DynaMed Plus - Thyroid Nodule

4/3/2019 DynaMed Plus: Thyroid nodule
Thyroid nodule
Overview and Recommendations
Background
A thyroid nodule is a discrete lesion in the thyroid gland that is radiologically distinct from surrounding
normal thyroid tissue.
Thyroid nodules are detected in up to 50%-65% of healthy individuals. They are 4 times more common in
women than in men, and occur more frequently with increasing age.
Most thyroid nodules are asymptomatic; palpable nodules often are discovered on physical exam, and
nonpalpable nodules frequently are detected incidentally on imaging studies performed for unrelated reasons.
Symptomatic patients may complain of symptoms related to hyperthyroidism or hypothyroidism (in about
5% of cases), compressive symptoms (in about 5% of cases), or cosmetic concerns.
Thyroid nodules may be caused by both benign (about 90%) and malignant (about 10%) lesions. Risk factors
for malignancy include family history of thyroid cancer and history of radiation.
While thyroid nodules may be associated with thyroid dysfunction or local mass effects, the primary clinical
concern is to identify and treat lesions that are malignant or at high risk for malignancy.
Evaluation
Begin the evaluation with a history and physical exam focused on identifying risk factors for malignancy,
including:
a past history of irradiation
a family history of thyroid cancer or multiple endocrine neoplasia type 2
rapid growth of nodule
hoarseness, dysphagia, hemoptysis
the presence of a firm, fixed nodule
Perform ultrasound of the thyroid gland and neck in all patients with known or suspected thyroid nodule
(Strong recommendation).
Suspicious features for malignancy on ultrasound include but are not limited to:
marked hypoechoic pattern
irregular microlobulated, infiltrative, or speculated margins
rim calcifications with soft tissue extrusion
nodule shape taller than wide (on transverse view)
evidence of extrathyroidal extension
No single feature is 100% predictive of malignancy but risk is increased if ≥ 1 characteristics are
present.
Measure serum thyroid-stimulating hormone (TSH) in all patients with thyroid nodules (Strong
recommendation).
If TSH is low, perform a radionuclide scan (scintigraphy) (Strong recommendation).
If the nodule is classified as hyperfunctioning ("hot") on scintigraphy
consider not performing fine needle aspiration (FNA) biopsy (Weak recommendation), owing to
low risk for malignancy.
consider evaluating and treating for thyrotoxicosis (Weak recommendation).
If the nodule is classified as hypofunctioning, consider ultrasound-guided fine needle aspiration (FNA)
biopsy based on clinical and sonographic features (Weak recommendation).
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If TSH is normal or elevated, consider ultrasound-guided fine needle aspiration (FNA) biopsy of the nodule.
Indications for fine needle aspiration (FNA) biopsy vary by organization:
Nodule
Size for AACE/ACE/AME ATA NCCN
Biopsy
≤ 0.5
FNA biopsy not recommended
mm
Consider either FNA biopsy or watchful
waiting for patients with high risk Consider FNA biopsy
sonographic features or with ≥ 1 of or active surveillance
additional clinical features including FNA biopsy not with serial ultrasound
subcapsular or paratracheal lesions recommended monitoring for nodules
0.5-1
suspicious lymph nodes or < 1 cm with suspicious
cm
extrathyroidal spread features
positive personal or family history
of thyroid carcinoma
suspicious coexistent clinical
findings
FNA biopsy
FNA biopsy
recommended for solid
recommended for
or mixed solid/cystic
nodules with high or
FNA biopsy recommended for high risk thyroid (with solid component >
≥ 1 cm intermediate suspicion
lesions (Weak recommendation) 1 cm) with suspicious
sonographic patterns
features on ultrasound
(Strong
(Weak
recommendation)
recommendation)
FNA biopsy
FNA biopsy
or mixed solid/cystic (if
recommended for
≥ 1.5 solid component > 1.5
NA nodules with low
cm cm) with or without
suspicion patterns (Weak
suspicious features on
recommendation)
ultrasound (Weak
recommendation)
FNA biopsy recommended for
Intermediate risk lesions (Strong
recommendation) FNA biopsy or
Low risk lesions if ≥ 1 of (Strong observation
recommendation) recommended for
≥ 2 cm Spongiform nodules
Increasing size or with high nodules with very low
risk history suspicion patterns (Weak
Planning thyroid surgery or recommendation)
minimally invasive ablation
procedures
Any nodule with none of criteria above
Nodules that do not meet Purely cystic nodules
No FNA biopsy not recommended for
the above criteria (cystic unless therapeutic
biopsy nodules that are functional on
or benign nodules) purpose
scintigraphy (Weak recommendation)
Abbreviations: AACE/ACE/AME, American Association of Clinical Endocrinologists/American College of
Endocrinology/Associazione Medici Endocrinologi; ATA, American Thyroid Association; FNA, fine needle
aspiration; NA, not applicable; NCCN, National Comprehensive Cancer Network.
Consider measuring serum calcitonin which may be increased in medullary thyroid carcinoma (Weak
recommendation).
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The evaluation of thyroid nodules is generally the same in children and adults. Avoid the use of radioactive
agents in pregnant women for diagnostic purposes (Strong recommendation).
Management
Manage thyroid nodules based on malignancy risk, as determined by the results of fine needle aspiration
(FNA) biopsy.
Recommended management of thyroid nodules is typically determined by cytopathology and varies
according to organization:
Estimated Risk of
Cytopathology Category Treatment
Malignancy
Repeat FNA biopsy with
ultrasound guidance (Strong
recommendation)
If repeatedly nondiagnostic,
consider
Close observation of
select predominantly
cystic nodules with no
suspicious ultrasound
I. Nondiagnostic 0%-5% features (Weak
recommendation)
Surgery for
histopathologic
diagnosis of nodules
with solid composition,
features, or clinical risk
factors for malignancy
(Weak recommendation)
Conservative management is
recommended for most
patients (Strong
II. Benign 0%-3%
recommendation)
Indications for repeat FNA
vary between guideline
III. AUS/FLUS about 10%-30% Consider conservative
management if
Low-risk indeterminate
lesions and favorable
clinical criteria (Weak
recommendation)
Repeat FNA cytology,
molecular testing, or
both are not performed
or inconclusive (Weak
recommendation)
Radiographic suspicion
of malignancy not high
Consider repeating FNA
biopsy in all patients to further
assess malignancy risk (Weak
recommendation) or in those
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With low-risk
indeterminate lesions
In whom radiographic
suspicion of malignancy
not high (Weak
recommendation)
Consider molecular testing
Perform diagnostic surgery for
high-risk indeterminate lesions
(Strong recommendation)
Consider diagnostic surgery if
radiographic suspicion of
malignancy not high (Weak
recommendation)
Lobectomy (plus isthmectomy)
or total thyroidectomy is
recommended for most
patients, particularly if high
clinical suspicion of
malignancy (Strong
IV. Suspicious for follicular or Hurthle recommendation)
25%-40%
cell neoplasm Close clinical follow-up in
highly select cases with
favorable clinical and
ultrasound features (Weak
recommendation)
Perform surgery (Strong
recommendation)
V. Suspicious for malignancy 50%-75%
only if it may alter extent of
surgery (Weak
recommendation)
Surgery generally
recommended for nodules with
cytology diagnostic of
VI. Malignancy 97%-99% differentiated thyroid
carcinoma, including papillary
thyroid cancer (Strong
recommendation)
Abbreviations: AUS/FLUS, atypia or follicular lesion of undetermined significance; FNA, fine needle
aspiration
Related Summaries
Multinodular goiter
Goiter (list of topics)
Thyroid cancer
Thyroid surgery considerations
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General Information
Description
thyroid nodule is a discrete lesion in the thyroid gland that is radiologically distinct from surrounding normal
thyroid tissue(2, 4)
thyroid nodules are detected in up to 50%-65% of healthy individuals; about 95% are asymptomatic and
discovered incidentally on physical exam or on imaging studies performed for reasons unrelated to thyroid
disease ("incidentalomas")(1, 4)
the majority of thyroid nodules (about 90%) are benign and most of these require no treatment(1, 4)
goal of evaluation is to exclude malignancy which occurs in 7%–15% of cases depending on age, sex,
radiation exposure history, family history, and other factors, and requires surgery (1, 2)
Definitions
thyroid nodule is a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding
thyroid parenchyma; palpable lesions that do not have these distinct radiologic abnormalities do not meet the
strict definition for thyroid nodules(2)
thyroid incidentaloma is a nonpalpable nodule detected incidentally on ultrasound or other imaging studies
performed for other reasons(2)
hot nodule is a hyperfunctioning nodule as evidenced by taking up more tracer on imaging studies than the
surrounding normal thyroid(2)
cold nodule is a nonfunctioning nodule that takes up less tracer than the surrounding normal thyroid(2)
warm nodule is an isofunctioning nodule whose tracer uptake is equal to the surrounding thyroid(2)
colloid nodule is one consisting of concentrated viscous solution of thyroglobulin in dilated follicles lined by
flattened epithelium (Biomed Pharmacother 2001 Feb;55(1):39)
cystic nodule is one containing fluid (Biomed Pharmacother 2001 Feb;55(1):39)
pseudonodule is a term that has been used to describe nodules caused by any of
inflammatory infiltrate (ISRN Endocrinol 2013;2013:673146)
lymphocytic infiltration
dense keloid-like fibrosis which distorts the thyroid architecture and imparts to the gland a lobular
appearance
Reference - CA Cancer J Clin 2018 Mar;68(2):97
follicular adenoma is an encapsulated, benign neoplastic proliferation of thyroid follicles (Surg Clin North
Am 2014 Jun;94(3):499)
goiter is enlargement of thyroid gland and may be nodular or diffuse (Diagn Cytopathol 2008 Jun;36(6):425)
multinodular goiter (MNG) is a clinically recognizable enlargement of the thyroid gland characterized by
excessive growth of > 1 nodule, which undergoes a structural and functional transformation within the
normal thyroid tissue (DICP 1990 Oct;24(10):1009)
thyroiditis is a broad term that indicates thyroid gland inflammation (Med Clin North Am 2012
Mar;96(2):223)
primary hypothyroidism
overt or clinical hypothyroidism - thyrotropin (thyroid-stimulating hormone [TSH]) concentrations
above the reference range and free thyroxine concentrations below the reference range
mild or subclinical hypothyroidism - TSH concentrations above the reference range and free thyroxine
(free T4) concentrations within the normal range
Reference - Lancet 2017 Sep 23;390(10101):1550
hyperthyroidism is a form of thyrotoxicosis due to inappropriately high synthesis and secretion of thyroid
hormone(s) by the thyroid
overt hyperthyroidism - subnormal (usually undetectable) serum thyrotropin (TSH) with elevated
serum levels of triiodothyronine (T3) and/or free thyroxine estimates (free T4)
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subclinical hyperthyroidism - low or undetectable serum TSH with values within the normal reference
range for both T3 and free T4
Reference - Thyroid 2016 Oct;26(10):1343
thyrotropin (TSH) receptor antibodies (TRAbs) refers to any type of antibody interacting with the TSH
receptor (Lancet Diabetes Endocrinol 2018 Jul;6(7):575)
Epidemiology
Who is most affected
women (reported to be 4 times more common in women than in men)(3)

elderly(1)
persons with iodine deficiency(1)
persons with history of radiation exposure(1, 3)
Incidence/Prevalence
prevalence and incidence of thyroid nodules has increased in recent years possibly due to increase in
diagnostic imaging (Lancet 2016 Dec 3;388(10061):2783)
estimated incidence of thyroid nodule reported to be(3, 4)
0.1% annually in general population of the United States (conferring a 10% lifetime risk of developing
a thyroid nodule) (Med Clin North Am 2012 Mar;96(2):329)
2% annually in individuals exposed to ionizing radiation to head or neck (peak incidence after 15-25
years) during childhood or as a result of occupational exposure (Med Clin North Am 2012
Mar;96(2):329)
estimated prevalence of thyroid nodule(1, 2, 3, 4)
palpable thyroid nodule reported in
3%-7% of general population
5% of women and 1% of men in iodine-sufficient regions of world
5% of US population > 50 years of age
about 16 million individuals in the United States in 2018
palpable multinodular goiter reported in about 1% of individuals aged 30-50 years in United States
(Med Clin North Am 2012 Mar;96(2):351)
thyroid nodules detected by imaging ("incidentalomas")(1, 2, 4)
ultrasound
19%-68% of general population reported to have nodule detected by high-resolution
ultrasound
up to 219 million individuals in the United States as of 2018 reported to have nodules
detected by ultrasound
20%-48% of patients with palpable thyroid nodule reported to have additional nodules
detected by ultrasound
thyroid nodule may be detected in about 15% of patients having computed tomography (CT) or
magnetic resonance imaging (MRI)
thyroid nodule may be detected in about 1%-2% of patients having 18fluorodeoxyglucose
positron emission tomography (PET) scan
prevalence of malignant incidentalomas
Prevalence of Nodules Based on Detection Mode and Risk for Malignancy:
Estimated Risk of
Detection Mode Prevalence
Malignancy
Palpable Nodule 3%-7% of general population 8%-16%
Ultrasound 19%-68% of general population NA
CT/MRI 15%-25% of nodules detected by 3.9%-11.3% of nodules
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contrast-enhanced CT scan detected by CT

