14
Histopathologic examination remains the gold standard for evaluation of thyroid
nodules and, consequently, autopsy studies likely provide the most accurate repre-
sentation of prevalence. Although the sample preparation techniques and definitions
of nodules are somewhat variable, most autopsy studies have found nodular thyroid
disease in 50% to 65% of patients.10
WHICH NODULES ARE CLINICALLY RELEVANT?
We have established that thyroid nodules are common and that there may be a set of
clinical features that predispose patients to them. The previously mentioned preva-
lence rates should be interpreted with caution, however, because a large proportion
of the nodules identified in these series were smaller than 1 cm. Consensus guidelines
from a variety of professional societies have suggested that 1 cm be the threshold of
significance for most nodules.1,5,15,16
An argument against the comprehensive evaluation of subcentimeter nodules
stems from an understanding of the natural history of well-differentiated (for the
most part papillary) carcinomas smaller than 1 cm (ie, microcarcinomas). Papillary
thyroid microcarcinoma has been found incidentally on 2% to 36% of autopsies,
suggesting that it may not be a clinically relevant finding in a number of individ-
uals.17–20Furthermore, there has been no established survival benefit to identi-
fying, or in some cases treating, papillary thyroid microcarcinoma.5,20,21Given
that papillary thyroid microcarcinoma has a generally benign course, identification
of these lesions may result in a patient being subject to potentially unnecessary
surgery. Despite all of these factors, some subcentimeter nodules may indeed
warrant further diagnostic evaluation. Indications for the detailed work-up of sub-
centimeter nodules are discussed later.
Another driving force behind the consensus guidelines stems from the inaccuracy of
fine-needle aspiration (FNA) biopsy among subcentimeter nodules. FNA is considered
to be the principal diagnostic tool in the evaluation of thyroid nodules. It has been
shown that specimen adequacy rates, sensitivity, and negative predictive value of
FNA are all reduced among nodules measuring 10 mm or less. These effects are
most pronounced when the nodule is smaller than 5 mm.22,23
THE THYROID INCIDENTALOMA
Similar to the subcentimeter nodules, thyroid incidentalomas may or may not be clin-
ically relevant depending on the circumstances of their identification. A thyroid inci-
dentaloma is defined as a nodule not previously suspected or clinically apparent,
but discovered on a radiographic study.5Incidentalomas have been described in
many clinical contexts. Not uncommonly, they are brought to light after carotid ultra-
sound. Steele and colleagues24found thyroid nodules in 9.4% of 168 patients under-
going carotid duplex sonography. Many were greater than 1 cm in size and nearly one
third harbored carcinomas (Fig. 1). It has been argued that any patient with an inciden-
taloma discovered on ultrasound should undergo dedicated thyroid and lateral neck
CT and MRI studies may also reveal occult nodular thyroid disease. Incidentalomas
have been observed in 10% to 17% of CTs and MRIs performed for nonthyroid indi-
cations (Fig. 2).25–27Although approximately 10% of the nodules ultimately prove to
be malignant, these modalities remain limited in their ability to differentiate benign
from cancerous nodules.25,26The presence of calcifications, anteroposterior to trans-
verse diameter ratio greater than 1, and attenuation greater than 130 Hounsfield units
on CT have been associated with an increased risk of carcinoma in one retrospective
review.25No definitive criteria have been established, however, and it is recommen-
ded that CT incidentalomas be followed-up by formal thyroid ultrasound and possibly
As positron emission tomography scanning has become more popular in recent
years, it has also become a more frequent means of detecting thyroid incidentalomas
(Fig. 3). Although large studies have found that only 1% to 2% of patients demonstrate
18F-fluorodeoxyglucose uptake in the thyroid,28–30the malignancy rates are high.
Fig. 1. Transverse ultrasound image of the right thyroid lobe in a patient who was inciden-
tally discovered to have a 2-cm thyroid nodule (asterisk) during carotid duplex scanning.
Visible are the trachea (Tr), internal jugular vein (IJV), and common carotid artery (CA).
The Patient with a Thyroid Nodule
Twenty-six percent to 67% of thyroid glands with focal18F-fluorodeoxyglucose avidity
are ultimately found to contain carcinoma. This does not hold true for glands with
diffuse18F-fluorodeoxyglucose uptake.29–31Consequently, it has been recommended
that any patient with evidence of a focal increase in18F-fluorodeoxyglucose uptake
undergo further evaluation.1,5
Ultrasound and FNA biopsy each play a prominent role in the evaluation of clinically or
incidentally discovered thyroid nodules. Indeed, ultrasound and FNA are critical points
in any management algorithm. Other historical, physical examination, imaging, and
laboratory findings, however, also interplay with these studies. Ultimately, each of
these elements assist in the further stratification of patients with nodules into lower-
and higher-risk groups for thyroid carcinoma and should guide the decision between
continued medical management and surgical referral.
