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Clinical Practice
CarenG. Solomon, M.D., M.P.H., Editor

Thyroid Nodules
KennethD. Burman, M.D., and Leonard Wartofsky, M.D.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal
guidelines, when they exist. The article ends with the authors clinical recommendations.

A 40-year-old woman presents with a thyroid nodule, 2.0 cm by 2.0 cm on palpation.

The nodule, located on the right side of the gland, was found on routine physical
examination. She has no history of childhood radiation exposure or family history of
thyroid abnormalities. She reports no symptoms of nervousness, weight loss, palpitation, fatigue, or neck discomfort. Ultrasonography confirms a thyroid nodule, 2.0 cm
by 2.0 cm by 2.5 cm (volume, 5.23 cm3), on the right side of the gland that does not
have ultrasonographic characteristics associated with an increased risk of cancer;
there is no cervical adenopathy. How should her case be managed?

The Cl inic a l Probl em

alpable thyroid nodules occur in approximately 4 to 7% of the

population, but only about 8 to 16% of thyroid nodules harbor thyroid cancer.1-6 Ultrasonography of the thyroid is more sensitive than palpation and
detects thyroid nodules in 19 to 67% of the population among persons without
suspected thyroid disease7; in one study, ultrasonography revealed nodules in 67 of
100 asymptomatic persons (22 of those screened had a solitary nodule and 45 had
multiple nodules).8
The differential diagnosis of an apparent thyroid nodule includes thyroidal and
nonthyroidal conditions. Subacute thyroiditis and chronic lymphocytic thyroiditis
may result in a nodular appearance; in rare cases, infiltrative disorders (e.g., hemochromatosis) or a metastatic tumor, parathyroid cyst, lipoma, or paraganglioma
can mimic a thyroid nodule.9 Risk factors for thyroid cancer10-14 are reviewed in
Table1; the frequency of nodules increases with age.1 The natural history of thyroid nodules is variable, but the majority of benign nodules remain relatively stable
in size.15 In a prospective, multicenter, observational study involving 992 patients
who had a thyroid nodule with benign cytologic findings on fine-needle aspiration
and who were followed for 5 years, 15% of patients had an increase in nodule size
(mean change in the largest diameter, 4.9 mm), and 19% had a decrease.15 Thyroid
cancer was identified in five (0.3%) of the original nodules, of which only two had
increased in size.

From the Endocrine Section, MedStar

Washington Hospital Center, and the
Department of Medicine, Georgetown

University School of Medicine both in

Washington, DC. Address reprint requests
to Dr. Burman at the Endocrine Section,
MedStar Washington Hospital Center,
Rm. 2A72, 110 Irving St., NW, Washington, DC 20010, or at kenneth.d.burman@
medstar.net.
N Engl J Med 2015;373:2347-56.
DOI: 10.1056/NEJMcp1415786
Copyright 2015 Massachusetts Medical Society.

An audio version
of this article is
available at
NEJM.org

S t r ategie s a nd E v idence
Pertinent History and Physical Examination

Figure1 provides an algorithm to address thyroid nodules. An appropriate history

includes questions relating to a history of head or neck irradiation and a family
history of thyroid cancer. Rapid growth of a thyroid nodule may suggest the presn engl j med 373;24nejm.org December 10, 2015

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Key Clinical Points

Thyroid Nodules
Thyroid nodules are common; the majority are benign.
Thyroid ultrasonographic characteristics and especially the results of ultrasonographically guided fineneedle aspiration are helpful in determining whether a nodule is likely to be benign or malignant.
The risk of cancer is approximately 14% for a thyroid nodule that is interpreted as atypia of
undetermined significance or follicular lesion of undetermined significance and approximately 25% for
a nodule that is interpreted as follicular neoplasm or possible follicular neoplasm. Such nodules should
be considered for molecular analysis.
In the absence of growth or suspicious clinical or radiologic findings, thyroid nodules with a benign
finding on fine-needle aspiration can be managed by observation.
Patients whose fine-needle aspirates are interpreted as suspicious for malignancy or as malignant
should be referred for a thyroidectomy.

