Thyroid Nodules: Advances in Evaluation and Management

298 American Family Physician www.aafp.org/afp Volume 102, Number 5

◆

September 1, 2020

Published online May 19, 2020.

New advances in molecular testing have changed the man-

agement of thyroid nodules. is article reviews the workup

for thyroid nodules, including how to interpret ultrasound

ndings and ne-needle aspiration (FNA) cytopathology,

and a comparison of new molecular testing modalities to

determine the appropriate management strategy.

Epidemiology

yroid nodules are detected by ultrasonography in up to

68% of healthy patients.

Most thyroid nodules are detected

incidentally when imaging is performed for another indica-

tion. ey are found on about 16% of computed tomography

or magnetic resonance imaging studies of the neck.

yroid nodules are more common in countries with

iodine-decient populations. e introduction of iodized

salt in 1924 virtually eliminated iodine deciency disorders

in the United States.

yroid nodules are four times more

common in women than in men, and their prevalence

increases with age and body mass index.

4-6

Most thyroid nodules (90% to 95%) are benign.

4,6

Risk

factors for thyroid cancer include ionizing radiation (e.g.,

from cancer treatments, occupational exposure, or nuclear

fallout, especially when the exposure occurs at a young age),

rapid nodule growth, hoarseness, and a family history of

thyroid cancer or cancer syndromes (e.g., multiple endo-

crine neoplasia type 2, familial adenomatous polyposis).

Patients with Graves disease who have hypofunctioning

Thyroid Nodules: Advances

in Evaluation and Management

Ravi Kant, MD, Medical University of South Carolina, Charleston, South Carolina

Amanda Davis, MD, AnMed Health Family Medicine Residency Program, Anderson, South Carolina

Vipin Verma, MD, Medical University of South Carolina, Charleston, South Carolina

Thyroid nodules can be detected by ultrasonography in up to 68% of the general population. They

are typically benign and are often discovered incidentally. The primary goal of thyroid nodule eval-

uation is to determine whether it is malignant. After thyroid ultrasonography has been performed,

the next step is measurement of serum thyroid-stimulating hormone. If levels are low, a radionuclide

thyroid uptake scan is indicated. Hyperfunctioning nodules are rarely malignant and do not require

tissue sampling. Nonfunctioning nodules and nodules in a patient with a normal or high thyroid-

stimulating hormone level may require ﬁne-needle aspiration based on ultrasound characteristics and

size. Nodules with suspicious features and solid hypoechoic nodules 1 cm or larger require aspiration.

The Bethesda System (categories 1 through 6) is used to classify samples. Molecular testing can be used

to guide treatment when aspiration yields an indeterminate result. Molecular testing detects mutations

associated with thyroid cancer and can help inform decisions about surgical excision vs. continued

ultrasound monitoring. Treatment of pregnant women with nonfunctioning thyroid nodules and of

children with thyroid nodules is similar to that for nonpregnant adults, with the exception of molecular

testing, which has not been validated in these populations. (Am Fam Physician. 2020;102(5):298-304.

WHAT’S NEW ON THIS TOPIC

Thyroid Nodules

Over the past few years, molecular testing of ﬁne-needle

aspiration specimens has changed the way thyroid nodules

with indeterminate cytology are managed. A benign pattern

on molecular testing signiﬁcantly decreases the risk of

malignancy in indeterminate thyroid nodules. However, these

nodules still require ultrasound surveillance.

There is growing evidence that low-risk micropapillary thyroid

cancers smaller than 1 cm can be followed with observation as

an alternative to immediate surgical excision.

CME

This clinical content conforms to AAFP criteria for

CME. See CME Quiz on page 267.

Author disclosure: No relevant ﬁnancial aliations.

Patient information: A handout on this topic is available

at https:// family doctor.org/condition/thyroid-nodules.

commercial use of one individual user of the website. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

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THYROID NODULES

nodules have a higher prevalence of papillary thyroid can-

cer (33% to 42%).

e U.S. Preventive Services Task Force recommends

against screening for thyroid cancer with neck palpation

or ultrasonography.