IMPORTANT HISTORICAL ELEMENTS
Several components of a patient’s medical, family, and social history may be germane
to the evaluation of their thyroid nodule. The most important of these seems to be
exposure to ionizing radiation. Patients exposed to radiation, particularly in childhood,
are among the highest-risk groups for the development of thyroid carcinoma.5,32–35
The latency period between exposure and development of carcinoma may be
Fig. 2. Axial CT scan demonstrating an incidentally discovered nodule in the right thyroid
lobe (arrow). Ultrasound-guided FNA biopsy revealed evidence of a follicular neoplasm.
Fig. 3.18F-fluorodeoxyglucose positron emission tomography/CT fusion image of a patient
who was being treated for a head and neck squamous cell carcinoma. This incidentally
discovered left-sided nodule (arrow) was found on FNA to contain papillary thyroid
decades long, reaching its peak between 25 and 30 years after exposure.35A history
of childhood malignancy, particularly Hodgkin’s and non-Hodgkin’s lymphoma, also
increases the relative risk of thyroid carcinoma by a factor of approximately 3.5 times
in a manner that seems to be independent of radiation therapy.33
Another historical risk factor to explore is a patient’s family history. A single parent
with a history of papillary thyroid carcinoma increases a patient’s risk by a factor of
three to five times.36,37The risk exceeds six times when the index patient has a sibling
with papillary cancer.36In the context of medullary carcinoma, the increase in familial
risk is staggering, with standardized incidence ratios in excess of 4000 for children of
affected parents.37Other familial disorders, such as Cowden syndrome, Carney
complex, familial polyposis, and the multiple endocrine neoplasia type 2 syndromes,
are associated with increased risk for thyroid cancer and should prompt detailed eval-
uation in affected individuals who present with nodules.1Age at presentation also
seems to have an effect; patients less than 45 years old are significantly more likely
to have malignancy in the presence of a thyroid nodule.38
When observed in the presence of a nodule, hoarseness may also be an indicator of
malignancy. Randolph and Kamani39found that this complaint, although not highly
sensitive, was very specific in the preoperative identification of patients with invasive
thyroid carcinoma. When coupled with laryngoscopy and confirmation of vocal fold
paresis, the sensitivity and specificity were 75% and 100%, respectively. Raza and
colleagues38found a similar relationship between vocal fold immobility and the pres-
ence of carcinoma. These studies help underscore the importance of vocal fold eval-
uation in the context of thyroid disease, particularly among those patients scheduled
to undergo thyroidectomy.
All patients with known or suspected thyroid nodules should undergo testing for thyro-
tropin levels, also known as ‘‘thyroid-stimulating hormone’’ (TSH). The risk of malig-
nancy in a thyroid nodule has been shown to be significantly greater in patients with
elevated TSH.40–42Patients with a nodule and concomitant hypothyroidism have an
adjusted odds ratio of malignancy in excess of 11.41Moreover, the risk of carcinoma
seems to increase incrementally within the range of normal TSH values.40,41Interest-
ingly, when compared with euthyroid and hypothyroid patients, individuals with low
serum TSH have a reduced risk of carcinoma that is highly statistically significant.42
As a result, a number of societies now recommend that serum TSH levels be drawn
at the time a nodule is identified.1,5,15,16The presence of an elevated or normal TSH
in the context of a nodule should prompt further testing to rule-out carcinoma. If the
TSH is low, however, scintigraphy is the most appropriate next step. In the context
of subclinical or overt hyperthyroidism, a ‘‘cold’’ nodule may still represent a thyroid
carcinoma and a biopsy should be obtained. Conversely, autonomously functioning
(ie, ‘‘hot’’) nodules on123I or pertechnetate scans are almost universally benign and
do not warrant additional testing.43,44
One additional study that merits mentioning is calcitonin. Calcitonin is a sensitive
and specific tumor marker used in the diagnosis, surveillance, and prognosis of
medullary thyroid carcinoma (MTCA).45In the context of a family history of medullary
carcinoma or multiple endocrine neoplasia syndromes, the presence of a nodule
should alert the examiner to the possibility of MTCA. If not already performed, genetic
testing for RET proto-oncogene and serum calcitonin levels should be obtained in this
scenario.45Patients with the familial type represent a minority of MTCA patients and
are likely to be identified on the basis of their family history and stigmata of the
The Patient with a Thyroid Nodule
associated syndromes. Sporadic cases of MTCA are more common, but may be less
clinically apparent. These patients are generally not distinguishable from any other
individual presenting with a thyroid nodule and are managed in the usual fashion.