ence of a thyroid cancer, although it may also

occur from hemorrhage into a benign thyroid
nodule or cyst.
Recent onset of hoarseness may be due to
tumor invasion of the recurrent laryngeal nerve.
Dysphagia or anterior neck discomfort may
suggest a malignant nodule, although these
symptoms may also occur with a benign nodule.
A family or personal history of thyroid cancer,
breast cancer, or colon cancer may suggest
Cowdens syndrome,16 as may a history of skin,
tongue, or mucosal small nodules (i.e., hamartomas) or of macrocephaly.16 In rare cases, a thyroid nodule may reflect one of the hereditary
nonmedullary thyroid cancer syndromes such as
familial adenomatous polyposis, Werners syndrome, Carney complex type 1, or Gardners
syndrome.17,18 A history of papillary thyroid cancer in at least one first-degree family member is
associated with an increased risk of a nodule
being malignant.19-21
Physical examination should focus on the
Table 1. Clinical Findings Associated with an Increased Risk That a Thyroid
Nodule Is Malignant.*
History of differentiated thyroid cancer in at least one first-degree relative
History of external-beam radiation or exposure to ionizing radiation as a child
or adolescent
Prior tissue or cytologic diagnosis of thyroid carcinoma
Male sex
Focal uptake of 18F-fluorodeoxyglucose by the thyroid
Personal or family history of multiple endocrine neoplasia type 2 or familial
medullary thyroid cancer
Serum calcitonin level >50 to 100 pg/ml
Residence near a nuclear-reactor accident
* Adapted with permission from the American Thyroid Association (ATA) guidelines.4

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thyroid gland and the lateral and central neck

and should assess for supraclavicular and submandibular adenopathy. Nodules that are firm
or immobile are more likely to harbor cancer
than those that are soft or mobile. Large, firm
cervical nodes ipsilateral to the thyroid nodule
should suggest the possibility of local metastases from thyroid cancer.
Laboratory Studies

Serum thyrotropin levels should be measured

routinely in a person with a thyroid nodule. A low
Figure 1 (facing page). Algorithm for Evaluation
of Thyroid Nodules.
This algorithm is devised mainly for thyroid nodules
1cm or larger in greatest dimension and is for general
application; decision making depends on clinical and
radiologic-imaging risk stratification. The 2015 American Thyroid Association guidelines13 recommend fineneedle aspiration (FNA) for nodules 1 cm or larger with
a high- or intermediate-suspicion pattern on sonography, nodules 1.5 cm or larger with a low-suspicion pattern on sonography, and nodules 2 cm or larger with
avery-low-suspicion pattern on sonography. Cervical
lymph nodes with suspicious features should be aspirated.13 In a multinodular gland, nodules 1 cm or larger
carry an independent risk of cancer, and the same recommendations apply regarding when to perform FNA.13 If
a gene-expression classifier suggests a benign lesion
in a patient with a low suspicion for cancer, the patient
can usually be monitored closely; if the findings of the
gene-expression classifier are suspicious, the risk of
cancer depends on many factors, including the pretest
probability of cancer. In this case, the decision for surgery or monitoring must take into account the entire
clinical context. In a patient who has a nodule that has
a high suspicion of being cancerous, if specific mutations (e.g., BRAF or RAS mutations) are present, a total
thyroidectomy is recommended; if no specific mutations
are noted, the decision for a thyroidectomy or monitoring depends on the entire clinical context.

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Clinical Pr actice

or undetectable level suggests a hyperfunctioning nodule. In a euthyroid patient, routine measurement of thyroid peroxidase or thyroglobulin
antibodies is not indicated.4 Serum thyroglobulin
measurement is not useful in evaluating a nodule.

Routine measurement of serum calcitonin has

been suggested for the early detection of medullary thyroid carcinoma but is not recommended
in the American Thyroid Association (ATA) guidelines.4,13,22-24

Thyroid nodules found clinically or incidentally on imaging

History taking, physical examination, measurement of thyrotropin level,

ultrasonography

Elevated or normal
thyrotropin

Low thyrotropin

Iodine-123 or technetium-99m
thyroid scanning

FNA in nodules 1 cm

Nonfunctioning nodule

Nondiagnostic

Repeat FNA with

ultrasonographic guidance

Hyperfunctioning nodule

Measure free thyroxine

and total triiodothyronine

If elevated, treat for

hyperthyroidism

Suspicious for malignancy

Thyroidectomy
Malignant

Benign

Repeat ultrasonography in 12 yr
If suspicious ultrasonographic characteristics
or relevant history or physical examination
findings, repeat ultrasonography in 612 mo
If >50% change in volume, 20% increase in
at least two nodule dimensions, or
appearance of new suspicious ultrasonographic characteristics, repeat FNA

