FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 559
jects 19 to 50 years of age had an incidental
nodule on ultrasonography. In addition, more
than one half of the thyroid glands studied
contained one or more nodules, with only
about one in 10 being palpable.
6
Approxi-
mately 23 percent of solitary nodules are actu-
ally dominant nodules within a multinodular
goiter.
7
Thyroid carcinoma occurs in roughly
5 to 10 percent of palpable nodules.
1
Of the
estimated 1,268,000 cancers that were
expected to be newly diagnosed in 2001 in the
United States, 19,500 were expected to be of
thyroid origin with 1,300 deaths attributable
to thyroid cancer.
8
Thyroid nodules are four times more com-
mon in women than in men
9
and occur more
often in people who live in geographic areas
with iodine deficiency.
5
After exposure to ion-
izing radiation, thyroid nodules develop at a
rate of 2 percent annually.
9
Presentation
The majority of thyroid nodules are asymp-
tomatic. Most persons with thyroid nodules
are euthyroid, with less than 1 percent of nod-
ules causing hyperthyroidism or thyrotoxico-
sis. Patients may complain of neck pressure or
pain if spontaneous hemorrhage into the
nodule has occurred. Questions about symp-
A
thyroid nodule is a palpable
swelling in a thyroid gland with
an otherwise normal appear-
ance. Thyroid nodules are com-
mon and may be caused by a
variety of thyroid disorders. While most are
benign, about 5 percent of all palpable nodules
are malignant.
1-4
Many tests and procedures
are available for evaluating thyroid nodules,
and appropriate selection of tests is important
for accurate diagnosis. Family physicians
should have a cost-effective method of differ-
entiating between nodules that are malignant
and those that will have a benign course. This
article provides a method for the outpatient
evaluation and treatment of thyroid nodules.
Epidemiology
Palpable thyroid nodules occur in 4 to 7
percent of the population (10 to 18 million
persons), but nodules found incidentally on
ultrasonography suggest a prevalence of 19 to
67 percent.
1,5
In one study,
6
30 percent of sub-
Palpable thyroid nodules occur in 4 to 7 percent of the population, but nodules found
incidentally on ultrasonography suggest a prevalence of 19 to 67 percent. The major-
ity of thyroid nodules are asymptomatic. Because about 5 percent of all palpable nod-
ules are found to be malignant, the main objective of evaluating thyroid nodules is to
exclude malignancy. Laboratory evaluation, including a thyroid-stimulating hormone
test, can help differentiate a thyrotoxic nodule from an euthyroid nodule. In euthyroid
patients with a nodule, fine-needle aspiration should be performed, and radionuclide
scanning should be reserved for patients with indeterminate cytology or thyrotoxico-
sis. Insufficient specimens from fine-needle aspiration decrease when ultrasound
guidance is used. Surgery is the primary treatment for malignant lesions, and the
extent of surgery depends on the extent and type of disease. Ablation by postopera-
tive radioactive iodine is done for high-risk patients—identified as those with metasta-
tic or residual disease. While suppressive therapy with thyroxine is frequently used
postoperatively for malignant lesions, its use for management of benign solitary thy-
roid nodules remains controversial. (Am Fam Physician 2003;67:559-66,573-4. Copy-
right© 2003 American Academy of Family Physicians.)
While most are benign, about 5 percent of all palpable thy-
roid nodules are malignant.
Thyroid Nodules
MARY JO WELKER, M.D., and DIANE ORLOV, M.S., C.N.P.
Ohio State University College of Medicine and Public Health, Columbus, Ohio
PRACTICAL THERAPEUTICS
O A patient informa-
tion handout on thy-
roid nodules, written
by the authors of this
article, is provided on
page 573.
Members of various
family practice depart-
ments develop articles
for “Practical Therapeu-
tics.” This article is one
in a series coordinated
by the Department of
Family Medicine at
Ohio State University
College of Medicine
and Public Health,
Columbus. Guest edi-
tor of the series is
Doug Knutson, M.D.
toms of hypothyroidism or hyperthyroidism
are essential, as are questions about any nod-
ule, goiter, family history of autoimmune thy-
roid disease (e.g., Hashimoto’s thyroiditis,
Graves’ disease), thyroid carcinoma, or famil-
ial polyposis (Gardner’s syndrome).