Screening results in overdiagnosis

and overtreatment without improving patient outcomes.

In South Korea, a widespread cancer screening program

increased the thyroid cancer diagnosis rate 15-fold but did

not change the mortality rate.

Evaluation

e rst step in evaluating a thyroid nodule is to measure

the thyroid-stimulating hormone (TSH) level and per-

form thyroid ultrasonography with a survey of the cer-

vical lymph nodes.

7,11,12

A normal or elevated TSH level

indicates that the thyroid nodule is nonfunctioning; a low

or suppressed TSH level suggests the diagnosis of primary

hyperthyroidism, and a radionuclide thyroid uptake scan

(technetium-99 or iodine-123) should be per-

formed. Focal increased uptake in the region of

the thyroid nodule is consistent with a hyper-

functioning or “hot” nodule. Hyperfunctioning

nodules are unlikely to be malignant and do not

require FNA. Nonfunctioning or “cold” nodules

should be further evaluated with FNA if they

meet clinical or ultrasound criteria.

Figure 1 suggests a management approach for

thyroid nodules based on laboratory and ultra-

sound features.

Nonfunctioning nodules have

a 14% to 22% risk of malignancy.

e risk of

malignancy should be further stratied by ultra-

sound ndings, which can be used to distinguish

suspicious nodules that require further evaluation

with FNA. According to the American

College of Radiology, the American

yroid Association, and the Euro-

pean yroid Association, ultrasound

features that strongly suggest malig-

nancy include hypoechoic echoge-

nicity, solid composition, irregular

margins, microcalcications, height

greater than width, extrathyroidal

extension, disrupted rim calcication,

and cervical lymph nodes with suspi-

cious features.

11,14,15

FNA should not

be performed on nodules smaller than

1 cm.

Micropapillary thyroid can-

cers typically have an indolent course.

However, patients younger than 40

years may have more progressive dis-

ease.

Most nodules smaller than 1 cm

that have highly suspicious ultrasound features (with the

exception of extrathyroidal extension and suspicious cer-

vical lymph nodes) can be followed with close surveillance

and repeat thyroid ultrasonography in six to nine months.

FNA can be considered for younger patients or if the patient

requests it.

Conversely, pure cystic nodules are rarely

malignant and do not require evaluation with FNA. Spon-

giform and predominantly cystic nodules also have very low

risk of malignancy, and biopsy should be considered only

if the nodule is 2 cm or larger.

ese nodules can also be

followed with thyroid ultrasonography in 12 to 24 months

without FNA.

FNA has a vital role in risk stratication of thyroid nod-

ules.

e American yroid Association recommends that

FNA cytopathology be reported using the six Bethesda Sys-

tem diagnostic categories

11,17

(Table 1

). Approximately 25%

of thyroid FNA samples are classied as Bethesda category 3

or 4, which are considered cytologically indeterminate

and

BEST PRACTICES IN ENDOCRINOLOGY

Recommendations from the Choosing Wisely

Campaign

Recommendation Sponsoring organization

Do not use nuclear medicine thyroid scans

to evaluate thyroid nodules in patients

with normal thyroid gland function.

Society of Nuclear Medicine

and Molecular Imaging

Source: For more information on the Choosing Wisely Campaign, see https://

www.choosingwisely.org. For supporting citations and to search Choosing

Wisely recommendations relevant to primary care, see https:// www.aafp.org/

afp/recommendations/search.htm.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation

Evidence

rating Comments

Thyroid ultrasonography with a survey of the

cervical lymph nodes should be performed in all

patients with thyroid nodules.

11,12

C Cross-sectional

prevalence studies

and expert opinion

The serum thyroid-stimulating hormone level

should be measured during the initial evaluation of

a thyroid nodule. If it is low, a radionuclide thyroid

uptake scan should be performed.