If suspicion is low, use gene-expression classifier

Atypia of undetermined
significance or follicular lesion
of undetermined significance

Follicular neoplasm or
suspicious for a follicular
neoplasm

If suspicion is high, check for molecular

abnormalities (e.g., mutations or rearrangements)

Thyroidectomy or lobectomy is preferred

Offer alternative of molecular testing

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Figure 2. Ultrasonographic Images of Thyroid Nodules.

Panel A shows a papillary thyroid carcinoma with hypoechogenicity. The other panels show nodular features that
raise suspicion for cancer. Panel B shows a thyroid nodule with blurred or indistinct margins. Panel C shows a nodule
that is higher (2.5 cm) than it is wide (1.6 cm). Panel D shows a nodule with microcalcifications.

Imaging Studies

All patients should undergo ultrasonography of

the thyroid to document the number, size, and
characteristics of thyroid nodules and to assess
for the presence of cervical lymphadenopathy.4
Ultrasonographic nodular features that may suggest cancer25,26 are shown in Figure 2, and in
Figure S1 and Table S1 in the Supplementary
Appendix, available with the full text of this
article at NEJM.org. Additional imaging (e.g.,
magnetic resonance imaging or computed tomography) is not routinely indicated except when
features of aggressive thyroid cancer (e.g., ex2350

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tensive adenopathy or tracheal invasion) are

suggested. A radioisotopic (iodine-123 or technetium-99m) scan with measurement of radioisotope uptake to confirm autonomous function
is indicated only if the thyrotropin level is suppressed.
Fine-Needle Aspiration of the Thyroid

Fine-needle aspiration, preferably performed under ultrasonographic guidance, is the most sensitive and cost-effective method to assess the
nature of thyroid nodules and the need for surgery.27 The number of needle passes recom-

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Clinical Pr actice

mended is two to five.28 Immediate cytologic

evaluation is helpful to ensure adequate specimens. The 2015 ATA guidelines13 (Table S1 in
the Supplementary Appendix) recommend fineneedle aspiration for nodules 1 cm or larger
inthe greatest dimension that have a high- or
intermediate-suspicion pattern on sonography,
nodules 1.5 cm or larger that have a low-suspicion pattern on sonography, and nodules 2 cm
or larger that have a very-low-suspicion pattern
on sonography. Cervical lymph nodes with suspicious features should be aspirated.13 In a multinodular gland, nodules 1 cm or larger carry an
independent risk of cancer, and the same recommendations apply regarding when to perform
fine-needle aspiration.13
Fine-needle aspiration samples should be interpreted by an experienced cytologist according
to the Bethesda classification system29 (Fig.3
and Table2). If the cytologic findings are interpreted as nondiagnostic, fine-needle aspiration
should be repeated within 1 to 2 months in an
effort to obtain sufficient cells for a more definitive diagnosis. A benign cytologic interpretation indicates a low likelihood of cancer and
generally does not require repeat fine-needle
aspiration unless suspicious features (e.g., increasing nodular size or enlarging cervical adenopathy) are noted during monitoring.13,31 However,
false negative cytologic results occur in approximately 5 to 10% of cases overall, with higher
rates reported for large nodules (11.7% for nodules 3 cm vs. 4.8% for those <3 cm) (see the
Management section, below).30-32 Nodules with
cytologic findings that are interpreted as malignant or suspicious for malignancy have a 94 to
100% and 53 to 97% chance, respectively, of
being malignant (usually papillary thyroid cancer)13,30 (Table2). Indeterminate nodules present
a special problem in management.