The various types of thyroid nodules are
listed in Ta b le 1. Colloid nodules are the most
common and do not have an increased risk of
malignancy. Most follicular adenomas are
benign; however, some may share features of
follicular carcinoma. About 5 percent of
microfollicular adenomas prove to be follicu-
lar cancers with careful study.
1
Thyroiditis also
may present as a nodule (Figure 1). Thyroid
carcinoma usually presents as a solitary palpa-
ble thyroid nodule. The most common type of
malignant thyroid nodule is papillary carci-
noma (Figure 2).
Several “red flags” that may indicate possi-
ble thyroid cancer are listed in Ta b le 2.
7,9
Physical Examination
Nodules are often discovered by the patient
as a visible lump, or they are discovered inci-
dentally during a physical examination. Thy-
roid nodules may be smooth or nodular, dif-
fuse or localized, soft or hard, mobile or fixed,
and painful or nontender. While palpation is
the clinically relevant method of examining
the thyroid gland, it can be insensitive and
inaccurate depending on the skill of the
examiner.
6,9
Nodules that are less than 1 cm in
diameter are not usually palpable unless they
are located in the anterior portion of the thy-
roid lobe. Larger lesions are easier to palpate,
except for those that lie deep within the
gland. Regardless, about one half of all nod-
ules detected by ultrasonography escape
detection on clinical examination.
9
In addi-
tion to palpation of the thyroid gland, a thor-
ough examination of the lymph glands in the
560
AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 3 / FEBRUARY 1, 2003
TABLE 1
Types of Thyroid Nodules
Adenoma
Macrofollicular adenoma (simple
colloid)
Microfollicular adenoma (fetal)
Embryonal adenoma (trabecular)
Hürthle cell adenoma (oxyphilic,
oncocytic)
Atypical adenoma
Adenoma with papillae
Signet-ring adenoma
Used with permission from Ernest Mazzaferri, M.D.
Carcinoma
Papillary (75 percent)
Follicular (10 percent)
Medullary (5 to 10 percent)
Anaplastic (5 percent)
Other
Thyroid lymphoma (5 percent)
Cyst
Simple cyst
Cystic/solid tumors
(hemorrhagic, necrotic)
Colloid nodule
Dominant nodule in a
multinodular goiter
Other
Inflammatory thyroid disorders
Subacute thyroiditis
Chronic lymphocytic thyroiditis
Granulomatous disease
Developmental abnormalities
Dermoid
Rare unilateral lobe agenesis
The Authors
MARY JO WELKER, M.D., is professor of clinical family medicine and chair of the
Department of Family Medicine at Ohio State University College of Medicine and Pub-
lic Health, Columbus. She received her medical degree from Ohio State University Col-
lege of Medicine and served a family practice residency at Riverside Methodist Hospi-
tal in Columbus, Ohio.
DIANE ORLOV, M.S., C.N.P., is a certified nurse practitioner in the Department of Fam-
ily Medicine at Ohio State University College of Medicine and Public Health and auxil-
iary faculty at Ohio State University College of Nursing. She earned a nursing degree
at Ohio State University College of Nursing, where she also earned a Master of Science
degree and completed the Nurse Practitioner Masters Degree Program.
Address correspondence to Mary Jo Welker, M.D., 2231 N. High St., Columbus, OH
43201. Reprints are not available from the authors.
head and neck should be performed. Indica-
tors of thyroid malignancy include the fol-
lowing: a hard, fixed lesion; lymphade-
nopathy in the cervical region; nodule greater
than 4 cm; or hoarseness.
Diagnosis
In 1996, the Thyroid Nodule Task Force of
the American Association of Clinical Endocri-
nologists and the American College of
Endocrinology created a practice guideline for
patients with thyroid nodules.
10
It was devel-
oped to formulate a clear, concise approach to
the evaluation of thyroid nodules and “to
increase the understanding of the diagnosis and
treatment of thyroid nodules for physicians and
patients.”
10
Figure 3
11
is a diagnostic algorithm
for the evaluation of a thyroid nodule.