11,12

C Cross-sectional

prevalence studies

and expert opinion

Fine-needle aspiration is recommended for thy-

roid nodules 1 cm or larger that have a suspicious

pattern on ultrasonography.

11,12

C Cross-sectional

prevalence studies

and expert opinion

Before molecular testing is performed, patients

should be counseled about the potential beneﬁts

and limitations of the test.

C Expert opinion

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality

patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert

opinion, or case series. For information about the SORT evidence rating system, go to https://

www.aafp.org/afpsort.

commercial use of one individual user of the website. All other rights reserved. Contact copyrights@aafp.org for copyright questions and/or permission requests.

300 American Family Physician www.aafp.org/afp Volume 102, Number 5

◆

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THYROID NODULES

FIGURE 1

Practical diagnostic approach for thyroid nodules.

Information from reference 11.

FNA = ﬁne-needle aspiration; TSH = thyroid-stimulating hormone.

*—Irregular margins, microcalciﬁcations, nodule taller than wide, extrathyroidal extension, disrupted rim calciﬁcation, or cervical lymphadenopathy.

†—Except when ultrasonography shows extrathyroid extension or cervical lymphadenopathy, in which case FNA should be performed. FNA can be

considered for younger patients or if the patient requests it.

Isoechoic or hyperechoic

nodule, or partially cystic nod-

ule with eccentric solid areas

< 1.5 cm

Follow-up ultra-

sonography in

12 to 24 months

≥ 1.5 cm

FNA

Spongiform or partially

cystic nodule without

eccentric solid nodule

< 2 cm

FNA or follow-up

ultrasonography in 12

months without FNA

≥ 2 cm

Follow-up ultra-

sonography in

12 to 24 months

Purely cystic nodule

No FNA; aspi-

ration for large

symptomatic cyst

Solid hypoechoic nodule or

partially cystic nodule with solid

hypoechoic component

< 1 cm

Follow-up ultra-

sonography in

12 to 24 months

≥ 1 cm

FNA

History, physical examination, TSH measurement, thyroid ultrasonography

Low TSH level Normal or high TSH level

Radionucleotide thyroid uptake scan

Nonfunctioning

(“cold”) nodule

Suspicious ultrasound features?*

No Yes

≥ 1 cm

FNA

< 1 cm

Repeat ultrasonography

in 6 to 9 months†

Hyperfunctioning

(“hot”) nodule

Radioiodine ablation,

surgery, or antithyroid

therapy

Incidental nodule dis-

covered on imaging

Palpable nodule discovered

by patient or physician

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Volume 102, Number 5 www.aafp.org/afp American Family Physician 301

THYROID NODULES

have a malignancy risk of 5% to 30%.

Previously, the usual

practice was to order diagnostic lobectomy in patients with

these types of nodules. However, about 80% were ultimately

found to be benign

; hence, surgical lobectomy is no longer

considered ideal for all cytologically indeterminate nodules.

Over the past few years, molecular testing of FNA spec-

imens has changed the way thyroid nodules with indeter-

minate cytology are managed.

Several molecular tests are

commercially available, and understanding their methodol-

ogy and performance is paramount in selecting the appro-

priate test (Table 2).

17, 2 0 -24

However, many clinicians may not

have a choice because most centers oer only one. ere has

been a trend toward performing reex molecular testing

on cytologically indeterminate thyroid nodules even when

testing is not directly ordered by physicians. e result is

that primary care physicians oen receive molecular test

results when they order FNA; therefore, it is important to

understand how to interpret these results.

e American yroid Association recommends that

aer consideration of clinical and ultrasound features,

molecular testing be used to further risk-stratify indeter-

minate thyroid nodules.

e patient should be counseled

about the potential benets and limitations of molecular

testing, and molecular testing should be ordered only aer

informed consent has been obtained. Validation studies on

molecular tests are limited because of the small number of

malignant nodules in these studies and insucient long-

term follow-up for benign nodules. In addition, the impact

of suspicious ultrasound patterns and high-risk clinical fea-

tures on the performance and interpretation of molecular

tests has not been studied. erefore, even though a benign

pattern on molecular testing signicantly decreases the risk

of malignancy in indeterminate thyroid nodules, ultra-

sound surveillance is still required. Consultation with an

endocrinologist may be helpful if there is uncertainty about

how to interpret a molecular test result.