sults interpreted as suspicious for malignancy

should, in general, be referred directly for thyroid lobectomy or total thyroidectomy. One molecular approach is to analyze the specimen by
means of a gene-expression classifier to rule out
cancer. In a report that assessed messenger RNA
expression of 167 genes from fine-needle aspiration samples from nodules 1 cm or larger in
diameter that were interpreted as indeterminate,
the negative predictive value of the gene-expression classifier was 95% for AUS/FLUS and 94%
for FN/SFN, and the positive predictive value was
38% for AUS/FLUS and 37% for FN/SFN.33 These
results suggest that, in general, patients with
AUS/FLUS or FN/SFN whose results are negative
on this molecular analysis can reasonably be
monitored without immediate thyroidectomy.
An alternative molecular approach is to directly assess the fine-needle aspirate for specific
genetic abnormalities associated with thyroid cancer (including BRAF and RAS mutations, RET/PTC
translocation and TERT promoter mutations for
papillary thyroid cancer, and RAS and PIK3A mutations and PAX8PPAR translocation for follicular thyroid cancer).12,34 When applied to nodules interpreted as AUS/FLUS or FN/SFN,
mutational analysis indicates cancer in approximately 20 to 40% of fine-needle aspiration
samples, with a positive predictive value of 87 to
88% and a negative predictive value of 86 to
94%.12,35 If the sample is positive for a BRAF mutation, the chance of cancer is close to 100%,36
and if thesample is positive for a RAS mutation,
the chance of cancer is 80 to 90%.12 A mutational analysis may be helpful in the case of
nodules classified as suspicious for malignancy to confirm the diagnosis and to aid in surgical planning (i.e., lobectomy vs. total thyroidectomy, with or without central lymph-node
dissection), although data are lacking to determine the effect of this additional information on
Molecular Analysis of Thyroid Fine-Needle
outcomes. Adding to the complexity of manageAspiration
ment, the interpretation of a thyroid fine-needle
Molecular analysis (in a laboratory that is ac- aspiration may be poorly reproducible between
credited by the College of American Pathologists cytologists,37 and the most effective use of moand certified according to the Clinical Labora- lecular testing remains uncertain.
tory Improvement Amendments) should be considered in the case of thyroid fine-needle aspira- Management
tion results that are interpreted as atypia of Although the cornerstone of the management
undetermined significance or follicular lesion of a thyroid nodule is the cytologic findings on
of undetermined significance (AUS/FLUS) or fol- fine-needle aspiration, these findings should
licular neoplasm or suspicious for a follicular be considered in the context of the clinical and
neoplasm (FN/SFN). Patients with cytologic re- ultrasonographic findings. When a sample is
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Figure 3. Thyroid Fine-Needle Aspiration Specimens.

The figure shows nodules in five different categories of the Bethesda System for Reporting Thyroid Cytopathology.29
Panel A shows a benign nodule. The thyroid follicular cells are evenly spaced and have a small and uniform nuclear
size. Panel B shows atypia of undetermined significance. In an otherwise benign aspirate, rare groups of follicular
cells show nuclear enlargement. The patient underwent a thyroidectomy, and final pathological analysis showed
benign nodular hyperplasia. Panel C shows a follicular neoplasm. Smears contain a cellular aspirate with only scant
colloid. The follicular cells are of normal size but form microfollicles (abnormal architecture). Final pathological
analysis showed follicular adenoma. Panel D shows a nodule suspicious for malignancy (papillary carcinoma).
Aspirate shows some features of papillary carcinoma, such as hypercellularity, nuclear enlargement, hyperchromasia, and an increased nuclear-to-cytoplasmic ratio. However, no definitive nuclear pseudoinclusions were identified.
Thyroidectomy was performed, and the final pathological analysis showed a follicular variant of papillary carcinoma.
Panel E shows a malignant nodule (papillary carcinoma). Smears show a cellular aspirate with numerous abnormal
follicular cells containing enlarged hyperchromatic nuclei. Nuclear pseudoinclusions are present (arrow).