LABORATORY EVALUATION
A sensitive thyroid-stimulating hormone
(TSH) test should be drawn on patients to
determine those with thyrotoxicosis or hypo-
thyroidism (Figure 4). When the TSH level is
normal, aspiration should be considered.
When this level is low, a diagnosis of hyper-
thyroidism should be considered; when the
value is elevated, hypothyroidism is a possibil-
ity. Serum calcitonin should be measured in
anyone with a family history of medullary
thyroid carcinoma. Thyroid function tests
should not be used to distinguish whether a
thyroid nodule is benign or malignant. T
4
,
antithyroid peroxidase antibodies, and thy-
roglobulin tests are not helpful in determining
whether a thyroid nodule is benign or malig-
Thyroid Nodules
FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 561
About 50 percent of all thyroid nodules detected on ultra-
sonography escape detection on clinical examination.
TABLE 2
“Red Flags” for Thyroid Cancer
Male gender
Extremes in age (younger than 20 years and older
than 65 years)
Rapid growth of nodule
Symptoms of local invasion (dysphagia, neck pain,
hoarseness)
History of radiation to the head or neck
Family history of thyroid cancer or polyposis
(Gardner’s syndrome)
Information from Walsh RM, Watkinson JC, Franklyn
J. The management of the solitary thyroid nodule: a
review. Clin Otolaryngol 1999;24:388-97, and Maz-
zaferri EL. Management of a solitary thyroid nodule.
N Engl J Med 1993;328:553-9.
FIGURE 1. Lymphocytic thyroiditis. Two clus-
ters of benign follicular cells are set in a back-
ground of lymphocytes. Diff-Quick stain.
FIGURE 2. Fine-needle aspirate of a thyroid
nodule showing microfragment of papillary
thyroid carcinoma. Papanicolaou stain.
nant, but they may be helpful in the diagnosis
of Graves’ disease or Hashimoto’s thyroiditis.
FINE-NEEDLE ASPIRATION
In euthyroid patients with a nodule, a fine-
needle aspiration (FNA) should be done first
(Figure 5). According to guidelines from the
American Association of Clinical Endocrinol-
ogists, it is “believed to be the most effective
method available for distinguishing between
benign and malignant thyroid nodules,”
10
with
an accuracy approaching 95 percent,
2
depend-
562
AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 3 / FEBRUARY 1, 2003
FIGURE 3. Algorithm for the evaluation of thyroid disorders.
TSH = thyroid-stimulating hormone; FNA = fine-needle aspiration.
Adapted with permission from Burch HB. Evaluation and management of the solid thyroid nodule. Endocrinol
Metab Clin North Am 1995;24:663-710.
Evaluation of Thyroid Disorders
Radioactive
iodine or
surgery
Insufficient Benign Suspicious Malignant
FNA Cold nodule Hot nodule
Scan
Euthyroid Thyrotoxic
TSH test
Solitary thyroid nodule
Observe
Total or partial thyroidectomy
Clinical suspicion
Regress Recurrence
Cystic Solid
Repeat
in six
months
Frozen section
Low High Thyroid lobectomy
Benign or
indeterminate
MalignantRepeat FNA
ing on the experience of the person perform-
ing the biopsy and the skill of the cytopatholo-
gist interpreting the slides. Analysis of the data
suggests a false-negative rate of 1 to 11 percent,
a false-positive rate of 1 to 8 percent, a sensi-
tivity of 68 to 98 percent, and a specificity of
72 to 100 percent.
2,10
Sampling errors occur in
very large (more than 4 cm) and very small
(less than 1 cm) nodules, and can be mini-
mized by using ultrasound-guided biopsy. The
results are interpreted as benign, malignant,
suspicious, or indeterminate.
About 69 to 74 percent of specimens are
found to be benign.
2
Indeterminate or suspi-
cious results occur in about 22 to 27 percent of
all specimens.
2
When specimens contain
insufficient material for diagnosis, a repeat
FNA should be performed. The incidence of
insufficient results can be improved with the
use of ultrasound-guided FNA. Finally, about
4 percent of specimens are positive for cancer
and most false-positive results usually indicate
Hashimoto’s thyroiditis.