Treatment and Follow-up

Radioactive iodine ablation should be considered for hyper-

functioning thyroid nodules. If this procedure cannot be

performed because of a contraindication or patient prefer-

ence, hyperthyroidism should be treated with an antithy-

roid drug. To avoid lifelong antithyroid therapy, surgery

should be considered aer the patient is euthyroid. Figure 2

reviews the management of thyroid nodules aer FNA. If

cytology and/or molecular test results show malignancy

(Bethesda category 6) or suspicion for malignancy (Bethesda

category 5, or category 3 or 4 with suspicious molecular test

results), surgical referral is recommended to remove the

aected thyroid lobe or the entire thyroid gland.

11,19

ere is growing evidence that low-risk micropapillary

thyroid cancers smaller than 1 cm can be followed with

observation as an alternative to surgical excision. An obser-

vational study of Japanese patients who were followed with

serial thyroid ultrasonography for an average of 75 months

showed that low-risk micropapillary thyroid cancers (with-

out extrathyroidal extension, metastatic cervical lymph

nodes, or distant metastases) usually have an indolent course,

without distant metastases or death.

However, patients

younger than 40 years had signicantly higher rates of new

cervical lymph node detection and tumor growth compared

with those older than 60 years. erefore, active surveillance

can be considered in patients with low-risk micropapillary

thyroid cancer as an alternative to lobectomy.

It is reason-

able to consult an endocrinologist when formulating an indi-

vidualized management plan for these patients.

Benign nodules (Bethesda category 2, or category 3 or 4

with benign molecular test results) should be followed with

repeat ultrasonography 12 to 24 months aer the initial

FNA, based on the ultrasound characteristics of the nodules

(Figure 2). If the nodules have not grown signicantly, the

interval may be extended to three to ve years.

An increase

of more than 50% in nodule volume or 20% in at least two

nodule dimensions is considered clinically signicant.

Nodules showing signicant growth on follow-up thyroid

ultrasonography should undergo repeat FNA or serial

ultrasonography, based on the suspicion for malignancy.

If molecular testing is not performed, patients with cate-

gory 4 nodules should be referred for diagnostic lobectomy,

TABLE 1

Bethesda System for Reporting Thyroid

Cytopathology

Bethesda

category Cytologic diagnosis

Risk of

malignancy (%)

1 Nondiagnostic or unsatisfactory 1 to 4

2 Benign 0 to 3

3 Atypia of undetermined sig-

niﬁcance or follicular lesion of

undetermined signiﬁcance

5 to 15

4 Follicular neoplasm or suspi-

cious for follicular neoplasm

15 to 30

5 Suspicious for malignancy 60 to 75

6 Malignant 97 to 99

Adapted with permission from Cibas ES, Ali SZ; NCI Thyroid FNA

State of the Science Conference. The Bethesda System for report-

ing thyroid cytopathology. Am J Clin Pathol. 2009; 132(5): 660.

302 American Family Physician www.aafp.org/afp Volume 102, Number 5

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September 1, 2020

THYROID NODULES

whereas those with category 3 nodules can undergo repeat

FNA.

Repeat FNA should be performed for most nodules

with a nondiagnostic cytology result (Bethesda category 1).

If the nodule has highly suspicious ultrasound features or

clinical risk factors, surgical excision should be considered

for denitive diagnosis.

ere have been reports of a higher prevalence of malig-

nancy and reduced diagnostic accuracy of FNA in nodules

4 cm or larger, but this has not translated into higher mor-

tality risk in patients who are followed without surgery.