Unfortunately, FNAmay be less reliablein the contextof MTCA:there isaconsiderable
amount of overlap of cytologic features with other tumors46and the sensitivity for
detecting MTCA is low in some series.47In response to these issues, Hahm and
colleagues47explored the role that calcitonin might play in ruling out MTCA. Their
work demonstrated that only 1% of normal controls had serum calcitonin levels above
10 pg/mL. Likewise, they found that none of the MTCA patients had levels below 10
pg/mL and that each of them had levels in excess of 100 pg/mL after pentagastrin
stimulation. This was true for both sporadic and familial MTCA.47These and similar
results have led many to suggest that calcitonin screening is an essential and cost-
effective component of the diagnostic algorithm for thyroid nodules.47,48This recom-
mendation has yet to gain widespread acceptance.
Once a patient with a known or suspected nodule has had a complete history, physical
examination, and serum TSH level completed, the next step in their evaluation should
include sonographic evaluation of the thyroid and lateral neck compartments.1,5,15,16
Ultrasound is the most sensitive and specific radiographic detection method for
thyroid nodules. It allows for the confirmation and further characterization of both
palpable nodules and incidentalomas. It has been the most widely studied imaging
modality in the context of nodular thyroid disease. The literature has provided count-
less examples of sonographic features associated with an increased risk for malig-
nancy. Among the most robustly predictive parameters are microcalcifications, size
greater than 4 cm, hypoechogenicity, solid nodules, intranodular vascularization,
irregular or microlobulated borders, length/width ratio greater than one, and the pres-
ence of solitary versus multiple nodules.49–54One additional feature worth noting is the
presence of nodal disease within the lateral compartments of the neck. The presence
of lymph nodes greater than 1 cm may be indicative of carcinoma and may portend
a worse prognosis in patients with microcarcinoma.5,21
Although no single sonographic finding is diagnostic, combinations of these are
known to be of high sensitivity and specificity for carcinoma53and are indications
for FNA biopsy. Likewise, in the proper clinical context, the presence of any one of
these characteristics may raise suspicion for thyroid cancer and prompt the clinician
to obtain a biopsy.
FNA is the most cost-effective and accurate means of evaluating thyroid nodules.1It is
generally recommended that FNA be performed for essentially any nodule greater
than or equal to 1 cm.1,5,15,16The Society of Radiologists in Ultrasound have some-
what more stringent criteria, recommending FNA for 1-cm nodules only if microcalci-
fications are present.55Subcentimeter nodules may also be considered for biopsy if
the patient has high-risk characteristics in their medical or family history (as noted
previously); suspicious sonographic features; enlarged lymph nodes in the lateral
compartment (again pointing to the importance of evaluating the entire neck during
sonography for thyroid nodules); or vocal fold paralysis.1,5,16,21,22Nodules smaller
than 5 mm should generally not be considered for biopsy, however, because of the
low sensitivity and accuracy of diagnosis for these lesions.1,22,23
In the context of a palpable nodule, FNA may be performed with or without
ultrasound guidance. The ultrasound-guided technique has been advocated as
a means to improve needle placement and diagnostic yield during FNA, even
among palpable disease. Ultrasound-guided FNA has been shown to reduce the
number of false-negative biopsies performed5,56for solitary nodules and, in the
context of multinodular goiter, it allows for more accurate sampling of a dominant
or suspicious nodule.57Ultrasound guidance is considered the procedure of
choice for all nonpalpable, cystic, and posteriorly placed nodules1and, in the
author’s opinion, any palpable nodule. Regardless of whether ultrasound is
used, on-site evaluation by a cytopathology professional is desirable. Although
the diagnosis may not always be rendered, the specimen can be examined for
adequacy. This step is vital to reducing the number of nondiagnostic results
and repeated aspirations.58
FOLLOW-UP AND SURGICAL REFERRAL
The decision to refer for surgical evaluation depends to a great extent on the interpre-
tation of the FNA. Reporting of FNA cytology varies between institutions and depends
on the training and classification system used by the cytopathologist. Although the
nomenclature may differ slightly, cytopathologists generally render their diagnoses
within one of the following broad categories: nondiagnostic or inadequate, benign,
cellular follicular lesion, follicular neoplasm, suspicious for malignancy, or malignant.59
Inadequate samples should prompt rebiobsy (with ultrasound guidance if not used
initially). Multiple nondiagnostic FNAs may be observed or referred to surgery.1Biop-
sies found to be benign on FNA have a very small probability of harboring carcinoma.