2
RADIOLOGY
While ultrasonography is not yet the stan-
dard of care, recent studies
12-15
support this
practice once a nodule has been palpated to
document size, location, and character of the
nodule (Figure 6). Ultrasound-guided aspira-
tion of nodules larger than 1 cm or smaller
than 1 cm if solid and hypoechoic provides the
highest cost-effective yield for detecting thy-
roid malignancy.
12
While ultrasonography
cannot distinguish benign from malignant
nodules, it can be used to determine changes in
size of nodules over time, either in the follow-
up of a lesion thought to be benign or in
detecting recurrent lesions in patients with
thyroid cancer. The incidence of indeterminate
specimens from FNA decreases from 15 per-
cent to less than 4 percent when ultrasound
guidance is used in conjunction with FNA.
13
Frequently, thyroid nodules are found inciden-
tally during ultrasonography of the neck for
reasons not relating to the thyroid gland.
Nuclear imaging cannot reliably distinguish
between benign and malignant nodules and is
Thyroid Nodules
FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 563
In a euthyroid patient with a palpable thyroid nodule, fine-
needle aspiration should be the first test ordered.
FIGURE 4. Interpretation of thyroid function
tests.
TSH = thyroid-stimulating hormone; T
4
= thyroxine;
T
3
= triiodothyronine.
Interpretation of Laboratory Values
FIGURE 5. Algorithm for fine-needle aspira-
tion of a thyroid nodule.
Fine-Needle Aspiration of Thyroid Nodule
Hashimoto’s
thyroiditis
Check T
4
and T
3
toxic
multinodular goiter or
autonomous adenoma
50 percent
monitor
50 percent
surgery
Fine-needle aspiration
*—Plus calcitonin if family history of
medullary cancer.
High
Normal Low
TSH* test
Follow-up
Negative Suspicious Inadequate or
indeterminate
Surgery
Repeat biopsy
not required if nodules are present. FNA
biopsy has replaced nuclear imaging as the
initial evaluation procedure. However, in
patients with a suppressed TSH level, a thy-
roid scan determines regional uptake or func-
tion and can be used as a secondary study.
The thyroid scan measures the amount of
iodine trapped within the nodule. A normal
scan indicates that the iodine (usually tech-
netium 99m isotope) uptake is similar in both
lobes of the thyroid gland. A nodule is classi-
fied as “cold” (decreased uptake), “warm”
(uptake similar to that of surrounding tissue),
or “hot” (increased uptake).
4
While a large pro-
portion of thyroid nodules may be cold on
radionuclide scan, only 5 to 15 percent of these
are malignant.
3
Radioiodine scans also are use-
ful in nodules with indeterminate cytology
results, because a hyperfunctional nodule is
almost always benign and can be managed
medically with radioactive iodine or surgery.
Magnetic resonance imaging (MRI) has no
place in the assessment of patients with thy-
roid nodules.
10
Increasingly, however, thyroid
nodules are being found incidentally during
MRI of the neck for reasons not relating to the
thyroid gland. The same is true for computed
tomography.
Treatment
The main indications for surgical treatment
of thyroid nodules are malignancy or indeter-
minate cytology on FNA, and suspicious his-
tory and physical examination. If the diagnosis
of thyroid cancer is known preoperatively,
many experts recommend partial or total thy-
roidectomy. However, this remains controver-
sial, and debate about partial thyroidectomy
continues.
16
Ablation by postoperative radio-
active iodine (I-131) is done for high-risk
patients (i.e., those with metastatic disease,
nodal disease, or gross residual disease). Post-
operative thyroid replacement therapy is a
common practice, although the benefits of
administration remain controversial, especially
in low-risk patients.
9,16,17
Following complete
resection of thyroid cancer, the TSH concentra-
tion should be in the target range of 0.5 µU per
mL (0.5 mU per L). Greater suppression may
be necessary for high-risk patients and those
with a metastatic or locally invasive tumor that
was not completely removed surgically or
ablated by postoperative I-131 therapy.
9,16,17
Nodules with indeterminate findings should
be surgically removed,
10
especially those found
to be cold nodules on nuclear imaging. Hot
functioning nodules may not require surgery,
but if they are toxic nodules (suppression of
sensitive TSH or symptoms such as atrial fib-
rillation), they will require treatment. Radioac-
tive iodine may be the treatment of choice for
patients with hot nodules, although some
patients may choose surgery.