26-28

It is not clear whether long-term follow-up of cytologically

benign nodules 4 cm or larger can be recommended. Even

if ultrasound surveillance is not indicated based on benign

cytology, larger nodules should be monitored for growth

that could result in compressive symptoms. e Amer-

ican yroid Association recommends follow-up with

repeat ultrasonography at 12 to 24 months for cytologically

benign nodules with low- to intermediate-suspicion ultra-

sound features.

Hence, it is reasonable to reevaluate larger

thyroid nodules that were benign on FNA with follow-up

ultrasonography at 12 to 24 months. Primary care physi-

cians should have a low threshold for surgical referral if

the nodule shows signicant growth or if follow-up ultra-

sonography demonstrates a new suspicious pattern. Recur-

rent cystic nodules with benign histology may be removed

surgically or percutaneously injected with ethanol if they

are symptomatic.

Solid nodules that are benign on repeat

FNA may be followed with ultrasonography or removed

surgically, depending on symptoms; however, repeat FNA

is not required, even if the nodule shows growth.

Studies

of levothyroxine suppression in benign nodules have shown

some reduction in nodule size,

but this treatment is not

recommended because the potential harm of thyrotoxicosis

outweighs the benet.

TABLE 2

Comparison of Commercially Available Molecular Tests

Molecular test

Risk of malig-

nancy with sus-

picious pattern/

positive result*

Risk of malig-

nancy with

benign pattern/

negative result* Recommended management†

Gene

Sequence

Classiﬁer

BC 3: 51%

BC 4: 41.7%

BC 3: 3.2%

BC 4: 5%

Suspicious pattern: Diagnostic lobectomy

Benign pattern: Conservative follow-up with repeat thyroid ultrasonogra-

phy in 12 to 18 months

Rosetta GX

Reveal

BC 3: 43%

BC 4: 43%

BC 3: 8%

BC 4: 8%

Positive result/suspicious pattern: Diagnostic lobectomy

Negative result/benign pattern: Consider repeat ultrasonography in 12

months; may consider repeat ﬁne-needle aspiration in six to 12 weeks

based on patient preference and clinical suspicion for malignancy

ThyGenX/

ThyraMIR

BC 3: 68%

BC 4: 82%

BC 3: 3%

BC 4: 9%

Positive for mutation/suspicious pattern: Surgical excision; type of muta-

tion detected may help determine extent of surgery (lobectomy vs. total

thyroidectomy)

Negative for mutations: Conservative follow-up with repeat thyroid

ultrasonography in 12 months for BC 3 nodule; for BC 4 nodule, consider

conservative follow-up with repeat thyroid ultrasonography in 12 months,

or diagnostic lobectomy based on patient preference and clinical suspicion

for malignancy

ThyroSeq v3

23,24

BC 3: 64%

BC 4: 68%

BC 3: 3%

BC 4: 2%

Positive for mutation/suspicious pattern: Surgical excision; type of muta-

tion detected may help determine extent of surgery (lobectomy vs. total

thyroidectomy)

Negative for mutation/benign pattern: Conservative follow-up with repeat

thyroid ultrasonography in 12 to 18 months

BC = Bethesda category.

*—Calculated from positive and negative predictive values reported in a published validation study for each test. Risk of malignancy without the

molecular test in BC 3 is 5% to 15%, risk in BC 4 is 15% to 30%.

†—Recommendations are based on available data for test performance. Validation studies were limited by small numbers of malignant nodules.

Information from references 17 and 20-24.

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Volume 102, Number 5 www.aafp.org/afp American Family Physician 303

THYROID NODULES

Special Populations

PREGNANT WOMEN

Pregnant women may have thyroid

nodules that grow in size. ere is no

evidence that thyroid nodules found

during pregnancy have an increased

risk of malignancy.