16%-18% of nodules detected by
MRI scan
FDG-PET 1%-2% 33%-55%
Autopsy 50%-60% NA
18
Abbreviations: CT, computed tomography; FDG-PET, fluorodeoxyglucose positron emission tomography;
MRI, magnetic resonance imaging; NA, not availableReference - CA Cancer J Clin 2018 Mar;68(2):97, N
Engl J Med 2015 Dec 10;373(24):2347
thyroid cancer(3)
may be most common endocrine malignancy (about 2.1% of all cancer diagnoses)
77% of thyroid cancer occurs in women
fifth most common cancer in women in the United States
62,000 new cases reported in men and women in 2015
lifetime risk of developing thyroid carcinoma reported to be 1.2% with peak incidence around age 50
years
incidence in the United States
based on analysis of United States National Cancer Institute Surveillance, Epidemiology, and
End Results (SEER) database
incidence per 100,000 person-years between 1992 and 2006
7.7 overall
11.3 in females
4.1 in males
Reference - Thyroid 2011 Feb;21(2):125
estimated 53,990 new cases of thyroid cancer expected in United States in 2018 (American
Cancer Society Cancer Facts & Figures 2018)
thyroid cancer accounts for about 3.1% of all new cancer cases in United States (American
Cancer Society Cancer Facts & Figures 2018)
estimated incidence 14.5 per 100,000 population per year
7.3 per 100,000 per year in men
21.4 per 100,000 per year in women
Reference - American Cancer Society Cancer Facts & Figures 2018
Risk for malignancy
overall rate of malignancy in thyroid nodules reported to be about 10%(4)

factors associated with increased risk of malignancy(1, 2, 3, 4)
age < 14 years or > 70 years
9%-18% of children having fine needle aspiration biopsy of thyroid nodule may have malignant
or suspicious results
thyroid nodules during childhood or adolescence associated with malignancy rate 3-4 times
higher than thyroid nodules in adults
male sex
symptoms including
cough
dysphonia
dysphagia
dyspnea
hoarseness
history of irradiation
head and neck irradiation, especially in childhood
total body irradiation for bone marrow transplantation
exposure to ionizing radiation from fallout in childhood or adolescence
increasing radiation exposure associated with thyroid nodules in atomic bomb survivors
based on cohort study
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4,091 men and women surviving 55-58 years after radiation exposure from Hiroshima and
Nagasaki atomic bombs
significant linear radiation dose response found for thyroid nodules including malignant
tumors, benign nodules, and cysts
Reference - JAMA 2006 Mar 1;295(9):1011, editorial can be found in JAMA 2006 Mar
1;295(9):1060, commentary can be found in JAMA 2006 Aug 2;296(5):512
17.6% prevalence of thyroid nodules ≥ 10 mm in atomic bomb survivors exposed in
childhood
2,668 men and women surviving 62-66 years after childhood radiation exposure from
Hiroshima and Nagasaki atomic bombs had thyroid examination including thyroid
ultrasound
470 participants (17.6%) had thyroid nodules ≥ 10 mm in diameter (including solid
nodules [malignant and benign] and cysts)
decreased age at exposure was significantly correlated with increasing radiation dose
effects for all nodules (p = 0.003) and solid nodules (p < 0.001) by linear dose response
analysis
increased radiation dose (per 1 Gy) associated with increased risk of
malignant tumors (odds ratio [OR] 4.4, 95% CI 1.75-9.97)
benign nodules (OR 2.07, 95% CI 1.16-3.39)
Reference - JAMA Intern Med 2015 Feb 1;175(2):228
personal or family history of(1, 2, 3)
thyroid cancer, including
medullary thyroid carcinoma
papillary thyroid carcinoma
syndromes associated with differentiated thyroid cancer including
familial medullary thyroid cancer (MTC), derived from calcitonin-producing C-cell tumors
nodule may be a component of multiple endocrine neoplasia (MEN)
type 2A along with findings including pheochromocytoma, MTC, and primary
hyperparathyroidism
type 2B along with findings including pheochromocytoma, MTC, marfanoid
habitus, and mucosal/digestive neurofibromatosis
nodule may also develop as sole component
familial nonmedullary thyroid cancer (derived from follicular cells) which have described
nodules in syndromes including
Cowden's disease
autosomal dominant condition resulting from mutation in the PTEN gene
characterized by hamartomatous neoplasms of the skin, oral mucosa,
gastrointestinal tract, central nervous and genitourinary systems
breast and thyroid cancers are the most commonly encountered malignancies
familial adenomatous polyposis
Carney complex
autosomal dominant condition
characterized by cardiac and cutaneous myxomas, spotty skin pigmentation,
various endocrinopathies, and malignancies of endocrine and nonendocrine
origin
Werner syndrome/progeria - main characteristic is premature aging and familial
polyposis (which is primarily associated with colon cancer)
other thyroid cancer-associated diseases including
hyperparathyroidism
pheochromocytoma
marfanoid habitus
mucosal neuromas
physical findings
nodule characteristics
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fixed nodule
firm or hard consistency
rapid growth
nodular tissue clearly different from normal glandular tissue
vocal cord paralysis
cervical adenopathy
increased serum thyrotropin (TSH) levels, even when the levels are still within reference limits
incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan(1,
2)
about 27%. of nodules detected by FDG-PET scan are malignant
increased malignancy risk associated with
focal uptake of tracer by thyroid
detection by technetium Tc 99m sestamibi scan
55% of nodules incidentally found on FDG-PET scan were histologically confirmed as
malignant
based on retrospective cohort study
1,342 patients with 1,364 nodules detected incidentally with FDG-PET were evaluated by
ultrasound
55% of 907 histologically confirmed nodules were malignant
rates of malignancy classified by ultrasound findings in analysis of 907 nodules
93% of 353 nodules classified as high risk
45% of 155 nodules classified as intermediate risk
8% of 272 nodules classified as low risk
0% of 4 nodules classified as very low risk
Reference - Thyroid 2018 Jun;28(6):762
ultrasound findings of confirmed thyroid nodules
high risk ultrasound findings vary between guideline organizations
according to American Association of Clinical Endocrinologists/American College of
Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME), high risk of
malignancy if nodules with high risk feature
marked hypoechogenicity (vs. prethyroid muscles)
spiculated or lobulated margins
microcalcifications
taller-than-wide shape
extrathyroidal growth
pathologic adenopathy
according to American Thyroid Association (ATA), high risk of malignancy if solid
hypoechoic nodule or solid hypoechoic component of partially cystic nodule with ≥ 1
high-risk feature including
irregular margins (for example, infiltrative or microlobulated)
microcalcifications
taller than wide shape
rim calcifications with small extrusive soft tissue component
evidence of extrathyroidal extension
according to National Comprehensive Cancer Network (NCCN), high risk of malignancy
if ≥ 1 suspicious features including
hypoechogenicity
microcalcifications
infiltrative margins
taller than wide shape in transverse plane
cervical lymph node involvement
factors associated with reduced risk of malignancy(1, 3)
low levels of thyrotropin (thyroid-stimulating hormone [TSH])
autonomously functioning thyroid nodules
similar risk of cancer in patients with
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nonpalpable nodules (incidentalomas) detected by ultrasound or other anatomic imaging studies and
palpable nodules of same size(2)
about 7% of incidentally-detected thyroid nodules reported diagnosis of malignancy
similar rates of diagnosis reported with ultrasound-detected thyroid nodules
Reference - Nat Rev Endocrinol 2016 Nov;12(11):646
solitary nodules and multinodular goiter (AACE/ACE/AME Grade B, Level 2)(1)
Etiology and Pathogenesis

Causes
thyroid nodules may be caused by

benign lesions
benign follicular nodules, including
hyperplastic (adenomatoid) nodules
benign changes characterized by the presence of hyperplasia and various
pathological changes such as
cyst formation
necrosis
hemorrhage
calcification
Reference - Thyroid 2011 Jan;21(1):37
high degree of cellularity compared with colloid nodules and nodules in
multinodular goiter
colloid nodules - hypocellular nodule consisting predominantly of colloid tissue
nodules in Graves disease in adults and children
autoimmune thyroid disorder
the most common cause of hyperthyroidism
incidence peaks between 30 and 50 years of age
lifetime risk is 3% for women and 0.5% for men
pathogenesis involves activation of autoantibodies directed against the thyrotropin
(TSH) receptor, which stimulate thyroid hormone production that is uncontrolled by
the hypothalamic–pituitary axis
prevalence of palpable thyroid nodules in GD may be 2-3 times higher than in the
general population (Clin Endocrinol (Oxf) 2001 Dec;55(6):711)
ultrasound-detected thyroid nodules reported in 17.8% of patients with Graves
disease (Thyroid 2011 Jan;21(1):37)
nodules in multinodular goiter
References -
N Engl J Med 2016 Oct 20;375(16):1552
Thyroid 2011 Jan;21(1):37
Diagn Cytopathol 2008 Jun;36(6):425
Biomed Pharmacother 2001 Feb;55(1):39
thyroiditis, including
chronic lymphocytic thyroiditis (Hashimoto thyroiditis)
autoimmune thyroid disorder
most common cause of hypothyroidism
most common clinical manifestation is an enlargement of goiter
clinico-pathological spectrum of six variants, all associated with marked
lymphocytic infiltration of the thyroid
lymphocytic infiltration and dense keloid-like fibrosis (in fibrous variant) may
produce benign thyroid pseudonodules
strongly associated with development of primary thyroid lymphoma
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thyroid nodules detected by ultrasound reported in 31.1% of patients with

Hashimoto thyroiditis
References -
CA Cancer J Clin 2018 Mar;68(2):97
Autoimmun Rev 2014 Apr-May;13(4-5):391
subacute granulomatous thyroiditis (also called subacute thyroiditis or de Quervain
thyroiditis)
the most common cause of thyroid pain
about 4 times more common in women than men
typically presents as a prodrome of low-grade fever, fatigue, and pharyngitis
symptoms with painful, tender thyroid gland which may be enlarged
likely caused by infection of certain viruses including
Coxsackie virus
Epstein-Barr virus
adenoviruses
influenza viruses
mumps
measles
primary human immunodeficiency virus infection
H1N1 influenza infection
ultrasonography may show inhomogeneous hypoechogenic texture with presence of
nodules caused by inflammatory process
Reference - Med Clin North Am 2012 Mar;96(2):223
acute thyroiditis (also called microbial inflammatory thyroiditis and acute suppurative
thyroiditis i)
rare because of the inherent resistance of the thyroid gland to infection (about 0.1–
0.7% of all thyroid disease)
most often in women 20 to 40 years of age
most patients have a preexisting thyroid disorder, usually nodular goiter
most often caused by the presence of Gram-positive bacteria in the thyroid gland,
especially Staphylococcus aureus
typically present with anterior neck pain and tenderness
radioactive iodine uptake may be normal or show cold nodules in areas of abscess
formation
References -
Med Clin North Am 2012 Mar;96(2):223
Thyroid 2010 Mar;20(3):247
Am Fam Physician 2000 Feb;61(4):1047
rare causes of nodules include
pyogenic infection
tuberculosis
fibrosing (Riedel’s) thyroiditis
parasites
dyshormonogenesis
amyloidosis
plasma cell granuloma
histiocytosis (also called Langerhans cell histocytosis and histiocytosis X)
infiltrative disorders (for example, hemochromatosis)
Reference -
Biomed Pharmacother 2001 Feb;55(1):39
N Engl J Med 2015 Dec 10;373(24):2347
malignant lesions including
thyroid carcinoma
well-differentiated carcinoma
account for > 95% of thyroid cancers
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originates from thyroid follicular epithelial cells

follicular thyroid carcinoma
about 5% of thyroid carcinoma cases
morphologically overlaps the benign follicular thyroid adenoma (FTA),
from which it is distinguished by its invasive features such as full
penetration of the tumor capsule or invasion of blood vessels
does not have a benign counterpart
Hurthle cell carcinoma (about 2% of thyroid carcinoma cases)
originates in the parafollicular neuroendocrine cells of the thyroid
most commonly presents as a solitary thyroid nodule in patients in the fourth
to sixth decade of life
70% of patients presenting with a palpable medullary thyroid cancer have
evidence of cervical node metastases at surgery
anaplastic thyroid cancer
usually presents as a rapidly growing neck mass
patients often develop hoarseness, dysphagia, and dyspnea
physical exam typically reveals large, firm palpable mass in the thyroid with
or without cervical adenopathy
primary thyroid lymphoma - reported to cause 1%-5% of all thyroid cancers and 0.37% of
cases of Hashimoto thyroiditis (CA Cancer J Clin 2018 Mar;68(2):97)
sarcoma
teratoma of head and neck
metastatic tumors
Reference -
Otolaryngol Clin North Am 2014 Aug;47(4):475
Lancet 2016 Dec 3;388(10061):2783
Cancer Genet Cytogenet 2010 Nov;203(1):21
solitary nodular vs. multinodular causes of thyroid nodules
multinodular thyroid disease
clinical presentation typically includes multinodular goiter
high prevalence of MNG reported in countries with history of iodine deficiencies
about 6% of elderly individuals previously suspected to have iodine deficiency reported to
have visible MNG
palpable MNG goiter detected in about 1% of patients aged 30-50 years (reported to
have high iodine intake) in Framingham study
patients may present as hypothyroid, euthyroid, or hyperthyroid (Diagn Cytopathol
2008 Jun;36(6):425)
hyperthyroidism is reported in up to 25% of patients with MNG
clinical presentation may be either subclinical or overtly symptomatic
causes include
autonomous nodules inside the MNG
iodine excess (from drugs, radiologic contrast dye, or diet)
References -
J Clin Endocrinol Metab 2011 May;96(5):1202
Langenbecks Arch Surg 2011 Dec;396(8):1127
Lancet 2016 Aug 27;388(10047):906
functioning vs. non-functioning causes of thyroid nodules(1, 2)
nodules are classified as either
cold - decreased uptake on scintiscan (about 50–85% of all nodules)
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normal - normal uptake on scintiscan (about 40% of all nodules)

hot - increased uptake on scintiscan (about 5-10% of all nodules)
about 1% of follicular adenomas reported to be toxic adenomas
toxic adenomas are almost always benign
symptomatic hyperthyroidism unlikely to occur until adenoma > 3 cm
References -
Langenbecks Arch Surg 2011 Dec;396(8):1127
Surg Clin North Am 2014 Jun;94(3):499
solid vs. cystic thyroid nodules
solid nodules; components may include
thyroid cells
other cells
accumulation of concentrated solution of thyroglobulin (colloid)
cystic nodules (fluid-filled) which may be either
completely fluid filled (simple cysts)
partly solid and partly fluid (complex cysts)
Reference - Biomed Pharmacother 2001 Feb;55(1):39
for additional information on thyroid carcinomas see
Papillary thyroid cancer
Follicular thyroid cancer
Medullary thyroid cancer
Anaplastic thyroid cancer
Pathogenesis
normal physiology of thyroid gland
largest endocrine gland in humans
contains 2 distinct hormone-producing cell types
the follicular cells
line the colloid follicles
take up iodine
synthesize thyroid hormone
C cells - parafollicular cells responsible for the production and secretion of calcitonin
Reference - Cancer Genet Cytogenet 2010 Nov;203(1):21
types of follicular lesions include
benign follicular adenoma
malignant follicular carcinoma
follicular variant of papillary cancer
Reference - Surg Clin North Am 2014 Jun;94(3):499
follicular adenomas
may be caused by
iodine deficiency (most common cause)
dietary goitrogens
inherited defects in thyroid hormone synthesis
Reference - Thyroid 2011 Jan;21(1):37
constitutively activating somatic mutations may develop in solitary toxic adenoma (Med Clin North
Am 2012 Mar;96(2):351)
molecular profiling studies suggest a biological continuum in tumor progression between follicular
adenomas and follicular thyroid cancer (Oncotarget 2018 Feb 13;9(12):10343)
hyperplasia of thyroid nodules may lead to
necrosis, due to a relative insufficiency of blood supply that is inadequate for the rapid growth of
the replicating neoplasia
colliquation
pseudocyst formation
Reference - Biomed Pharmacother 2001 Feb;55(1):39
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development of nodular thyroid disease(2)

iodine deficiency (or other goitrogenic stimuli) may lead to hyperplasia of follicular cells
(Langenbecks Arch Surg 2011 Dec;396(8):1127)
proliferation and increased number of cell divisions may lead to mutagenesis and formation of cell
clones
some contain somatic mutations of genes regulating thyroid growth and hormone synthesis
leading to autonomously functioning thyroid nodules
others contain mutations that lead to dedifferentiation, thus becoming cold nodules or cold
adenomas
History and Physical