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Clinical Pr actice

adequate and is evaluated by an experienced

cytologist who documents a benign finding on
fine-needle aspiration and there are no suspicious clinical or ultrasonographic findings, we
generally recommend repeat ultrasonography in
1 to 2 years (assuming that no apparent growth
or concerning clinical findings are noted earlier).
A recent study involving follow-up of more than
2000 cytologically benign nodules, however, suggested that a longer time interval of 2 to 4 years
may be reasonable.38 For cases with suspicious
sonographic features, an indeterminate fineneedle aspirate, or relevant adverse clinical history or physical examination findings, it is reasonable to perform repeat imaging earlier, in
6to 12 months. If there is evidence of nodule
growth (>50% change in volume or 20% increase in at least two nodule dimensions with an
increase of 2 mm), a repeat fine-needle aspiration is recommended.4 It is important to measure all three nodule dimensions, to calculate
the nodule volume, and to compare the results
with those of the previous and initial ultrasonograms.
When evaluation has failed to achieve a definitive characterization of the nodule as either
benign or malignant, management options include either continued close monitoring or a
thyroidectomy. There is no role for thyroid hormone treatment for a biochemically euthyroid
patient who has a benign nodule.
A total thyroidectomy is generally recommended in the following situations: the nodule
has a specific oncogene abnormality with a high
positive predictive value for cancer (e.g., BRAF
mutation); the fine-needle aspirate is interpreted
as malignant or suspicious for malignancy;
there is bilateral nodular disease with an indication for surgery in at least one nodule; there is a
history of radiation to the head or neck during
childhood or adolescence or a family history of
thyroid cancer; or the nodule is larger than 4 cm
in diameter. Total thyroidectomy should also be
considered in patients who do not meet any of
these criteria but who have clinically significant
cardiorespiratory disease or other coexisting
conditions, in order to avoid the possible need
for a second procedure (completion thyroidectomy). Total thyroidectomy is best performed by
an experienced thyroid surgeon in a comprehensive care medical center.39 When patients undergo
total thyroidectomy, they incur small risks of

Table 2. Diagnostic Categories of Thyroid Nodules and Risk of Cancer.*

Diagnostic Category

Percent Risk of Cancer

median (range)

Nondiagnostic or unsatisfactory

20 (932)

Benign

2.5 (110)

Atypia of undetermined significance or follicular

lesion of undetermined significance

14 (648)

Follicular neoplasm or suspicious for a follicular

neoplasm

25 (1434)

Suspicious for malignancy

70 (5397)

Malignant

99 (94100)

* Adapted with permission from the 2015 ATA guidelines.13

The categories are those of the Bethesda System for Reporting Thyroid Cyto
pathology.29
Values are based on the meta-analysis of eight studies reported by Bongio
vanni et al.30 The risk was calculated on the basis of the number of nodules
in each diagnostic category that were surgically excised, and the time between
thyroid fine-needle aspiration and surgery can vary among individual cases
and among studies. In our review of the published literature, the false negative rate of a nodule with a benign finding on fine-needle aspiration is about
5 to 10%.30-32 The false negative rate of a thyroid fine-needle aspiration depends on multiple factors, including the adequacy of the sample obtained,
the experience of the cytologist, and the size of the nodule.

permanent hypocalcemia (approximately 0.2 to

1.9%) and voice change owing to damage to the
recurrent laryngeal nerve (0.4%).39,40 Lifelong
exogenous levothyroxine therapy (with periodic
monitoring) is required in all patients who have
undergone a total thyroidectomy as well as in
many patients who have undergone thyroid lobectomy.41

A r e a s of Uncer ta in t y
Although the ATA guidelines recommend fineneedle aspiration only for nodules that are 1 to
2 cm or larger in the greatest dimension, further
evaluation of smaller nodules may be warranted
in the presence of suspicious ultrasonographic
or clinical findings,13 although it is not known
whether this approach results in improved
outcomes. Whether large thyroid nodules (e.g.,
>4 cm) should be considered for surgery even in
the context of a benign finding on fine-needle
aspiration is controversial. In one report,42 the
risk of cancer (mainly papillary thyroid cancer)
did not increase consistently with increasing nodule size, although among malignant nodules, the
proportion with follicular cancer increased with
nodule size. However, a study of a series of patients with nodules 4 cm or larger who were

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undergoing fine-needle aspiration and surgery

suggested that larger nodules were associated
with an increased risk of cancer, even in the absence of suspicious ultrasonographic features.43
For nodules that are cytologically indeterminate on biopsy, questions remain regarding
whether to perform molecular analysis and
which molecular test to use in various circumstances. The use of next-generation sequencing or whole-genome sequencing, including the
use of microRNA, has been proposed as a
means of better distinguishing between benign
and malignant nodules,44,45 but more data are
needed to inform the role of these methods in
practice.
For thyroid nodules with benign findings on
fine-needle aspiration, there is uncertainty regarding the appropriate frequency of follow-up
ultrasonography; whether repeat fine-needle
aspiration is indicated is also controversial, though
this has been suggested for nodules with clinically or sonographically suspicious features.46-48
Concern has been raised about the overdiagnosis and overtreatment of thyroid nodules and
thyroid cancer and about the clinical significance of incidentally discovered papillary microcarcinoma, which may have a biologically indolent behavior.49 A case series showing favorable
outcomes without surgical intervention among
patients with small nodules without worrisome
features, but suggestive or diagnostic of papillary cancer on fine-needle aspiration, suggests
that this approach may suffice in lieu of more
aggressive management, although confirmatory
data are needed.49,50