Between 1% and 11% of lesions called benign on FNA ultimately prove to be malig-
nancies.16,60,61These nodules may be followed with serial ultrasound examinations
every 6 to 18 months.1If clinical or sonographic features change, it may be reasonable
to perform a repeat biopsy. If a second or third FNA results in a benign diagnosis,
however, the likelihood of malignancy is minimal and either medical therapy or expec-
tant management is appropriate.60,62,63Benign solid nodules have been treated
successfully using levothyroxine suppression, ethanol sclerosis, or percutaneous
laser ablation.63–65Recurrent cysts may either be removed surgically or treated with
Cellular follicular lesions carry an approximately 5% to 20% risk of malignancy.16,59
The decision to refer to surgery in this group relies heavily on clinical suspicion for
carcinoma. High-risk factors for cancer include age greater than 60 years, male
gender, size greater than 4 cm, rapid growth, rock-hard texture of the nodule, vocal
cord paralysis, previous exposure to radiation, family history of thyroid cancer, and
growth during adequate thyroxine suppression.59The presence of any of these factors
in the presence of a cellular follicular lesion is an indication for surgery.1,15Alterna-
tively, if these risk factors are not present, a repeat ultrasound with or without rebiopsy
may be performed in 6 to 18 months.
Follicular neoplasia is a more worrisome finding. Approximately 25% to 30% of
follicular neoplasms are malignant on permanent histopathologic sectioning.16,66,67
The rate approaches 45% in the presence of cytologic atypia.68Patients with these
lesions should be referred for surgery. Likewise, the ‘‘suspicious for malignancy’’ cate-
gory carries with it a 50% to 75% risk ofcancer. These patients also should be referred
to the surgeon. FNA diagnostic of malignancy should also be referred for surgical
thyroidectomy. Repeat biopsy is not generally used because the false-positive rate
is less than 2% in most series (Fig. 4).61
The Patient with a Thyroid Nodule
The specifics of surgical management are often the subject of controversy and are
beyond the scope of this article. In general, patients with suspicious lesions should
undergo at least thyroid lobectomy and isthmusectomy, with completion thyroidec-
tomy reserved for histopathologic confirmation of malignancy on frozen or permanent
section. Patients with confirmed malignant disease by FNA should undergo total
thyroidectomy with nodal dissection of the at-risk or involved neck compartments.1,15
Recently, a number of new technologies have been introduced into the arena of
thyroid surgery. Advances in endoscopic, minimally invasive, and robotic techniques
have allowed thyroidectomy to be performed through smaller and more cosmetically
appealing incisions.69–71These approaches have been touted as being less invasive
and less prone to complications. The only variables that have definitive benefits
with respect to complication rates of thyroid surgery, however, are the experience
and volume of individual surgeons and hospitals.72This underscores the importance
of referral to centers and surgeons that frequently perform thyroidectomy.
Regardless of technique, the most worrisome complications of thyroidectomy
maybereduced bytheuseofintraoperative nervemonitoring.73Permanent hypopara-
patients undergoing total thyroidectomy.74Close monitoring and, when necessary,
replacement of serum calcium in the postoperative period are essential.
When one considers the fact that a significant number of patients with ‘‘suspicious’’
cytology and an even larger proportion of those with ‘‘follicular’’ lesions undergo
Fig. 4. A basic algorithm for the management of palpable or incidentally discovered thyroid
nodules. Please refer to the text for more detailed recommendations regarding manage-
ment and follow-up. FNA, fine-needle aspiration; NL, normal; TSH, thyroid-stimulating
thyroidectomy for benign disease, it is apparent that FNA may not be a specific
enough test in some contexts. To combat this, much attention has been paid to
molecular characterization of FNA biopsy specimens. Several genetic mutations
have been identified that are specific to papillary or follicular carcinoma. These muta-
tions (BRAF, RET/PTC, RAS, and PAX8/PPARg) have been identified in preoperative
FNA specimens by Nikiforov and colleagues.75In their series of 470 FNA samples,
97% of mutation-positive nodules were found to be malignant on permanent histo-
logic sectioning. The authors concluded that testing for these mutations improved
the accuracy of FNA when used in a complementary fashion. Other studies have
used galectin-3,76BRAF,77and transcriptional profiles (ie, microarrays)78as adjuncts
to FNA. Unfortunately, these tests are not widely available and are not sufficiently
sensitive or specific for the diagnosis of carcinoma. They remain investigational at
this point, but may in time become standard adjuncts to or even replacements for
Thyroid nodules are common occurrences. Although they are often palpable, many
are discovered incidentally during unrelated radiographic studies. All patients with
nodular thyroid disease should undergo serum TSH testing and, if euthyroid or hypo-
thyroid, dedicated thyroid and lateral neck ultrasound. FNA biopsy should be per-
formed on all nodules greater than 1 cm, all positron emission tomography
incidentalomas, and all nodules 5 mm or larger in patients with high-risk clinical or
sonographic features. Suspicious or frankly malignant cytology on FNA biopsy should
prompt referral to a surgeon with expertise in thyroidectomy.
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