Clinical presentation
thyroid nodules may be discovered

by palpation during a general physical examination
as thyroid incidentalomas using radiographic studies performed for medical evaluations, such as
carotid duplex ultrasound
computed tomography (CT) scans
magnetic resonance imaging (MRI) scans
18fluorodeoxyglucose positron emission tomography (FDG-PET) scanning
most patients with benign and malignant thyroid nodules are asymptomatic(1, 4)
patients from iodine-deficient areas are more likely to present with symptoms including local symptoms and
symptoms of functional autonomy or hyperthyroidism(1)
a minority of patients present with symptoms including(4)
those of hyperthyroidism or hypothyroidism (in about 5% of cases)
compressive symptoms (in about 5% of cases)
cosmetic concerns
presence of symptoms from a thyroid nodule depends on its size and location(1, 4)
globus sensation
sensation of a lump or foreign body in the throat
more likely to be associated with
nodule size > 3 cm
position close to the trachea (isthmic nodules more than paraisthmic nodules)
dysphagia or swallowing complaints (stasis, choking, odynophagia) may be associated with nodules
positioned in the left lobe with posterior extension and compression of the cervical esophagus
respiratory complaints (dyspnea, orthopnea, stridor, cough) may occur with intrathoracic extension
causing tracheal compression (Med Clin North Am 2012 Mar;96(2):351)
dysphonia or hoarseness may be due to tumor invasion of the recurrent laryngeal nerve (N Engl J Med
2015 Dec 10;373(24):2347)
pain may be
sudden onset associated with, for example,
bleeding in cystic nodule
subacute thyroiditis
progressive in patients with
anaplastic thyroid carcinoma
rare forms of chronic thyroiditis (for example, Riedel disease)
primary lymphoma of the thyroid
rapidity of growth (1)
slow growth - benign hyperplastic nodules may have a slow constant growth
progressive nodule growth (during weeks or months) - may suggest malignancy
rapid growth
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hemorrhage into a benign thyroid nodule or cyst (N Engl J Med 2015 Dec 10;373(24):2347)
rare aggressive tumors including
anaplastic carcinoma
thyroid lymphoma
patients with multinodular goiter (MNG)(1)
typically asymptomatic
clinical presentation may include
cosmetic complaints
sudden transient pain with enlargement of a side of the MNG if hemorrhage occurs
slow-onset cervical symptoms and signs associated with compression (or deviation) of
trachea, especially with intrathoracic extension of the MNG (substernal goiter)
symptoms include
dyspnea
stridor
cough
symptoms of respiratory distress are amplified in a recumbent position
esophagus leading to globus sensation or dysphagia (Lancet 2016 Aug 27;388(10047):906)
some present with signs and symptoms related to subclinical or clinical hyperthyroidism due to
autonomous nodules inside the MNG
excess of nutritional iodine or iodinated drugs, or radiological contrasts containing iodine
References -
J Clin Endocrinol Metab 2011 May;96(5):1202
patients with acute thyroiditis
often report a history of preexisting thyroid disorder, usually nodular goiter
typically present with anterior neck pain and tenderness; pain is often worse during swallowing and
radiates locally
other findings may include fever, pharyngitis and dermal erythema
tachycardia is common, along with leukocytosis and an elevated ESR
Reference - Am Fam Physician 2000 Feb 15;61(4):1047
patients with subacute granulomatous thyroiditis (also called subacute thyroiditis or de Quervain thyroiditis)
usually present with prodrome of
low-grade fever
fatigue
pharyngitis symptoms
thyroid gland is typically extremely painful
patient may complain of anterior neck pain or pain radiating up to the jaw or ear
pain may be unilateral or bilateral, and may be associated with dysphagia
thyroid tender to palpation, and may be enlarged up to 3 to 4 times its normal size
Reference - Science 1987 Oct 2;238(4823):67
patients with malignant thyroid nodules(1, 2, 3, 4)
about 50% are discovered during routine physical exam, as incidental finding on imaging study or
during surgery for benign disease
about 50% noticed first by patient, usually as an asymptomatic nodule
pretest probability of malignancy in a nodule increases when signs or symptoms are present
(compression symptoms more common than pain)
absence of symptoms does not rule out malignancy (AACE/ACE/AME Grade A, Level 2)
increased risk of malignancy suggested if nodules are any of
firm
stiff
solitary
fixed
matted
other characteristics suggesting malignancy may include
cervical lymphadenopathy
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vocal cord paralysis

symptoms of dysphonia, dysphagia, or dyspnea
progressive nodule growth (during weeks or months) may suggest malignancy
rapid growth may occur with aggressive tumors (e.g., anaplastic carcinoma, thyroid lymphoma)
History
History of present illness (HPI)
ask about (AACE/ACE/AME Grade B, Level 2)(1, 4)

visible neck mass/swelling, including time of onset and rate of growth
compression symptoms including
globus sensation
dysphagia
dyspnea
symptoms associated with invasion of surrounding structures, such as dysphonia or hoarseness from
tumor invasion of the recurrent laryngeal nerve (N Engl J Med 2015 Dec 10;373(24):2347)
neck pain
symptoms of thyroid dysfunction(4)
hyperthyroidism
palpitations
fatigue
tremor
anxiety
altered mood
disturbed sleep
weight loss
heat intolerance
sweating
polydipsia
heat intolerance
increased stool frequency
menstrual disturbances in women (oligomenorrhea or amenorrhea)
loss of libido
eye symptoms (swelling, pain, redness, double vision)
Reference -
N Engl J Med 2016 Oct 20;375(16):1552
Lancet 2016 Aug 27;388(10047):906
hypothyroidism
fatigue
lethargy
cold intolerance
weight gain
constipation
change in voice
dry skin
Reference - Lancet 2017 Sep 23;390(10101):1550
pain from thyroiditis
types of thyroiditis more commonly associated with symptoms of pain include
rare cases of thyroiditis caused by radioactive iodine administration or trauma
types not typically associated with pain include
Hashimoto thyroiditis
silent thyroiditis
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postpartum thyroiditis
drug-induced thyroiditis
Riedel thyroiditis
Past medical history (PMH)
ask about(1, 2, 4)
recent or current pregnancy
personal history of thyroid disease or cancer (AACE/ACE/AME Grade A, Level 2)
history of total body irradiation for bone marrow transplantation
previous history of head or neck irradiation (AACE/ACE/AME Grade A, Level 2)
Medications
ask about use of iodine-containing drugs or supplements (AACE/ACE/AME Grade A, Level 2)(1)
Family history (FH)
ask about family history of benign or malignant thyroid disease (AACE/ACE/AME Grade A, Level 2)(1)
ask about family history of inherited conditions such as(2)
malignancies including
familial medullary thyroid carcinoma
familial papillary thyroid carcinoma
anaplastic carcinoma
primary thyroid lymphoma
sarcoma
teratoma of head and neck
metastatic tumors
types of thyroiditis including
acute thyroiditis
Riedel thyroiditis
Graves disease
familial adenomatous polyposis
Cowden disease (type of hamartoma tumor syndrome)
Werner syndrome (increased susceptibility to radiation toxicity)
Carney complex
Physical
General physical
check for common signs of

hyperthyroidism including
tachycardia, dysrhythmia
systolic hypertension
weight loss
hypothyroidism including
weight gain
bradycardia
coarse, brittle hair
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dry skin
facial puffiness or edema
Neck
examination should include inspection and palpation of the thyroid gland and the anterior and lateral nodal
compartments of the neck (AACE/ACE/AME Grade B, Level 3)(1, 4)
physical examination more likely to be normal if nodules are(4)
small
located in posterior location within gland
of similar consistency as thyroid gland
examine for(1, 4)
visible lumps
volume and consistency of thyroid (AACE/ACE/AME Grade B, Level 3)
location, consistency, size, and number of nodules (AACE/ACE/AME Grade B, Level 3)
fixation of nodule to surrounding tissue
neck tenderness or pain (AACE/ACE/AME Grade B, Level 3)
cervical adenopathy (AACE/ACE/AME Grade B, Level 3)
HEENT
check for ocular signs of hyperthyroidism including

stare
eyelid retraction
eyelid lag
proptosis (exophthalmos)
double vision
periorbital edema
check for signs of hypothyroidism including
facial or eyelid puffiness
macroglossia
Cardiac
check for signs of hyperthyroidism including

tachycardia
atrial fibrillation
present in about 5%-10% of patients with thyrotoxicosis, especially common in older patients
findings may include
irregularly irregular rhythm
variable intensity of first heart sound (S1)
absence of previously heard fourth heart sound (S4)
heart failure
may be due to thyroid storm or decompensation in patient with underlying heart disease
findings may include S3 and S4 heart sounds (gallop rhythm) or elevated jugular venous pressure
bradycardia
signs of pericardial effusion including distant heart sounds with pulsus paradoxus
early systolic click or late systolic murmur of mitral valve prolapse (MVP)
Lungs
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pleural effusion
respiratory depression (severe hypothyroidism)
Neuro

resting tremor
proximal muscle weakness
hyperactive reflexes
cerebellar ataxia
lethargy
somnolence
possibly memory defects or other cognitive dysfunction
Skin

warm, moist skin
hair loss
hair thinning
palmar erythema
onycholysis
dry, cool skin (possibly yellowish)
coarse, brittle hair
Diagnosis
Making the diagnosis
thyroid nodule is diagnosed by ultrasound or other anatomic imaging studies(2)

once thyroid nodule is identified further evaluation to determine cause includes a combination of clinical and
ultrasound examination, and when appropriate, fine-needle aspiration biopsy(1)
primary goal of evaluation is exclusion of malignant lesions(1, 2)
other goals include identification of nodules that are (4)
causing (or are at risk for causing) compressive symptoms (about 5%)
associated with thyroid dysfunction (about 5%)
Differential diagnosis
other causes of neck masses include

congenital conditions
lateral neck: brachial anomalies, cystic hygroma
central neck: thyroglossal duct cysts
inflammatory/infectious diseases
lymphadenopathy
sialadenitis
neck abscess
tuberculosis
Bartonella henselae (cat-scratch disease) (Bartonella lymphadenitis)
parathyroid hemorrhage
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neck trauma
Reference - Thyroid 2010 Mar;20(3):247
Testing overview
for all patients with a thyroid nodule, including those discovered as incidentaloma
perform an ultrasound of thyroid gland and neck (ATA Strong recommendation, High-quality evidence;
NCCN Category 2A)
check thyroid-stimulating hormone (TSH) (AACE/ACE/AME Grade A, Level 1; ATA Strong
recommendation, Moderate-quality evidence; NCCN Category 2A)
if TSH is low, perform radionuclide scan (scintigraphy) (AACE/ACE/AME Grade A, Level 2;
ATA Strong recommendation, Moderate-quality evidence; NCCN Category 2A)
hyperfunctioning ("hot") nodules have low malignancy risk (patients with low TSH and
hot nodule should be evaluated and treated for hyperthyroidism)
hypofunctioning ("cold") nodules require further evaluation for potential malignancy
for patients who are at increased risk for malignancy based on clinical and ultrasound findings, perform fine
needle aspiration (FNA) biopsy for cytologic classification and determination of malignancy risk
consider ultrasound-guided FNA to improve diagnostic yield
consider testing cytologic molecular markers for indeterminate cytology (ATA Weak recommendation,
Moderate-quality evidence; NCCN Category 2A)
if FNA not indicated, consider either
ultrasound surveillance every 1-2 years if low risk ultrasound features
no follow-up if purely cystic or very low risk nodules (by size and features) (ATA Weak
recommendation, Low-quality evidence)
serum calcitonin may be useful (AACE/ACE/AME Grade A, Level 2) in patients with family history or
suspicion of medullary thyroid cancer or multiple endocrine neoplasia type 2
nodules appearing in patients with Graves disease or Hashimoto thyroiditis should be evaluated similarly to
other nodules
in patients with multinodular goiter evaluate ≤ 2 nodules with most suspicious ultrasound characteristics vs.
largest nodules (AACE/ACE/AME Grade C, Level 3)
evaluate children and pregnant women similarly to nonpregnant adults (AACE/ACE/AME Grade B, Level
3), but avoid radioactive agents in pregnant women (AACE/ACE/AME Grade A, Level 2)
Blood tests
Thyroid-stimulating hormone, thyroid hormone, and thyroid antibody testing
check thyroid-stimulating hormone (TSH) level at initial evaluation in all patients with known or suspected
thyroid nodules (AACE/ACE/AME Grade A, Level 1; ATA Strong recommendation, Moderate-quality
evidence; NCCN Category 2A) to exclude hyperfunctioning nodules (which comprise about 5% of all
nodules)(1, 2, 3)
if TSH is decreased (1)
measure free thyroxine (T4) and total or free triiodothyronine (T3) (AACE/ACE/AME Grade A, Level
2) to evaluate for hyperthyroidism
check anti-TSH receptor antibody (TRAb) levels if Graves disease suspected (AACE/ACE/AME
Grade B, Level 3)
perform radionuclide (preferably 123I) thyroid scan (ATA Strong recommendation, Moderate-quality
evidence; NCCN Category 2A) to determine functionality of nodule
if nodule is autonomously functioning (hot), evaluate and treat for thyrotoxicosis (NCCN
Category 2A)
if nodule is hypofunctional consider ultrasound-guided fine needle aspiration (FNA) biopsy
based on clinical and sonographic features (NCCN Category 2A)
if TSH increased (associated with a higher risk of malignancy)(1, 2, 4)
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measure free T4 and antithyroid peroxidase antibody (TPOAb) (AACE/ACE/AME Grade A, Level 2)
to evaluate for autoimmune thyroiditis
high serum TPOAb, and firm, diffusely enlarged or small thyroid are highly suggestive of autoimmune
thyroiditis
radionuclide scan should not be performed as the initial imaging evaluation (ATA Strong
recommendation, Moderate-quality evidence)
consider ultrasound-guided fine needle aspiration (FNA) biopsy based on clinical and sonographic
feature (NCCN Category 2A)
if TSH normal
no further blood tests or radionuclide imaging needed in most patients unless central hypothyroidism
suspected (both TSH and T4 may be low)(1)
consider ultrasound-guided fine needle aspiration (FNA) biopsy based on clinical and sonographic
features (NCCN Category 2A)
antithyroglobulin antibodies - check only in patients with clinical and ultrasound findings suggestive of
chronic lymphocytic thyroiditis when serum TPOAb levels are normal (AACE/ACE/AME Grade B, Level 3)
Serum thyroglobulin
thyroglobulin
produced by the follicular cells of the thyroid
precursor of thyroid hormones
Reference - Thyroid 2014 Aug;24(8):1195
thyroglobulin (Tg) levels(1, 2, 4)
most commonly used to monitor the treatment of patients with differentiated thyroid cancer
neither sensitive nor specific test for diagnosis of thyroid cancer
may be elevated in most benign thyroid disorders (for example multinodular goiter and thyroiditis)
routine measurement not recommended in initial evaluation or diagnosis of thyroid nodules
(AACE/ACE/AME Grade A, Level 2; ATA Strong recommendation, Moderate-quality evidence)
consider preoperative serum Tg level only in patients undergoing surgery for cancer
(AACE/ACE/AME Grade D, Level 4) to avoid overlooking the rare cases of falsely-negative serum Tg
value due to decreased Tg immunoreactivity or heterophilic antibodies
antithyroglobulin antibodies - check only in patients with normal TPOAb levels but clinical and ultrasound
findings suggestive of chronic lymphocytic thyroiditis (AACE/ACE/AME Grade B, Level 3)(1)
Calcitonin
calcitonin(1, 4)
produced by parafollicular C cells of thyroid
serves as serum marker for medullary thyroid carcinoma
levels may correlate with tumor burden
causes of increased calcitonin include(1)
medullary thyroid carcinoma - calcitonin serves as serum biomarker which correlates with tumor
burden
pulmonary or pancreatic endocrine tumors
kidney failure
autoimmune thyroiditis
hypergastrinemia (for example, with proton pump inhibitor therapy)
alcohol consumption
smoking
sepsis
heterophilic anticalcitonin antibodies
no recommendations for or against routine measurement of serum calcitonin in initial evaluation of thyroid
nodule (AACE/ACE/AME Grade D, Level 3; ATA No recommendation, Insufficient evidence)(1, 2)
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measure basal calcitonin levels in patients with family history or clinical suspicion of medullary thyroid
cancer or multiple endocrine neoplasia type 2 (1)
if basal levels are increased, confirm results in the absence of modifiers (AACE/ACE/AME Grade A,
Level 2) including alcohol use and smoking
if elevated basal calcitonin confirmed with levels > 100 pg/mL, diagnosis of medullary thyroid cancer
is common with sensitivity about 60% and specificity about 100%
if elevated basal calcitonin confirmed but levels < 100 pg/mL, consider performing calcium stimulation
test to improve diagnostic accuracy (AACE/ACE/AME Grade C, Level 3)
calcium stimulation test may be performed with either of
pentagastrin
limited in Europe and unavailable in the United States and Canada
pentagrastin stimulation test not recommended due to lack of availability
(AACE/ACE/AME Grade C, Level 3)
calcium
may be better tolerated with similar diagnostic efficacy compared to pentagastrin
protocol includes
4 hour fast
intravenous infusion of calcium gluconate (25 mg or 2.3 mg of elemental calcium/kg
of ideal body weight)
calcitonin measurements before and 2, 5, and 10 minutes after calcium gluconate
injection
potential adverse effects include
flushing
feeling of warmth
facial paresthesias
altered gustatory sensation
sinus bradycardia (rare)
contraindicated in patients with sinus bradycardia, atrioventricular block, or electrolyte
imbalance
consider obtaining calcitonin levels in patients(1, 2)
with nodules of indeterminate or suspicious cytology to rule out medullary thyroid cancer
(AACE/ACE/AME Grade B, Level 3)
with a nodular goiter undergoing thyroid surgery to avoid the risk of incomplete surgery
in whom an elevated calcitonin may change the diagnostic or surgical approach including those
being considered for less than total thyroidectomy
with suspicious cytology not consistent with papillary thyroid cancer
Other blood tests
check serum calcium and parathyroid hormone (PTH) if nodular lesions are suggestive of intrathyroidal
parathyroid adenoma on ultrasound (AACE/ACE/AME Grade B, Level 3)(1) (see also Primary
hyperparathyroidism)
Imaging studies
Ultrasound
General considerations
high-resolution ultrasound is reported to be the most sensitive test available for detecting thyroid nodules(1)
ultrasound widely used to(2, 4)
stratify the risk of malignancy in thyroid nodules
aid decision-making about whether fine-needle aspiration biopsy (FNA) is indicated
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determine type, frequency, and the need for follow up