Most patients with benign biopsies can be
564
AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 3 / FEBRUARY 1, 2003
The main indications for surgery are malignancy or indeter-
minate cytology on fine-needle aspiration, and a suspicious
history and physical examination.
FIGURE 6. Thyroid ultrasonography may help to localize lesions and
improve adequacy of fine-needle aspirates.
followed without surgery and monitored
carefully; however, some patients choose
surgery after being fully informed of the risks.
Patients who prefer surveillance should be
monitored for changes in nodule size and
symptoms, and repeat ultrasonography or
FNA biopsy should be performed if the nod-
ule grows. Repeated recurrence of cystic
lesions is sufficient reason for surgical removal
of the cyst.
Most incidental nodules found on routine
testing with ultrasonography are benign and
can be monitored with no further testing and
follow-up observation. However, FNA biopsy
is indicated if the nodule becomes palpable,
has findings suggestive of malignancy on
ultrasonography, or is larger than 1.5 cm, or if
the patient has a history of head or neck irra-
diation (especially in childhood) or a strong
family history of thyroid cancer.
5
SUPPRESSION TREATMENT
Patients who benefit most from suppression
therapy postoperatively are those who
received radiation in childhood for benign
conditions such as acne or an enlarged thy-
mus. In this group, the recurrence rate of thy-
roid nodules after surgical removal is almost
five times lower when thyroxine is given post-
operatively than when it is not.
18
Use of TSH suppressive therapy with thyrox-
ine to manage benign, solitary thyroid nodules
remains controversial. The lack of universal
efficacy makes such therapy optional in most
patients. Some randomized, controlled stud-
ies
7,9
suggest that short-term thyroxine therapy
is not superior to placebo in patients with a
solitary hypofunctioning colloid nodule. The
efficacy of thyroxine is less certain for solitary
nodules than for a diffuse or multinodular goi-
ter. However, some patients may benefit, and
suppressive therapy is considered an appropri-
ate alternative as long as the patient is followed
carefully at six-month intervals.
11,17
When thyroxine therapy is selected to man-
age a benign thyroid nodule, the medication
should be prescribed in dosages sufficient to
suppress the TSH level to 0.1 to 0.5 µU per mL
(0.1 to 0.5 mU per L) for six to 12 months.
11
More prolonged therapy should be reserved
for patients in whom a decrease in nodule size
is documented by ultrasonography. After 12
months, the dosage of thyroxine should be
decreased to maintain the serum concentra-
tion of TSH in the low normal range. The
patient and physician must weigh the benefits
of long-term therapy and the potential risks.
While this option could be considered in
younger women, decreased bone density and
cardiac side effects, such as atrial fibrillation,
present a concern and potential risk in post-
menopausal women.
THYROID NODULES IN CHILDREN AND DURING
PREGNANCY
While the prevalence of thyroid nodules is
less common in children, the risk of malig-
nancy appears to be much higher (14 to 40
percent in children as opposed to 5 percent in
adults).
19
Recent reports suggest FNA biopsy
has an important role in the diagnosis and
management of thyroid nodules in chil-
dren.
10,19,20
However, studies involving chil-
dren have been limited, and false-negative
results have raised concerns about the accu-
racy of this test in children.
19
Thyroid nodules in pregnant women can be
managed in the same way as in nonpregnant
patients, except that radionuclide scanning is
contraindicated.
10
FNA biopsy can be per-
formed during pregnancy, and surgical
removal of thyroid nodules is relatively safe
during the second trimester, which is the safest
time for surgery during pregnancy. Surgery
also can be deferred until after the pregnancy.
The authors wish to acknowledge John E. Baumert
Jr., M.D., for his expertise in reviewing this article
and for the radiographs. The authors also wish to
acknowledge Dr. Paul Wakely, senior surgical
pathologist and FNA expert at Ohio State University,
for his contribution of the pathology slides.
The authors indicate that they do not have any con-
flicts of interest. Sources of funding: none reported.
Thyroid Nodules
FEBRUARY 1, 2003 / VOLUME 67, NUMBER 3 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 565
Thyroid Nodules
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