Guidel ine s
The ATA has published guidelines for the evaluation and management of thyroid nodules, and
these guidelines were updated recently.13 The
guidelines suggest that molecular testing may be
useful after consideration of clinical and radiologic findings and after a discussion with the
patient regarding the advantages and disadvantages of such an approach.13 The recommendations in the current article are generally concordant with the ATA guidelines and with a separate
set of guidelines from the American Association
of Clinical EndocrinologistsAssociazione Medici
EndocrinologiEuropean Thyroid Association.24
The latter guidelines differ from the ATA guide2354

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lines13 in recommendations for repeat fine-needle

aspiration; largely on the basis of expert opinion,
these guidelines suggest that repeat fine-needle
aspiration may be performed in 6 to 18 months
in selected patients who have an initial benign
finding on fine-needle aspiration. These guidelines also suggest that on initial evaluation,
nodules considered to be suspicious on historical or sonographic grounds should be considered for aspiration if they are less than 10 mm
in diameter.24

C onclusions a nd
R ec om mendat ions
The discovery of a thyroid nodule, as in the
woman described in the vignette, should prompt
a careful history taking and physical examination, measurement of thyrotropin levels, and an
ultrasonographic examination. Nodule size, clinical context, and ultrasonographic characteristics
guide the decision to perform fine-needle aspiration. Fine-needle aspiration is indicated in the
patient described in the vignette on the basis of
the nodule size (2 cm in greatest dimension),
even in the absence of suspicious characteristics;
when suspicious ultrasonographic characteristics
are present, fine-needle aspiration is recommended for nodules 1 cm or larger. The fine-needle
aspirate should be interpreted by an experienced
cytopathologist according to the Bethesda classification system.29 If the aspirate shows benign
cytologic features, we would generally recommend repeating thyroid ultrasonography in approximately 1 to 2 years to ensure that there has
been no clinically significant growth. In the absence of growth or suspicious clinical or sonographic findings, we would generally not repeat
the thyroid fine-needle aspiration.
If the cytologic findings are indeterminate, a
second review by an experienced cytologist may
be useful; options for management include a
repeat fine-needle aspiration in 6 to 12 months
or mutational analysis or molecular profiling to
better estimate the risk of cancer. In selected
circumstances, surgery may be indicated. Although long-term outcome trials are required to
better inform the use of these ancillary tests, we
would tend to use a gene-expression classifier
(which has a high negative predictive value and
high sensitivity) if there is low suspicion for cancer and to consider mutational analysis (which

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Clinical Pr actice

has a high positive predictive value and high depending on the estimated risk of cancer, the
specificity) if the clinical or radiologic features experience and skill of the surgeon, and the
raise suspicion for cancer and the likelihood of patients preference.
referral for thyroidectomy is higher. AlternaDr. Burman reports receiving honoraria from Medscape and
tively, the patient could proceed to diagnostic grant support from Pfizer, Eisai, Amgen, and AstraZeneca; and
surgery, if she is uncomfortable with the uncer- Dr. Wartofsky, receiving fees for serving on advisory boards
tainty associated with watchful waiting and de- from Asuragen, IBSA/Akrimax Pharmaceuticals, and Eisai and
lecture fees from Genzyme/Sanofi. No other potential conflict
pending on her personal preferences. If further of interest relevant to this article was reported.
testing is performed but is inconclusive, diagDisclosure forms provided by the authors are available with
nostic lobectomy is often reasonable; however, the full text of this article at NEJM.org.
We thank Dr. Athanasios Bikas for advice and editorial asnodules with more suspicious findings on cyto- sistance, Dr. Wen Lee for providing the cytologic images, and
logic analysis may justify total thyroidectomy, Dr. Alan Ost for providing the ultrasonographic images.
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