goals of ultrasound are to (1, 2, 4)
diagnose difficult cases such as chronic lymphocytic thyroiditis (Hashimoto thyroiditis)
look for coincidental thyroid nodules or diffuse thyroid changes
detect ultrasound features suggestive of malignancy
select lesions for fine needle aspiration (FNA) biopsy
choose biopsy needle gauge and length and the safest approach for the procedure
assess the presence of extracapsular growth or suspicious lymph nodes
measure baseline volume of thyroid gland and of lesions that will be followed without surgery
ultrasound may alter clinical management by detecting nonpalpable nodules and preventing unneeded
biopsy of palpable nodules (level 2 [mid-level] evidence)
based on retrospective chart review
173 patients referred to thyroid nodule clinic after abnormal thyroid physical exam and had
ultrasonography and ultrasound-guided fine needle aspiration
among 114 patients who had solitary nodule
ultrasound detected additional nonpalpable nodules ≥ 1 cm in 27 patients
ultrasound ruled out need for aspiration in 23 patients
among 59 patients who had diffuse goiter or multinodular gland
ultrasound detected discrete nodules ≥ 1 cm in diameter that required aspiration in 39 patients
ultrasound ruled out need for aspiration in 20 patients
clinical management altered in 109 patients (63%)
Reference - Ann Intern Med 2000 Nov 7;133(9):696, commentary can be found in Ann Intern Med
2001 Sep 4;135(5):383
Indications for thyroid ultrasound
indications for thyroid ultrasound vary slightly between guideline organizations(1, 2, 3)

National Comprehensive Cancer Network (NCCN) recommends ultrasound of thyroid and neck in all
patients with a known, suspected, or incidentally detected thyroid nodule of any size (NCCN Category
2A)
AACE/ACE/AME recommends thyroid ultrasound in patients with ≥ 1 of
risk factors for malignancy (AACE/ACE/AME Grade A, Level 2), including
history of head and neck irradiation
family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, or
age < 14 or > 70 years
male sex
growth of the nodule
firm or hard nodule consistency
cervical adenopathy
fixed nodule
persistent dysphonia, dysphagia, or dyspnea
palpable thyroid nodules or goiter (AACE/ACE/AME Grade A, Level 2)
lymphadenopathy suggestive of a malignant lesion (AACE/ACE/AME Grade A, Level 2),
because of the risk of a metastatic lesion from an otherwise unrecognized papillary
microcarcinoma
thyroid lesions discovered on computed tomography (CT), magnetic resonance imaging (MRI),
or 18fluorodeoxyglucose positron emission tomography (FDG-PET) scans performed for other
reasons
American Thyroid Association (ATA) recommends thyroid ultrasound with survey of the cervical
lymph node in all patients with known or suspected thyroid nodules (ATA Strong recommendation,
High-quality evidence), including those with
suspected thyroid nodule
nodular goiter
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thyroid lesions discovered on CT, MRI or FDG-PET scan performed for other reasons
low serum TSH levels who have undergone radionuclide thyroid scintigraphy suggesting
nodularity - ultrasound used to evaluate presence of nodules that are either
hyperfunctioning and do not require fine needle aspiration (FNA) biopsy
nonfunctioning and may require FNA if sonographic criteria for FNA met
ultrasound not suggested for(1, 4)
patients with normal thyroid on palpation and low clinical risk of thyroid disease (AACE/ACE/AME
Grade C, Level 4)
nonspecific symptoms or abnormal laboratory test results (such as fatigue, increased serum thyrotropin
[TSH] levels, or autoimmune thyroiditis)
general population screening (AACE/ACE/AME Grade C, Level 4)
Ultrasound findings
American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici

Endocrinologi (AACE/ACE/AME) recommendations for describing ultrasound findings(1, 2)
for single nodule, describe (AACE/ACE/AME Grade A, Level 2)
position
size (volume)
shape
may be assessed as the ratio between the anteroposterior and transverse diameters of a
nodule
ratio ≥ 1 indicates a taller-than-wide shape and reflects a centrifugal pattern of growth
a more tall-than-wide shape is highly suggestive of malignancy
margins
regular and smooth profile or, alternatively, irregular, spiculated, or lobulated contours
malignancy is suggested by presence of
ill-defined, irregular margins
spiculated margins (even when well demarcated from surrounding thyroid
parenchyma)
interobserver reproducibility is low
content
solid or cystic content
hemorrhagic cysts may contain blood, necrotic debris, and iron-laden histiocytes
most thyroid nodules are inhomogeneous with
mixed fluid and solid pattern
solid, yet nonuniform, structure due to necrotic or inflammatory changes
aggregation of multiple microcystic components that comprise more than 50% of the
volume (“spongiform nodule”)
82%–91% of thyroid cancers are solid
the risk of malignancy increases with the amount of the solid component
of 360 consecutively thyroid cancers surgically removed at the Mayo clinic
88% were reported to be solid or minimally cystic (< 5%)
9% reported to be < 50% cystic
3% reported to be 50% cystic
coexistent microcalcifications suggest an increased risk of malignancy
echogenic pattern
hypoechoic solid lesions found in
most thyroid carcinomas
about half of benign thyroid nodules
hypoechogenicity in solid nodules reported to be a sensitive (80-85%), but poorly specific
(15-25%), predictor of malignancy
marked hypoechogenicity (defined as a nodular texture that appears darker than the
prethyroid muscles on ultrasound) is highly suggestive of malignancy (reported positive
predictive value up to 94%)
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vascular features of the nodule

for multiple nodules, describe the nodule(s) bearing the ultrasound characteristics associated with
malignancy rather than describing the largest (dominant) nodule (AACE/ACE/AME Grade A, Level 2)
for suspicious regional neck lymph nodes, describe (AACE/ACE/AME Grade A, Level 2)
cervical compartment
number
shape
size
margins
content
echogenic pattern
presence of hilum
vascular features
American Thyroid Association (ATA) recommendations for ultrasound findings include description of(2)
thyroid parenchyma (homogeneous or heterogeneous)
thyroid gland size
nodule
size (in three dimensions)
location within the thyroid gland
sonographic characteristics
composition (solid, cystic proportion, or spongiform)
echogenicity
margins
presence and type of calcifications
shape if taller than wide
vascularity
presence or absence of any suspicious cervical lymph nodes in the central or lateral compartments
ultrasound findings suggestive of benign thyroid nodule(1)
isoechoic spongiform appearance (microcystic spaces comprise > 50% of nodule)
simple cystic composition with thin regular margins
primarily cystic (> 50%) composition with colloid (hyperechoic spots with comet-tail sign)
regular "eggshell" calcification around periphery
ultrasound findings suggestive of malignant thyroid nodule(1, 2)
all tumor types (majority being papillary thyroid carcinoma [PTC])
presence of microcalcifications
nodule hypoechogenicity compared with the surrounding thyroid or strap muscles
irregular margins (defined as either infiltrative, microlobulated, or spiculated)
shape taller than wide measured on a transverse view
deeply hypoechoic
solid nodule
irregular shape
other findings reported in systematic review of 41 studies include
absent halo sign
intranodular vascularization
nodule size ≥ 4 cm
single nodule
if papillary carcinoma may include
solid hypoechoic appearance (compared to prethyroid muscle), possibly containing hyperechoic
foci without posterior shadowing (for example, microcalcifications)
solid hypoechoic composition with intranodular vascularity and absence of peripheral halo
shape taller than wide (anteroposterior diameter > transverse diameter)
hypoechogenicity with irregular (spiculated or lobulated) margins
hypoechoic mass with broken calcifications along rim and tissue extension beyond calcified
margin
if follicular neoplasm (adenoma or carcinoma) may include
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isoechoic or mildly hypoechoic homogeneous appearance with intranodular vascularization and

well-defined halo
indeterminate ultrasound features may include(1)
isoechogenicity or hyperechogenicity with hypoechoic halo
mild hypoechogenicity (compared to parenchyma) with smooth margins
peripheral vascularization
intranodular macrocalcification
Malignant thyroid nodule. : A sagittal image of a 3.5-cm, solid thyroid nodule with suspicious
ultrasonographic features, including hypoechogenicity, microcalcification, and irregular margins. This
nodule proved to be a papillary carcinoma on histopathologic analysis.
High-resolution ultrasonography of thyroid cyst. : A 59-year-old patient with left-sided neck pain for 3
days. Examination revealed a left thyroid mass. Ultrasonography showed a 2.3 x 1.9-cm left thyroid
cyst. FNAB yielded 1.5 mL of bloody fluid and benign cytologic results. Observation was
recommended.
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Hypoechoic thyroid nodule. : A transverse image of a 2.5-cm hypoechoic nodule in the right lobe of
the thyroid. This nodule has a taller-than-wide appearance.
Cystic thyroid nodule. : A transverse image of a 1.5-cm, purely cystic nodule in the right lobe of the
thyroid.
ultrasound features associated with increased risk of malignancy in thyroid nodules may include
"taller than wide" shape, absent halo sign, microcalcifications, and nodule size ≥ 4 cm (level 2 [mid-
level] evidence)
based on systematic review of observational studies
systematic review of 41 studies evaluating ultrasonographic features of 29,678 thyroid nodules in >
10,000 patients
malignancy was confirmed by histology in all studies
ultrasound features associated with increased risk of malignancy
27/85
nodule with height greater than width (odds ratio [OR] 10.15, 95% CI 6.72-15.33) in analysis of
10 studies
absent halo sign (OR 7.14, 95% CI 3.71-13.71) in analysis of 4 studies
microcalcifications (OR 6.76, 95% CI 4.72-9.69) in analysis of 21 studies
irregular margins (OR 6.12, 95% CI 3.12-12.02) in analysis of 15 studies
hypoechogenicity (OR 5.07, 95% CI 3.47-7.43) in analysis of 17 studies
solid nodule structure (OR 4.69, 95% CI 2.63-8.36) in analysis of 10 studies
intranodular vascularization (OR 3.76, 95% CI 2.04-6.95) in analysis of 15 studies
nodule size ≥ 4 cm (OR 1.63, 95% CI 1.04-2.55) in analysis of 6 studies
single nodule (OR 1.43, 95% CI 1.09-1.88) in analysis of 12 studies
all analyses limited by significant heterogeneity except absent halo sign
Reference - Eur J Endocrinol 2014;170(5):R203 full-text
"taller than wide" shape and microcalcifications features may be most predictive of malignancy in
patients with thyroid nodules but most ultrasound features have limited ability to rule out malignancy
(level 2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies with selection bias
systematic review of 52 cohort studies evaluating ultrasound features in patients with 12,786 thyroid
nodules
most studies only included patients with cold nodules
malignancy confirmed by fine needle aspiration (FNA) biopsy or surgery
pooled diagnostic performance of ultrasound features for detecting malignancy
US Feature Sensitivity Specificity +LR -LR
Taller than wide shape 26.7% 96.6% 8.07 0.75
Irregular margins 50.5% 83.1% 2.99 0.59
Microcalcifications 39.5% 87.8% 3.26 0.68
Hypoechogenicity 62.7% 62.3% 1.66 0.62
Central vascularization 45.9% 78% 2.09 0.69
Absence of elasticity 87.9% 86.2% 6.39 0.13
Abbreviations: +LR, positive likelihood ratio; -LR, negative likelihood ratio; US, ultrasound.
pooled diagnostic performance of ultrasound features in subgroup analysis of nodules with
indeterminate cytology
US Feature Sensitivity Specificity +LR -LR
Hypoechogenicity 49.7% 56% 1.12 0.89
Microcalcifications 45.6% 81.9% 2.52 0.66
Central vascularization 8.4% 96% 2.13 0.95
Abbreviations: US, ultrasound; +LR, positive likelihood ratio; -LR, negative likelihood ratio
Reference - Thyroid 2015 May;25(5):538 full-text
thyroid ultrasound may not be accurate for detecting malignancy but spongiform appearance or
presence of cystic content may indicate benign nodules (level 2 [mid-level] evidence)
based on systematic review limited by heterogeneity
systematic review of 31 diagnostic studies evaluating sonographic features of 18,288 nodules (mean
size 15 mm) in patients having thyroid ultrasound
reference standards included thyroid surgery, core biopsy, 2 consecutive FNA biopsies, or 1 FNA
biopsy with minimum 6-month follow-up
analyses limited by heterogeneity in level of experience of ultrasound reader, type of cancer and
nodule, and reference standard
pooled prevalence of thyroid cancer was 20% by reference standards
for detection of malignant nodules in pooled analysis of 3,137 nodules, "taller than wide" characteristic
had (all limited by significant heterogeneity)
sensitivity 53% (95% CI 50%-56%)
specificity 93% (95% CI 91%-94%)
positive likelihood ratio 5.4 (95% CI 3.9-7.6)
28/85
negative likelihood ratio 0.6 (95% CI 0.5-0.8)

for detection of benign nodules
spongiform appearance in pooled analysis of 880 nodules had
specificity 99% (95% CI 99%-100%)
positive likelihood ratio 10.1 (95% CI 0.5-208), results limited by significant heterogeneity
cystic content in pooled analysis of 5,559 nodules had (all limited by significant heterogeneity)
negative likelihood ratio 0.81 (95% CI 0.7-1)
Reference - J Clin Endocrinol Metab 2014 Apr;99(4):1253 full-text
Risk stratification systems
classification of risk by ultrasound features varies according to different organizations(1, 2, 3)