Nonfunctioning

thyroid nodules in pregnant women

can be managed in the same way as

those in nonpregnant women, with the

exception of molecular testing, which

has not been validated in this popu-

lation.

Pregnant women with hyper-

functioning thyroid nodules can be

treated with antithyroid medications,

but radionuclide thyroid uptake scans

must be deferred until aer pregnancy

and lactation.

PATIENTS WITH MULTIPLE

NODULES

Because each thyroid nodule carries

an independent risk of malignancy,

patients with multiple nodules may

require FNA for more than one nodule.

Nodules with highly suspicious ultra-

sound features should be preferentially

biop sied. A radionuclide thyroid uptake

scan can be considered in patients with

a low to low-normal TSH level to iden-

tify target nodules for FNA.

CHILDREN

yroid nodules in children are rare,

but they carry a greater risk of malig-

nancy than those in adults (22% to

26%).

e evaluation and treatment

are similar to those for adults; how-

ever, because thyroid volume increases with age, ultra-

sound features rather than size alone should be used to

identify nodules that require FNA in children.

Molecular

testing of FNA specimens has not been validated in chil-

dren, so surgery is recommended for those with indetermi-

nate results.

This article updates previous articles on this topic by Knox

and

by Welker and Orlov.

Data Sources: We searched PubMed for articles published

since 2010 using the key terms thyroid nodule, thyroid epide-

miology, thyroid nodule management, thyroid nodules in chil-

dren, and thyroid nodules in pregnancy. The search included

meta-analyses, randomized controlled trials, clinical trials,

reviews, and guidelines from the American Thyroid Associa-

tion. An evidence summary from Essential Evidence Plus was

also reviewed and relevant studies referenced. Search dates:

September 13, September 30, and October 7, 2019, and April

19, 2020.

The Authors

RAVI KANT, MD, is an endocrinologist at AnMed Health,

Anderson, S.C., and an aliate associate professor in the

Division of Endocrinology, Diabetes, and Metabolism at the

Medical University of South Carolina, Charleston.

AMANDA DAVIS, MD, is a faculty member at AnMed Health

Family Medicine Residency Program, Anderson, S.C., and an

FIGURE 2

Management of thyroid nodules after FNA based on Bethesda category.

FNA = ﬁne-needle aspiration.

*—Irregular margins, microcalciﬁcations, nodule taller than wide, extrathyroidal extension, dis-

rupted rim calciﬁcation, or cervical lymphadenopathy.

Referral for diag-

nostic lobectomy

≥ 4 cm?

Consider molecular testing;

choose test based on availability

and informed patient preference

Proceed with molecular testing?

Recommended

management

(Table 2)

Category 4

Referral for

diagnostic

lobectomy

Category 3

Repeat

FNA in 6 to

12 weeks

Yes No

Category 3 or 4:

indeterminate

Suspicious ultra-

sound features*

Category 2:

benign

Follow-up

ultrasonog-

raphy in 12 to

24 months

Category 1:

nondiagnostic

Repeat FNA in

6 to 12 weeks

Category 5:

suspicious for

malignancy

Referral

for surgical

excision

Category 6:

malignant

Referral

for surgical

excision

FNA

Cytopathology result: Bethesda category 1 to 6

304 American Family Physician www.aafp.org/afp Volume 102, Number 5

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September 1, 2020

THYROID NODULES

aliate associate professor in the Department of Family Med-

icine at the Medical University of South Carolina.

VIPIN VERMA, MD, is a faculty member at AnMed Health

Family Medicine Residency Program and an aliate assistant

professor in the Department of Medicine at the Medical Uni-

versity of South Carolina.

Address correspondence to Ravi Kant, MD, Medical University

of South Carolina/AnMed Campus, 2000 E. Greenville St., Ste.

3100, Anderson, SC 29621 (email: kant.ravi.md@ gmail.com).

Reprints are not available from the authors.

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