Ultrasound Feature Classification Systems:
AACE/ACE/AME ATA NCCN
Class 1. Low-risk lesions Low risk features include
(expected risk of malignancy Cystic or
about 1%) spongiform
Cysts (fluid component > composition
80%) (defined as
Mostly cystic (> 50%) multiple
nodules with microcystic
reverberating artifacts Benign pattern (estimated risk components
without suspicious of malignancy < 1%) composing > 50%
features Purely cystic nodule (no nodule volume)
Isoechoic spongiform solid component) Solid composition
nodules (either confluent with
or with regular halo) isoechogenicity or
hyperechogenicity
Mixed cystic/solid
composition with
no suspicious
features
Very low suspicion pattern
(estimated risk of malignancy <
3%)
Spongiform or partially NA
cystic nodule without any
low-, intermediate-, or
high-suspicion patterns
Low suspicion pattern NA
(estimated risk of malignancy
5%-10%)
Isoechoic or hyperechoic
solid nodule or partially
cystic nodule with
eccentric solid area and
without
Microcalcifications
Irregular margins
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Extrathyroidal
extension
Taller than wide
shape*
Class 2. Intermediate-risk
lesions (expected risk of
malignancy 5%-15%)
Slightly hypoechoic
(compared to thyroid
tissue) or isoechoic Intermediate suspicion
nodules with ovoid/round (estimated risk of malignancy
shape and smooth or ill- 10%-20%)
defined margins hypoechoic solid nodule
Additional features may with smooth margins and
include without NA
Intranodular microcalcifications
vascularization extrathyroidal
Elevated stiffness extension
at elastography taller than wide
Macrocalcifications shape*
or continuous rim
calcifications
hyperechoic spots
of indeterminate
significance
High suspicion (estimated risk
of malignancy 70%-90%)
Class 3. High-risk lesions
Solid hypoechoic nodule
(expected risk of malignancy
or solid hypoechoic
50%-90%)
component of partially
Nodules with ≥ 1 of High risk of malignancy
cystic nodule with ≥ 1 of
Marked if ≥ 1 suspicious feature
Irregular margins
hypoechogenicity including
(for example,
(vs. prethyroid Hypoechogenicity
infiltrative or
muscles) Microcalcifications
microlobulated)
Spiculated or Infiltrative margins
Microcalcifications
lobulated margins Taller than wide
Taller than wide
Microcalcifications shape in transverse
shape*
Taller-than-wide plane
Rim calcifications
shape* Cervical lymph
with small
Extrathyroidal node involvement
extrusive soft
growth
tissue component
Pathologic
Evidence of
adenopathy
extrathyroidal
extension
Endocrinology/Associazione Medici Endocrinologi; ATA, American Thyroid Association; NA, not available;
NCCN, National Cancer Center Network. * Anteroposterior diameter > transverse diameter.
other classification systems of thyroid ultrasound findings include(1)
Thyroid Imaging Reporting and Data System (TIRADS)
classification system developed by the American College of Radiology (ACR)
focuses on negative predictive value (NPV) of thyroid imaging
based on 10 ultrasound patterns combined into categories with increasing risk of malignancy
demonstrates good correlation with cytologic findings
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may be most appropriate for use at thyroid referral centers due to complexities
South Korean US-Based Management of Thyroid Nodules - nodule classified into 1 of 3 diagnostic
categories
probably benign
indeterminate
suspicious for malignancy
Kim Classification of Thyroid US findings - nodule classified into 1 of 5 diagnostic categories
benign
probably benign
borderline
possibly malignant
malignant
British Thyroid Association (BTA) of Thyroid Cancer - classifies ultrasound features in 5 categories at
increasing risk of malignancy from U1 (normal thyroid gland) to U5 (very suspicious lesion)
Enhanced ultrasound techniques
ultrasound with elastography(1, 2)

may provide information about nodule stiffness that is complementary to grayscale findings
recommended as complementary tool with grayscale ultrasound in nodules with indeterminate
ultrasound or cytologic findings (AACE/ACE/AME Grade A, Level 2)
consider performing fine needle aspiration (FNA) biopsy if increased stiffness (AACE/ACE/AME
Grade B, Level 2)
other considerations
performance reported to be variable and may depend on operator experience
may have limited utility in
patients with cystic or partially cystic nodules
patients with multiple, overlapping, or coalescent nodules
patients with obesity
ultrasound with contrast media(1)
not recommended in diagnostic evaluation of thyroid nodules (AACE/ACE/AME Grade C, Level 3)
may be considered in assessment of tissue ablation induced by minimally invasive techniques
ultrasound elastography appears moderately sensitive and specific for malignant thyroid nodules (level
2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies with unclear blinding
systematic review of 24 diagnostic cohort studies evaluating ultrasound elastography and B-mode
ultrasound for diagnosis of malignant nodules
reference standard was histopathologic or cytopathologic confirmation with imaging follow-up
pooled performance of ultrasound elastography for diagnosis of malignant thyroid nodules
elasticity score in analysis of 21 studies with 2,581 nodules, results limited by significant
heterogeneity
strain ratio in analysis of 10 studies with 1,081 nodules
low-to-moderate diagnostic performance (positive likelihood ratios < 4, negative likelihood ratios >
0.3) for individual B-mode ultrasound features including
hypoechogenicity
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microcalcifications
irregular margins
absent halo sign
nodule shape with anterior-to-transverse ratio ≥ 1
intranodular vascularization in color Doppler flow pattern
Reference - AJR Am J Roentgenol 2013 Jun;200(6):1317
DynaMed commentary -- comparison of elastography vs. composite ultrasound interpretation not
reported (described as not readily derivable from available studies) and would be more informative to
determine if elastography provides greater clinical utility than ultrasound alone
ultrasound with qualitative elastography might rule out malignancy in patients with completely soft
thyroid nodules (level 2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies with reference standard not applied to all
patients
systematic review of 20 studies evaluating ultrasound with qualitative elastography in 3,908 thyroid
nodules
Asteria elastography (ES) classification used to assess nodule elasticity (4-point scale, with increasing
score indicating increasing stiffness)
reference standard (histologic or cytologic evaluation) applied to < 40% of nodules in all but 1 study
prevalence of malignancy ranged from 5% to 39%
pooled diagnostic performance of qualitative elastography for detection of malignancy
with cutoff ES score > 2 in analysis of all studies, results limited by heterogeneity
positive predictive value 40% (95% CI 34%-48%)
negative predictive value 97% (95% CI 94%-98%)
with cutoff ES score > 1 in analysis of 14 studies with 2,102 nodules
sensitivity 99% (95% CI 96%-100%)
Reference - Eur J Radiol 2015 Apr;84(4):652
ultrasound elastography stiffness and strain index measures may help diagnosis of malignant nodules ≥
1 cm, but have limited performance for smaller nodules (level 2 [mid-level] evidence)
based on diagnostic cohort study without independent validation
212 patients (median age 57 years) with 243 thyroid nodules were assessed with ultrasound
elastography for differentiation of malignant and benign thyroid nodules of different sizes
elastographic strain index (SI) calculated as ratio of thyroid nodule strain to strain of softest area
of parenchyma
elastography stiffness calculated as proportion of nodule appearing pure blue (indicating
maximal stiffness) on color flow Doppler ultrasound
89.7% thyroid nodules included in analyses
21 nodules were malignant by fine-needle aspiration cytology plus histologic verification (reference
standard)
diagnostic performance of ultrasound elastography findings for detection of malignancy
Stiffness Cutoff ≥ 57.6 Strain Index Cutoff ≥ 4.24
Sensitivity Specificity Sensitivity Specificity
Nodule < 1 cm 42.9% 73.3% 28.6% 66.7%
Nodule 1-2 cm 100% 88.2% 88.9% 90.9%
Nodule > 3 cm 80% 97.8% 80% 97.8%
All nodule sizes 76.2% 89.4% 66.7% 90.6%
Reference - Endocr Pract 2015 May;21(5):474
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contrast-enhanced ultrasound appears moderately sensitive and specific for diagnosis of malignant
thyroid nodules (level 2 [mid-level] evidence)
based on systematic review of diagnostic studies with methodologic limitations
systematic review of 7 diagnostic studies evaluating contrast-enhanced ultrasound for diagnosis of
malignant thyroid nodules
reference standard was surgical histopathology with or without biopsy
pooled prevalence of malignant nodules was 43% by reference standard
all studies had ≥ 1 limitation including
unclear description of reference standard execution
unclear blinding of reference standard
unclear time delay between reference standard and test under investigation
pooled diagnostic performance of contrast-enhanced ultrasound for detection of malignant thyroid
nodules in analysis of all studies with 597 nodules
Reference - Otolaryngol Head Neck Surg 2014 Dec;151(6):909
Thyroid scintigraphy (radionuclide scanning)
overview of thyroid scintigraphy(1, 2)

should be performed using either technetium pertechnetate (99mTc) or 123I
provides a measure of the iodine-trapping function in a nodule compared with the surrounding thyroid
tissue and thus best assesses the functional status of a particular nodule
reported to have high sensitivity for detecting functioning nodules
about 83% with 123I scanning
about 91% with technetium scanning
utility of thyroid scintigraphy in the evaluation of thyroid nodules is limited to confirming the
functional status of suspected autonomously-functioning thyroid nodules
classifies nodules as
hyperfunctioning (hot)
rarely malignant
patients with low TSH and thyroid nodules classified as hot on scintigraphy should be
evaluated and treated for hyperthyroidism
fine needle aspiration (FNA) biopsy not indicated
hypofunctioning (cold) - reported to have 3%-15% risk of malignancy
indeterminate - reported to have 3%-15% risk of malignancy
hyperfunctioning multinodular goiter may include both hot and cold lesions)
Reference - J Clin Endocrinol Metab 2011 May;96(5):1202
Cold nodule. : 123I anterior image of the neck shows a cold nodule in the right upper pole of the
thyroid gland.
recommendations for radionuclide scanning of thyroid nodules

in patients with normal or increased TSH levels, radionuclide scan should not be used as initial
imaging evaluation (ATA Strong recommendation, Moderate quality evidence)(2)
consider scintigraphy if low-normal TSH (about 0.5-1 milliunits/L)(1, 2)
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in patients with thyroid nodule or multinodular goiter who reside in iodine-deficient regions to
exclude autonomy of nodule (AACE/ACE/AME Grade B, Level 3)
in patients with multinodular goiter to determine functionality of nodules ≥ 1 cm (ATA Weak
should be directly compared with ultrasound images
fine needle aspiration (FNA) biopsy may be performed exclusively on isofunctioning or
nonfunctioning nodules with suspicious sonographic patterns
other indications for scintigraphy include(1)
suspected ectopic thyroid tissue or retrosternal goiter (AACE/ACE/AME Grade A, Level 2)
if contemplating radioiodine therapy to determine patient eligibility (AACE/ACE/AME Grade B,
Level 2)
radioisotope considerations(1)
preferred agents for scintigraphy include iodine (123I), sodium pertechnetate 99mTcO4-, or
technetium sestamibi (AACE/ACE/AME Grade C, Level 3)
sodium iodide (131I) not recommended for routine diagnostic use unless low-uptake
thyrotoxicosis suspected (AACE/ACE/AME Grade B, Level 3)
avoid radioactive agents for diagnostic and therapeutic purposes in pregnant and breastfeeding women
with thyroid nodules (AACE/ACE/AME Grade A, Level 2)(1)
in patients with normal thyroid gland function, nuclear medicine thyroid scans to evaluate thyroid
nodules are recommended against by
Society of Nuclear Medicine and Molecular Imaging (Choosing Wisely 2013 Feb 21)
Canadian Association of Nuclear Medicine (Choosing Wisely Canada 2015 Jun 2)
Fluorodeoxyglucose positron emission tomography (FDG-PET)
18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan of thyroid nodules(1, 2)

not recommended for evaluation of patients with newly detected thyroid nodules or thyroidal illness
when used for other purposes, may reveal thyroid incidentaloma
FDG-PET uptake in the thyroid gland can be either of
focal
incidentally detected in 1%-2% of patients
conveys an increased risk of thyroid cancer
most often corresponds to a clinically relevant thyroid nodule
US examination is recommended to define thyroid anatomy
focal FDG-PET uptake increases malignancy risk in an affected nodule (thus further
clinical evaluation including fine needle aspiration [FNA biopsy] of nodules is
recommended)
diffuse
2% of patients demonstrate diffuse thyroid uptake
most often represents benign disease corresponding to inflammatory uptake in the setting
of chronic lymphocytic thyroiditis (Hashimoto’s disease) or other diffuse thyroidal illness
diffuse FDG-PET uptake in the thyroid should prompt ultrasound to ensure no evidence of
clinically relevant nodularity
most patients demonstrate diffuse heterogeneity on sonographic examination (no FNA is
required, but thyroid function should be evaluated)
resolution for detection of nodules on FDG-PET is lower compared to computed tomography (CT) or
magnetic resonance imaging (MRI)
prediction of malignancy
diagnostic performance reported for FDG-PET in detection of malignancy in thyroid nodules of
indeterminate cytology
sensitivity 89%
specificity 55%
positive predictive value 41%
34/85
negative predictive value 93%

diagnostic performance may be similar to molecular testing with 167-gene expression classifier
test (GEC)
recommendations
if FDG-PET uptake is
focal and nodule ≥ 1 cm on ultrasound, perform FNA on nodules (due to increased
malignancy risk) (AACE/ACE/AME Grade A, Level 2; ATA Strong recommendation,
Moderate-quality evidence)
diffuse, in conjunction with sonographic and clinical evidence of chronic lymphocytic
thyroiditis, no further imaging or FNA required (ATA Strong recommendation, Moderate-
quality evidence)
routine preoperative FDG-PET scans are not recommended (ATA Strong recommendation, Low-
quality evidence)
FDG-PET imaging is not routinely recommended for the evaluation of thyroid nodules with
indeterminate cytology (ATA Weak recommendation, Moderate-quality evidence)(2)
negative result on fluorodeoxyglucose-positron emission tomography (FDG-PET) may help rule
out thyroid cancer in patients with indeterminate FNA biopsy of thyroid nodule, especially in
lesions > 15 mm (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 6 studies evaluating FDG-PET in 241 patients with indeterminate fine
needle aspiration biopsy of thyroid nodule
definition of positive FDG-PET varied across studies
definition of malignancy varied across studies, and may or may not include papillary
microcarcinomas and malignant lesions located distant from index nodule
reference standard was final histopathologic diagnosis in all studies
pooled prevalence of malignancy in thyroid nodule was 26% (range 14%-42%)
pooled performance of FDG-PET for detection of malignancy in thyroid nodule in analysis of
225 patients from 6 studies
specificity 48% (95% CI 40%-56%), results limited by heterogeneity (p < 0.001)
positive predictive value was 39% and negative predictive value was 96%, assuming 26%
prevalence of malignancy
in subgroup analysis of 164 lesions > 15 mm in greatest dimension, sensitivity was 100% and
specificity was 47%
Reference - Cancer 2011 Oct 15;117(20):4582
Magnetic resonance imaging (MRI) or computed tomography (CT) scan
magnetic resonance imaging (MRI) or computed tomography (CT) scan(1, 2)

overview of CT and MRI
rarely diagnostic for malignant lesions except in advanced cases
assessment of goiter should include features such as size and positioning with surrounding
structures
may be helpful in the assessment of patients with any of
large goiters
suspected substernal extension of a nodular goiter
obstructive or pressure symptoms
presence of pathologic lymph nodes in cervical regions that are not visualized by US scan
CT scans often underestimate thyroid nodule size (CA Cancer J Clin 2018 Mar;68(2):97)
CT contrast medium usually contains iodine, which may induce hyperthyroidism, especially in
iodine-deficient geographic areas
recommendations
35/85
CT and MRI not recommended for routine thyroid nodule evaluation (AACE/ACE/AME Grade
A, Level 2)
consider MRI and CT for assessment of features not visualized by ultrasound including
airway compression
substernal extension of a nodular goiter
presence of pathologic lymph nodes in cervical regions
preoperative use
consider MRI, CT, and/or PET/CT scan in select patients to preoperatively stage malignant
nodules with aggressive features (AACE/ACE/AME Grade B, Level 3)
perform cross-sectional imaging studies (CT or MRI) with IV contrast plus ultrasound if
advanced disease (including invasive primary tumor, clinically apparent multiple or bulky
lymph node involvement) is suspected (ATA Strong recommendation, Low-quality
evidence)
Fine needle aspiration (FNA) biopsy
FNA used to obtain

cells for cytologic diagnosis, supplemented by immunocytochemistry
material for genetic and molecular testing
tissue samples for chemical testing
Reference - Otolaryngol Clin North Am 2014 Aug;47(4):509
may be performed using(1, 2)
manual palpation
ultrasound-guidance (preferred method)
makes the procedure safer, more reliable, and more accurate
reported to reduce prevalence of inadequate samples from 8.7% to 16.0% down to 3.5% to
7.0% (Otolaryngol Clin North Am 2014 Aug;47(4):509)
reported to decrease the false-negative rate of a benign cytology diagnosis
reduces patient discomfort by limiting number of needle passes required
enhances precision, feedback, and documentation to the FNA
considerations for fine needle aspiration (FNA) biopsy(1)
cytologic results may be misleading
false negative results usually due to inappropriate target selection or inadequate sampling
false positive results usually due to samples with nondiagnostic (but often suspicious) findings
suggested practices to decrease false negative results include
routine use of FNA by clinician
aspiration of ≥ 2 sites within nodule
if multiple nodules present, prioritize nodules for aspiration according to ultrasound results
for cystic lesions
sampling of solid or vascularized areas
sending cyst fluid for analysis
review or second opinion from experienced cytopathologist
follow-up of benign nodules
repeat FNA biopsy in benign nodules with suspicious clinical or ultrasound features
sampling peripheral/solid areas to avoid fluid or necrotic zones in large nodules
Recommendations for fine needle aspiration biopsy
indications for fine needle aspiration (FNA) biopsy vary by organization(1, 2, 3)

36/85
Indications for FNA Biopsy:

Nodule
Size for AACE/ACE/AME ATA NCCN
Biopsy
Consider FNA biopsy
or active surveillance
≤ 0.5 FNA biopsy not with serial ultrasound
FNA biopsy not recommended
mm recommended monitoring for nodules
< 1 cm with suspicious
features
Consider either FNA biopsy or watchful
waiting for patients with high risk
sonographic features or with ≥ 1 of
Consider FNA biopsy
additional clinical features including
or active surveillance
Subcapsular or paratracheal lesions
0.5-1 FNA biopsy not with serial ultrasound
Suspicious lymph nodes or
cm recommended monitoring for nodules
extrathyroidal spread
< 1 cm with suspicious
Positive personal or family history
features
of thyroid carcinoma
Suspicious coexistent clinical
findings
FNA biopsy
recommended for
FNA biopsy
nodules with high (ATA
Strong recommendation,
or mixed solid/cystic
FNA biopsy recommended for high risk thyroid Moderate-quality
≥ 1 cm (with solid component >
lesions (AACE/ACE/AME Grade B, Level 2) evidence) or intermediate
1 cm) with suspicious
suspicion sonographic
features on ultrasound
patterns (ATA Strong
(NCCN Category 2A)
recommendation, Low-
quality evidence)
FNA biopsy
FNA biopsy recommended for solid
recommended for or mixed solid/cystic (if
≥ 1.5 nodules with low solid component > 1.5
NA
cm suspicion patterns (ATA cm) with or without
Weak recommendation, suspicious features on
Low-quality evidence) ultrasound (NCCN
Category 2A)
FNA biopsy recommended for
Intermediate risk lesions
(AACE/ACE/AME Grade A, Level FNA biopsy or
2) observation
Low risk lesions if ≥ 1 of recommended for
(AACE/ACE/AME Grade A, Level nodules with very low
≥ 2 cm Spongiform nodules
2) suspicion patterns (ATA
Increasing size or with high Weak recommendation,
risk history Moderate-quality
Planning thyroid surgery or evidence)
minimally invasive ablation
procedures
No Any nodule with none of criteria above Nodules that do not meet Purely cystic nodules
biopsy FNA biopsy not recommended for the above criteria (cystic unless therapeutic
nodules that are functional on or benign nodules) purpose
37/85
scintigraphy (AACE/ACE/AME Grade B,

Level 2)
aspiration; NA, not applicable; NCCN, National Comprehensive Cancer Network.
American Association of clinical Endocrinologists/American College of Endocrinology/Associazione Medici
Endocrinologi (AACE/ACE/AME) recommendations for FNA biopsy of thyroid nodules(1)
FNA biopsy is procedure of choice for management of thyroid nodules as indicated by ultrasound and
clinical evaluation (AACE/ACE/AME Grade A, Level 2)
FNA biopsy method
ultrasound-guided FNA biopsy is preferred due to higher reliability and lower rates of
nondiagnostic results compared to palpation-guided FNA biopsy (AACE/ACE/AME Grade A,
Level 2)
may consider palpation-guided if a diagnostic ultrasound confirms presence of predominantly
solid nodule detected by initial palpation
FNA biopsy indicated for
high-risk thyroid lesions ≥ 1 cm (AACE/ACE/AME Grade A, Level 2)
intermediate-risk thyroid lesions > 2 cm (AACE/ACE/AME Grade A, Level 2)
low-risk thyroid lesions if > 2 cm plus either of (AACE/ACE/AME Grade A, Level 2)
increase in size or high risk history
before thyroid surgery or minimally invasive ablation therapy
nodules between 0.5-1 cm with suspicious US features (high-risk thyroid lesions), FNA instead
of observation is recommended if ≥ 1 of (AACE/ACE/AME Grade B, Level 3)
subcapsular or paratracheal lesions
suspicious lymph nodes or extrathyroid spread
personal or family history of thyroid cancer
coexisting suspicious clinical findings or symptoms (for example dysphonia)
nodules found on 18fluorodeoxyglucose positron emission tomography (FDG-PET) scan
(particularly if focal uptake) (AACE/ACE/AME Grade A, Level 2)
consider ultrasound surveillance instead of FNA biopsy for (AACE/ACE/AME Grade B, Level 3)
most nodules ≥ 5 mm but < 1 cm, except with high risk features
all nodules < 5mm, regardless of ultrasound features
for multinodular glands and lymph nodes
if suspicious cervical lymphadenopathy, perform FNA biopsy to assess nodule plus lymph nodes
(AACE/ACE/AME Grade A, Level 2)
obtain serum thyroglobulin (Tg) or calcitonin on FNA washout of suspicious lymph nodes
avoid FNA biopsy of > 2 nodules (AACE/ACE/AME Grade C, Level 3) or hot nodules (if
scintigraphy available) (AACE/ACE/AME Grade B, Level 2)
for complex thyroid nodules
submit both FNA specimen and drained fluid for cytologic examination (AACE/ACE/AME
Grade A, Level 2)
consider sampling parts of lesions which are
solid (AACE/ACE/AME Grade B, Level 3)
more vascularized (AACE/ACE/AME Grade C, Level 4)
for thyroid incidentalomas
manage thyroid incidentalomas according to previously described criteria for nodule diagnosis
perform ultrasound evaluation of incidentalomas detected by computed tomography (CT) or
magnetic resonance imaging (MRI) before consideration of FNA biopsy (AACE/ACE/AME
Grade A, Level 2)
thyroid incidentalomas detected by 18fluorodeoxyglucose positron emission tomography (FDG-
PET)
38/85
if focal uptake, perform ultrasound and FNA biopsy of nodule due to high risk of
malignancy (AACE/ACE/AME Grade A, Level 2)
if diffuse uptake
consider initial ultrasound evaluation as diffuse thyroid uptake of FDG tracer may
be associated with inflammatory conditions
perform FNA biopsy only of confirmed nodular lesions
for nodules that are functional on scintigraphy
FNA biopsy is not generally recommended for nodules functional on scintigraphy
children are possible exception due to higher incidence of nodule malignancy; consider surgical
removal of both cold and hot nodules (AACE/ACE/AME Grade C, Level 3)
hormone measurement on FNA needle washout
measurement of thyroglobulin, calcitonin, or parathyroid hormone (PTH) levels on FNA
washout of suspicious thyroid lesions or lymph nodes is recommended to confirm malignancy if
appropriate (AACE/ACE/AME Grade A, Level 2)
PTH levels in FNA washout may help to confirm ultrasound localization of enlarged parathyroid
glands
reference ranges for hormone measurement from FNA biopsy washout samples vary according
to institution (AACE/ACE/AME Grade B, Level 3)
American Thyroid Association (ATA) recommendations for FNA biopsy(2)
FNA is the procedure of choice in the evaluation of thyroid nodules as clinically indicated (ATA Strong
recommendation, High-quality evidence)
FNA biopsy indicated for
nodules ≥ 1 cm if
high suspicion pattern on ultrasound (ATA Strong recommendation, Moderate-quality
evidence)
intermediate suspicion pattern on ultrasound (ATA Strong recommendation, Low-quality
evidence)
nodules ≥ 1.5 cm if low suspicion patternon ultrasound (ATA Weak recommendation, Low-
quality evidence)
nodules ≥ 1 cm found on 18fluorodeoxyglucose positron emission tomography (FDG-PET) scan
(particularly if focal uptake) due to increased risk of malignancy (ATA Strong recommendation,
consider observation or FNA biopsy for nodules ≥ 2 cm with very low suspicion pattern on ultrasound
(ATA Weak recommendation, Moderate-quality evidence)
FNA biopsy not required for (ATA Strong recommendation, Moderate-quality evidence)
purely cystic nodules
nodules which do not meet criteria listed above
National Comprehensive Cancer Network (NCCN) recommendations for FNA biopsy(3)
FNA is procedure of choice for patients with thyroid nodule and normal or elevated serum thyrotropin
(TSH) levels if indicated based on clinical and sonographic features (NCCN Category 2A)
consider performing FNA biopsy in (NCCN Category 2A)
solid or mixed cystic solid (≥ 50% solid) nodules if
≥ 1 cm with suspicious features
≥ 1.5 cm without suspicious features
spongiform nodule (aggregation of microcystic spaces > 50% total volume) if ≥ 2 cm
case with suspicious cervical lymph node involvement (FNA of node with or without FNA of
associated thyroid nodule)
avoid performing FNA biopsy on simple cystic nodules except as therapeutic modality (NCCN
Category 2A)
Efficacy of FNA biopsy for detecting malignancy
39/85
FNA biopsy may identify 90% of malignant palpable thyroid nodules, but validity of published data is
uncertain (level 2 [mid-level] evidence)
based on systematic review of trials with methodologic limitations
systematic review of 12 studies assessing sensitivity of FNA for detecting thyroid malignancy in
palpable thyroid nodules
reference standard (surgical biopsy or thyroidectomy) applied to < 25% of patients with negative FNA
biopsy in 11 studies
pooled diagnostic performance of FNA biopsy for detecting malignancy
sensitivity about 90% (95% CI 88%-92%)
statistical modeling conducted to estimate risk of malignancy in patients with negative FNA who did
not have surgery
assuming no risk of malignancy with negative FNA, pooled estimated sensitivity 95%
assuming risk of malignancy equivalent to patients with negative FNA who subsequently had
surgery, sensitivity 66% (95% CI 65%-68%)
Reference - Ann Surg 2007 Nov;246(5):714, commentary can be found in Ann Surg 2008
Aug;248(2):343
FNA biopsy appears sensitive for differentiating malignant from benign thyroid nodules in children
based on systematic review of studies with methodologic limitations
systematic review of 12 studies evaluating FNA biopsy in the diagnosis of thyroid nodule in 643
children
all trials had ≥ 1 methodologic limitation including
reference standard not applied to all patients
unclear blinding of outcome assessors
reference standard not fully explained in most studies (1 study reported surgical histopathology)
pooled diagnostic performance of FNA for detection of malignancy in analysis of 530 nodules
sensitivity 94% (95% CI 86%-100%)
positive predictive value 83.6% (assuming 20% of nodules are malignant)
negative predictive value 55.3%
Reference - J Pediatr Surg 2009 Nov;44(11):2184
FNA biopsy has moderate ability to identify benign lesions from among thyroid nodules > 4 cm (level 2
[mid-level] evidence)
206 large thyroid nodules (> 4 cm) from 198 patients were sampled by fine needle aspiration (FNA)
biopsy
all samples with indeterminate and malignant cytology (Bethesda classification III-VI) results by FNA
biopsy considered positive for malignancy
23.8% of nodules confirmed malignant by surgical histopathology (reference standard)
diagnostic performance of FNA biopsy for detection of malignancy
sensitivity 80%
specificity 82%
Reference - Endocr Pract 2016 Jul;22(7):791
cytopathologic and histopathologic evaluations of thyroid nodules appear to have inter- and
intraobserver variability
based on prospective cohort study
776 surgically resected thyroid nodules ≥ 1 cm from 653 patients were assessed for
intraobserver concordance among ≥ 2 central histopathologists who independently read
histopathology slides was calculated
interobserver concordance between diagnoses made by central histopathologists and those made
by local pathologists were calculated
40/85
intra- and interobserver concordance for cytopathology was calculated by comparing diagnoses
made by local pathologists with those made by central panel of 3 cytopathologists
rates of concordance
on histopathologic distinction between benign and malignant diagnoses
91% comparing local with central histopathologists
90% comparing 2 central histopathologists
on cytopathologic distinction between categories of Bethesda classification system
64% comparing local with central cytopathologists
74.7% comparing 2 central cytopathologists
Reference - Ann Intern Med 2013 Sep 3;159(5):325
Procedural analgesia
lidocaine/prilocaine (EMLA) cream may provide noninvasive analgesia for patients having FNA (level
based on randomized trial with inadequate blinding
99 patients with nodular thyroid disease randomized to EMLA cream (lidocaine 2.5%/prilocaine 2.5%)
vs. placebo 60 minutes before ultrasound-guided FNA biopsy (4 biopsies per nodule)
clinician applying EMLA or placebo cream unblinded
comparing EMLA vs. placebo
mean 100-mm visual analog pain score 25 vs. 40 (p = 0.006)
mean 11-point numeric pain score 2.9 vs. 4 (p = 0.02)
Reference - Clin Endocrinol (Oxf) 2007 May;66(5):691
Classification and malignancy risk (based on histopathologic analysis)
FNA biopsy cytology of thyroid nodule should be classified according to Bethesda system (ATA Strong
recommendation, Moderate-quality evidence; NCCN Category 2A)(2, 3, 4)
Bethesda Classification System for Thyroid Nodule Cytopathology:
Predicted Risk of Diagnosis Rates
Cytopathology Category
Malignancy (Median %)
I. Nondiagnostic; examples may consist of any of
Cyst fluid only
0%-5% 20% (range 9%-32%)
Virtually acellular specimen
Obscuring blood or artifacts
II. Benign; examples include
Benign follicular nodule (such as adenomatous
nodule or colloid nodule) 0%-3% 2.5% (range 1%-10%)
Chronic lymphocytic thyroiditis
Granulomatous thyroiditis
III. Atypia or follicular lesion of undetermined
significance (AUS/FLUS); may include any of
Focal nuclear atypia
about 10%-30% 14% (range 6%-34%)
Predominantly Hurthle cells
Microfollicular pattern in hypocellular
specimen
25% (range
IV. Suspicious for follicular or Hurthle cell neoplasm 25%-40%
14%-34%)
V. Suspicious for malignancy including
Papillary thyroid carcinoma
70% (range
Medullary thyroid carcinoma 50%-75%
53%-97%)
Metastatic carcinoma
Lymphomas
41/85
VI. Malignancy confirmed; examples include 97%-99% 99% (range

Papillary thyroid carcinoma 94%-100%)
Poorly differentiated carcinomas
Medullary thyroid carcinoma
Squamous cell carcinoma
Carcinoma with mixed features
Anaplastic (undifferentiated) carcinoma
rates of malignancy may be somewhat variable in thyroid nodules classified as benign and
nondiagnostic according to Bethesda system
based on 2 retrospective cohort studies
25,445 FNA biopsy samples were classified according to Bethesda System
histology available for 6,362 samples (25%) after surgery
rates of malignancy confirmed by histology
16.8% of 530 nondiagnostic nodules
3.7% of 1,563 benign nodules
15.9% of 957 nodules with atypia of undetermined significance (AUS/FLUS)
26.1% of 1,791 nodules suspicious for follicular neoplasm
75.2% of 501 nodules suspicious for malignancy
98.6% of 1,020 malignant nodules
Reference - Acta Cytol 2012;56(4):333 full-text
3,080 FNA biopsy samples were classified according to Bethesda System
histology available for 892 samples (29%) after surgery
surgically confirmed malignancy rates by histology
8.9% of 135 nondiagnostic nodule
1.1% of 1,792 benign nodules
17% of 53 nodules with atypia of undetermined significance (AUS/FLUS)
25.4% of 177 nodules suspicious for follicular neoplasm
70% of 56 nodules suspicious for malignancy
98.1% of 154 malignant nodules
Reference - Am J Clin Pathol 2010 Sep;134(3):450 full-text
risk of malignancy of thyroid nodules classified as Bethesda categories I, III, or IV may vary by
ethnicity
1,541 patients with 2,068 thyroid nodules were assessed by 2,258 FNA biopsies for cytologic
classification
326 patients (mean age 51 years, 86% female) with 504 FNA biopsies classified as Bethesda I-VI by
FNA biopsy had surgical excision and were assessed by histopathology
31% of patients were African American, 31% were Hispanic, and 14% were white
4% of samples classified as Bethesda I, 53% as Bethesda II, and 43% as Bethesda III-VI
mean nodule diameter 3.1 cm
Bethesda II classification of patients having surgery varied across ethnic groups (63% in African
Americans, 48% in Hispanics, and 45% in whites)
27% of nodules overall were malignant by histopathology
16% in African Americans
29% in Hispanics
38% in whites
rates of malignancy confirmed by histopathology for each Bethesda classification in patients overall
and by ethnicity
Rates of Malignancy by Bethesda Cytology Classification
Patient
I II III IV V VI
Population
19% of 21 3% of 266 37% of 99 41% of 54 100% of 19 100% of 45
Overall
FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies
42/85
African 20% of 5 2% of 99 32% of 28 33% of 15 100% of 2 100% of 6

American FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies
20% of 10 2% of 76 37% of 27 33% of 18 100% of 10 100% of 15
Hispanic
FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies
0% of 2 FNA 3.2% of 31 21% of 14 63% of 8 100% of 2 100% of 12
White
biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies FNA biopsies
Abbreviations: Bethesda I, nondiagnostic; Bethesda II, benign; Bethesda III, atypia or follicular lesion
of undetermined significance; Bethesda IV, Follicular neoplasm or suspicious for follicular neoplasm;
Bethesda V, suspicious for malignancy; Bethesda VI, malignant; FNA, fine needle aspirate
Reference - Head Neck 2019 Feb 21 early online
rates of malignancy in thyroid nodules classified as nondiagnostic or benign may be higher at some
institutions
18,359 FNA biopsy samples taken at single hospital over 9-year period were classified by system
similar to Bethesda System except 5 categories instead of 6 (2 of indeterminate categories combined)
histology available for 2,047 samples (11.1%) after surgery
surgically confirmed rates of malignancy by histology
24% of 96 nondiagnostic nodules
11% of 674 benign nodules
26.4% of 711 nodules of indeterminate cytology
92.7% of 151 nodules suspicious for malignancy
100% of 415 malignant samples
Reference - Cytopathology 2011 Jun;22(3):164
malignancy may develop in 0.3%-1.3% over 5 years in patients with benign thyroid nodules
based on 2 retrospective cohort studies
992 patients with 1,567 benign thyroid nodules and 5 years of follow-up were analyzed
nodule growth occurred in 15.4% of patients and 11.1% of nodules (mean 5-year largest diameter
increase 4.9 mm)
nodule shrinkage occurred in 18.5% of nodules
thyroid cancer diagnosis in 5 original nodules (0.3%)
Reference - JAMA 2015 Mar 3;313(9):926, editorial can be found in JAMA 2015 Mar
3;313(9):903
268 patients with 330 benign thyroid nodules on ultrasound-guided fine needle aspiration had follow-
up of 1 month to 5 years
estimated 5-year growth > 15% in 89% of nodules
thyroid cancer in 1 of 74 reaspirated nodules (1.3%) with mean volume increase of 69%
Reference - Ann Intern Med 2003 Feb 18;138(4):315, commentary can be found in Am Fam
Physician 2003 Oct 1;68(7):1415
Immunohistochemistry
immunohistologic markers may help determine malignancy risk of indeterminate cytology; these include(1)
galectin-3
HBME- 1
fibronectin-1
CITED-1
cytokeratin
these markers are not routinely used for diagnosis due to(1)
absence of method standardization
possible pitfalls
difficulty differentiating between follicular adenomas and differentiated thyroid carcinomas
technical limitations include(1)
number of slides involved in testing
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decoloration of previous stain

intracellular antigens may be difficult targets to reach
immunocytochemistry is suggested for lesions that are suspected of having nonfollicular origin (including
parathyroid gland, medullary thyroid carcinoma, lymphoma, and metastases from other organs)
(AACE/ACE/AME Grade B, Level 3)(1)
combined analysis of histologic markers cytokeratin-19, galectin-3, and Battifora mesothelial-1 may
help detect cancer in thyroid nodules (level 2 [mid-level] evidence)
based on systematic review limited by clinical heterogeneity
systematic review of 66 diagnostic studies evaluating molecular markers cytokeratin-19, galectin-3,
and Battifora mesothelial-1 (by immunohistochemistry and immunocytochemistry) in 5,168 adult
patients with thyroid nodules
cutoffs ranged from 5% to 50% of cells for positive assay result across studies
pooled diagnostic performance of immunohistochemistry for detection of malignant thyroid tumors
combined markers cytokeratin-19 + galectin-3 + Battifora mesothelial-1 in analysis of 3 studies
had
similar results were found for immunocytochemistry of individual markers
Reference - Diagn Pathol 2012 Aug 13;7:97 full-text
Molecular testing
general considerations for molecular testing of thyroid nodules

principal use of molecular markers is to confirm or rule out malignancy in thyroid nodules with
indeterminate cytology by biopsy(2)
molecular diagnostic testing (cytologic molecular markers) may include(1, 2, 4)
testing for individual mutations in genes involved in MAP kinase (MAPK) and P13K/AKT cell
signaling pathways such as
BRAF
RAS
RET/PTC
PAX8/PPAR (peroxisome proliferator-activated gamma receptors)
multi-gene molecular assays such as 7-gene molecular panel, which identifies point mutations in
BRAF and N-/H-/K-RAS, and translocations in PAX8/PPAR and RET/PTC
pattern recognition approaches using molecular classifiers (gene expression classifier [GEC]
measuring ≥ 140 genes)
next-generation sequencing (NGS) assays - comprehensive 60-gene assay that tests for 91% of
known mutations associated with thyroid cancer; reported to have high rule-in and rule-out
Reference - Thyroid 2015 Jul;25(7):760 full-text
no single molecular test has been proven to confirm or rule out malignancy in all cases of
indeterminate cytology, and long-term outcome data for clinical utility are needed(2)
molecular profiling may not be useful if
nodule does not meet criteria for fine needle aspiration (FNA) biopsy (only indicated if FNA
biopsy also indicated)
nodule has definitive cytology of benign or malignant (Bethesda II or VI)
high prevalence of malignancy at institution
molecular testing is generally not recommended for nodules with established benign or malignant
cytology (AACE/ACE/AME Grade A, Level 2)(1)
recommendations for molecular testing of thyroid nodules
Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME)
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no recommendation for or against the use of(1)

gene expression classifiers (GECs) for nodules with indeterminate cytology
mutation testing as a guide to determine the extent of surgery (except BRAFV600e
mutation which is reported in almost 100% of papillary thyroid carcinoma)
consider molecular testing(1, 2)
to support but not replace cytologic evaluation (AACE/ACE/AME Grade A, Level 2)
when results may affect clinical management (AACE/ACE/AME Grade A, Level 2)
for nodules of indeterminate cytology if assays for detection of BRAF, RET/PTC,
PAX8/PPAR-gamma, and RAS family mutations are available (AACE/ACE/AME Grade B,
Level 2)
according to American Thyroid Association (ATA)
consider molecular testing for nodules of indeterminate cytology after evaluation of clinical and
sonographic features, to support malignancy risk assessment and management (surveillance or
diagnostic surgery) (ATA Weak recommendation, Moderate-quality evidence)
if molecular testing is being considered, counsel patients regarding (ATA Strong
recommendation, Low-quality evidence)(2) GRU2
potential benefits and limitations of testing
possible uncertainties in the therapeutic and long-term clinical implications of results
evidence for individual gene mutations
presence of BRAF mutation appears to predict malignancy in thyroid nodules of indeterminate
cytology (level 2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies
systematic review of 32 cohort studies evaluating BRAF mutation for prediction of malignancy
in 3,150 thyroid nodules with undetermined cytology on biopsy
undetermined cytology defined as Bethesda classification of any of
follicular lesion of undetermined significance (AUS/FLUS)
follicular neoplasm or suspicious for follicular neoplasm (FN/SFN)
nodules suspicious for malignancy
malignancy confirmed by histopathology after surgical excision of nodule
for prediction of malignancy in pooled analysis of all studies, BRAF mutation had
specificity 100% (95% CI 98%-100%)
positive likelihood ratio 98.7
Reference - Eur J Surg Oncol 2017 Jul;43(7):1219
presence of ≥ 1 mutation, particularly in BRAF or fusion gene RET/PTC3, may predict
malignancy in thyroid nodules identified as cytologically benign by biopsy(level 2 [mid-level]
evidence)
779 biopsy samples from 626 patients with benign thyroid nodules were tested for somatic
mutations
polymerase chain reaction (PCR) assays assessed expression of single nucleotide polymorphisms
(SNPs) in BRAF and RAS family genes, and fusion genes (RET/PTC3 and PAX/PPAR-gamma)
reference standard was surgical histopathology
≥ 1 mutation reported in 9.4% of all samples at baseline (39 BRAF, 23 NRAS, 9 HRAS, 1 KRAS,
and 1 RET/PTC3)
surgically confirmed rates of malignancy
6.7% of all samples were malignant at 1 year with 46.2% of malignancies having ≥ 1
mutation (22 BRAF, 1 NRAS, and 1 RET/PTC3)
6% of 504 samples were malignant at 2 years with 30% of malignant samples having ≥ 1
mutation (8 BRAF and 1 RET/PTC3)
5.2% of 250 samples were malignant at 3 years with 31% of malignant samples having ≥ 1
mutation (4 BRAF and 1 RET/PTC3)
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diagnostic performance of presence of ≥ 1 mutation for detection of malignancies over 3-year

period
sensitivity 38.5%
specificity 96.2%
positive predictive value 35.7%
Reference - Endocr Pract 2016 Sep;22(9):1081
malignant thyroid nodules with BRAF mutations may be more likely to have suspicious
ultrasound features than RAS mutations (level 2 [mid-level] evidence)
101 patients with malignant thyroid nodules were evaluated by ultrasound and biopsy
30 patients had BRAF-positive nodules
71 patients had RAS-positive nodules
comparing features of BRAF-positive nodules vs. those of RAS-positive nodules
hypoechogenicity in 79% vs. 20% (p < 0.001)
irregular or lobulated margins in 59% vs. 36% (p = 0.04)
extranodular extensions in 29% vs. 4% (p = 0.02)
mean size of largest nodule 18 mm vs. 25 mm (p = 0.04)
abnormal lymph node involvement in 17% vs. 0% (p = 0.05)
follicular variants of papillary thyroid cancer on histology in 70% vs. 96% (no p value
reported)
Reference - J Clin Endocrinol Metab 2016 Dec;101(12):4938 full-text
evidence for 7-gene mutation panel
7-gene panel may have moderately high specificity to detect malignancy in thyroid nodules (level
769 biopsy samples from thyroid nodules ≥ 1 cm in size of 618 patients were assessed by 7-gene
panel testing for
point mutations in BRAF, HRAS, KRAS, and NRAS
fusion genes (translocations) PAX8-PPARG, RET-PTC1, and RET-PTC3
9.2% tested positive for ≥ 1 mutation overall
109 samples were evaluable by histopathology after surgery (reference standard)
51.4% of samples were malignant by histology
80% of malignant samples tested positive for ≥ 1 mutation
diagnostic performance of 7-gene panel for malignancy
sensitivity 66%
specificity 89%
Reference - Thyroid 2014 Oct;24(10):1479
evidence for gene expression classifier (GEC)
gene expression classifier (GEC) might rule out malignancy in patients with thyroid nodules of
indeterminate cytology, especially in institutions that have lower rates of malignancy (level 2
based on diagnostic cohort study without blinding
154 biopsy samples from 145 patients with thyroid nodules of indeterminate cytology (Bethesda
category III or IV) on biopsy were assessed by gene expression classifier (GEC)
reference standard was histologic confirmation of malignancy after surgery
45% of samples were malignant by histology
diagnostic performance of GEC for malignancy
sensitivity 78%
specificity 40%
in pooled analysis of 11 studies totaling 1,303 nodule samples
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pooled prevalence of malignancy 31%

pooled diagnostic performance of GEC for malignancy
Reference - JAMA Otolaryngol Head Neck Surg 2017 Apr 1;143(4):403
gene-expression classifier may help rule out cancer in thyroid nodules with indeterminate
cytology (level 2 [mid-level] evidence)
based on validation cohort study without tests applied to all samples
577 samples from cytologically indeterminate thyroid nodules > 1 cm were evaluated using
gene-expression classifier
gene-expression classifier consists of 167 genes previously shown to be associated with benign
thyroid nodules
reference standard was histopathologic confirmation after surgical excision
32% of 265 evaluable samples were malignant
diagnostic performance of gene-expression classifier for malignant lesions
Reference - N Engl J Med 2012 Aug 23;367(8):705, editorial can be found in N Engl J Med
2012 Aug 23;367(8):765
DynaMed commentary -- use of this test could help identify low-risk patients that do not need
diagnostic hemithyroidectomy, thus avoiding risk of surgery
evidence for other emerging molecular tests
microRNA-based assay is moderately sensitive for ruling out malignancy in thyroid nodules of
indeterminate cytology (Bethesda category III-V) (level 1 [likely reliable] evidence)
based on diagnostic cohort study with independent derivation and validation cohorts
derivation cohort included 375 biopsy samples from thyroid nodules profiled by microRNA
(miRNA) assay
validation cohort included 189 similar samples of indeterminate cytology
assay classifies samples as suspicious for malignancy or benign based on miRNA expression
measured by polymerase chain reaction (PCR) in previously studied thyroid tumor samples
reference standard for malignancy was histopathologic confirmation of surgical sample
determined by ≥ 2 of 3 pathologists
48.7% of samples malignant in validation cohort of 189 evaluable samples
diagnostic performance of miRNA assay in validation cohort
sensitivity 85%
specificity 72%
Reference - J Clin Pathol 2017 Jun;70(6):500 full-text
NGS panel appears to predict malignancy in thyroid nodules with follicular lesion of
undetermined significance (AUS/FLUS) cytology (level 2 [mid-level] evidence)
462 biopsy samples from thyroid nodules with follicular lesion of undetermined significance
(FLUS) cytology were analyzed by next generation sequencing (NGS) panel (ThyroSeq version
2.1)
panel assesses 14 point mutations and 42 fusion gene mutations identified in thyroid cancer
22% of 96 nodules that were surgically removed were confirmed malignant
for prediction of malignancy, NGS panel had
sensitivity 90.9%
specificity 92.1%
47/85
Reference - Thyroid 2015 Nov;25(11):1217 full-text
Core needle biopsy
core needle biopsy(1)

performed under US guidance with an 18- to 21-gauge cutting needle
may offer additional information to FNA results in cases of thyroid or neck lesions with repeatedly
inadequate FNA
consider ultrasound-guided core needle biopsy in solid thyroid nodules with persistently inadequate FNA
cytologic findings (AACE/ACE/AME Grade C, Level 3)(1)
no recommendation for or against core needle biopsy for nodules with indeterminate cytologic results
(AACE/ACE/AME Grade D, Level 4)(1)
consider core needle biopsy to supplement FNA biopsy info in the management of patients with(1)
anaplastic tumors
thyroid lymphomas
pathologic lymph nodes
other malignant neck diseases
core needle biopsy may have better utility for making a diagnosis for thyroid nodules compared to
FNA, particularly if nodule is initially non-diagnostic or indeterminate (level 2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies limited by heterogeneity
systematic review of 20 studies evaluating diagnostic performance of core needle biopsy and/or fine
needle aspiration (FNA) biopsy for detection of malignancy in 4,746 thyroid nodules from 4,580
patients
reference standard was histologic confirmation after surgery or biopsy
comparing core needle biopsy vs. FNA biopsy, pooled prevalence of
non-diagnostic findings 5.5% vs. 22.6% (p < 0.001)
indeterminate cytology findings 8% vs. 40.2% (p < 0.001)
for detection of malignancy in pooled analysis of all studies
core needle biopsy had
sensitivity 91% (95% CI 81%-96%), results limited by significant heterogeneity
specificity 99% (95% CI 98%-100%)
FNA biopsy had
specificity 100% (95% CI 95%-100%)
for detection of malignancy in pooled subgroup analysis of initially non-diagnostic nodules
core needle biopsy had
specificity 100% (95% CI 96%-100%)
fine needle biopsy had
sensitivity 58% (95% CI 42%-73%) results limited by significant heterogeneity
specificity 100% (95% CI 91%-100%)
no significant difference in rate of complications comparing core needle biopsy vs. FNA biopsy
Reference - Endocrine 2016 Nov;54(2):315
Management by FNA Classification

Overview of management
clinical management of thyroid nodules guided by combination of(1)

clinical data
results of ultrasound evaluation
cytopathologic evaluation by FNA biopsy (performed if appropriate)
usual treatment based on cytopathologic classification after FNA biopsy(1, 2, 3, 4)
48/85
Cytopathology Category Estimated Risk of Usual treatment

Malignancy
Repeat FNA biopsy with ultrasound
I. Nondiagnostic 0%-5%
guidance
II. Benign 0%-3% Clinical and sonographic follow-up
Repeat FNA biopsy, molecular
III. AUS/FLUS About 10%-30%
testing, or lobectomy
IV. Suspicious for follicular or Hurthle
25%-40% Molecular testing, lobectomy
cell neoplasm
Near total thyroidectomy or
V. Suspicious for malignancy 50%-75%
lobectomy
VI. Malignancy 97%-99% Near total thyroidectomy
Abbreviation: AUS/FLUS, atypia or follicular lesion of undetermined significance; FNA, fine needle
aspiration.
pregnant women and children generally managed similarly to nonpregnant adults, except radioactive agents
for any purpose should be avoided in pregnant women (AACE/ACE/AME Grade A, Level 2)
Nondiagnostic cytology
Bethesda criteria for nondiagnostic classification includes samples with any of(4)
cyst fluid only
virtually acellular specimen
obscuring blood
artifacts
risk of malignancy reported to be 0%-5%(4)
nondiagnostic FNA specimens may result from any of(1)
cystic nodules that yield few or no follicular cells
benign or malignant sclerotic lesions
nodules with a thick or calcified capsule
abscesses
hypervascular or necrotic lesions
sampling error
inadequate biopsy technique
most nodules with a nondiagnostic cytology interpretation are benign(2)
repeat nondiagnostic FNA cytology results are more likely to be malignant if ultrasound shows ≥ 1 of
microcalcifications
irregular margins
a taller than wide shape
hypoechogenicity
repeating FNA biopsy(1, 2)
repeat FNA biopsy with ultrasound guidance is reported to produce diagnostic cytology specimen in
60%–80% of nodules; higher yield when cystic component is < 50%
optimal timing for repeat procedure has not been established, but a waiting period of ≥ 1 month is
suggested to avoid biopsy-induced reactive changes
about 10% of nodules may continue to be nondiagnostic on repeat biopsy even if adequate technique
due to factors inherent to nodule
malignancy reported to develop in 2% to 16% of nondiagnostic specimens(1)
Recommendations
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if initial fine needle biopsy is nondiagnostic, repeat ultrasound-guided fine needle aspiration (FNA) biopsy
with on-site cytologic evaluation, if available (AACE/ACE/AME Grade A, Level 2; ATA Strong
recommendation, Moderate-quality evidence)(1, 2)
for nodules that are repeatedly nondiagnostic(1, 2)
consider close observation of select predominantly cystic nodules with no suspicious ultrasound
features (AACE/ACE/AME Grade C, Level 3; ATA Weak recommendation; Low-quality evidence)
consider surgery for histopathologic diagnosis of nodules with solid composition, suspicious ultrasound
features, or clinical risk factors for malignancy (AACE/ACE/AME Grade C, Level 3; ATA Weak
other recommendations for nodules that are repeatedly nondiagnostic vary by organization
American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione
(AACE/ACE/AME) recommendations
if nodule is solid
with favorable clinical and ultrasound features consider clinical and ultrasound follow-up
consider ultrasound-guided core needle biopsy to obtain clearer cytologic results
and hypoechoic, consider surgical excision for histopathologic diagnosis
if nodule is predominantly cystic (> 50%) with no suspicious ultrasound features, consider
clinical and ultrasound follow-up (AACE/ACE/AME Grade C, Level 3)
American Thyroid Association (ATA) recommendations(2)
consider close observation or surgical excision for diagnosis in nodules without suspicious
features on ultrasound (ATA Weak recommendation, Low-quality evidence)
consider surgical excision for histopathologic diagnosis if any of
high suspicion pattern on ultrasound (ATA Weak recommendation, Low-quality evidence)
growth of the nodule > 20% in 2 dimensions during ultrasound surveillance (ATA Weak
patient has other clinical risk factors for malignancy (ATA Weak recommendation, Low-
quality evidence)
consider 7-gene molecular panel testing in select patients with suspicious features on ultrasound
or high clinical suspicion for malignancy
if mutation positive, perform initial oncologic thyroidectomy due to high likelihood of
malignancy
if negative, manage nonoperatively unless other clinical reasons for surgery
Reference - ATA statement on surgical application of molecular profiling for thyroid
nodules (Thyroid 2015 Jul;25(7):760)
Benign cytology
nodules with benign cytology fulfill criteria for any of(4)

benign follicular nodules (for example, adenomatoid nodules or colloid nodules)
granulomatous thyroiditis (subacute thyroiditis)
estimated risk of malignancy is 0%-3%(4)
generally, routine repeat FNA biopsy not necessary because of its low upgrading diagnostic value(1)
rate of false negative results on FNA biopsy of thyroid reported to be < 3%(4)
repeat FNA biopsy is suggested for patients with initially benign cytologic results if nodule shows ≥ 1 of(1, 4)
suspicious ultrasound findings
repeat biopsy within < 12 months
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20% of benign nodules with suspicious features vs. 0.6% of benign nodules without suspicious
features reported to develop malignancy
suspicious changes in ultrasound features during follow-up
becoming symptomatic
progressive growth
reported in 11%-15% of benign nodules over 5 years
consider repeating biopsy if size increase > 50% over 12 months
false negative rate with growing nodules may be less than with nodules with suspicious
ultrasound patterns
routine follow-up with FNA biopsy is typically not necessary in asymptomatic patients with nodules of
benign cytology on 2 biopsies plus no suspicious ultrasound findings(1)
Recommendations
suggested management of benign nodules varies according to organization(1, 2)

Treatment Options and Indications for Benign Nodules:
Treatment Strategy AACE/ACE/AME ATA
Nodules with benign cytology with
Conservative management No associated symptoms
All nodules with benign cytology
(follow-up) No suspicious ultrasound
features
Consider repeat biopsy +/-
ultrasound surveillance of
nodules with low or
intermediate suspicion
ultrasound patterns if either
Asymptomatic nodules with benign of
cytology but ≥ 1 of 20% increase plus ≥ 2
Suspicious ultrasound mm in size in ≥ 2
Repeat FNA biopsy
feature(s) nodule dimensions
> 50% increase in volume > 50% change in
Become symptomatic volume
Consider repeat ultrasound-
guided biopsy + ultrasound
within 12 months in nodules
with high suspicion
ultrasound pattern
LT4 suppressive therapy Not recommended Not recommended
Any nodules associated with either
of
Radioiodine therapy Clinical findings suggesting NA
hyperfunctioning nodule
Symptomatic goiter
Recurrent cystic nodules with
PEI Relapsing benign cystic nodules compressive symptoms or
cosmetic concerns
Solid or complex thyroid nodules
with ≥ 1 of
Ablation progressive growth NA
associated symptoms or
cosmetic concerns
Iodine supplementation NA Consider iodine supplementation
(150 mcg) in patients who have
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inadequate iodine intake with

benign and solid or mostly solid
nodules
Consider diagnostic surgery
following repeat FNA
biopsy for growing nodules
associated with ≥ 1 of
Consider diagnostic surgery for
Large size (> 4 cm)
benign nodules if ≥ 1 of
Compressive or
Surgery local pressure symptoms
structural symptoms
Clinical concern
feature(s)
Consider surgical excision of
recurrent cystic nodules
associated with compressive
or cosmetic concerns
aspiration; LT4, levothyroxine; NA, not available; PEI, percutaneous ethanol injection.
clinical and ultrasound follow-up is recommended for most patients (AACE/ACE/AME Grade A, Level 2;
ATA Strong recommendation, High-quality evidence)(1, 2)
Endocrinologi (AACE/ACE/AME) recommendations for treatment of benign nodules(1)
follow up
for asymptomatic benign nodules and no suspicious clinical or US features
perform clinical follow-up examination (AACE/ACE/AME Grade A, Level 2)
consider a repeat clinical and ultrasound examination plus TSH measurement in about 12
months (AACE/ACE/AME Grade C, Level 3)
if nodules are unchanged, repeat ultrasound after 24 months (AACE/ACE/AME Grade C,
Level 3)
repeat FNA indicated for
asymptomatic benign nodules and suspicious clinical or US features (AACE/ACE/AME Grade
A, Level 2)
nodules with a > RR = 50% increase in volume or in those that become symptomatic [BEL 3,
GRADE B](AACE/ACE/AME Grade B, Level 3)
medical treatment (levothyroxine)
levothyroxine suppressive therapy not recommended (AACE/ACE/AME Grade A, Level 1)
levothyroxine to prevent recurrence after lobectomy not recommended in patients with in-range
serum thyrotropin (TSH) levels (AACE/ACE/AME Grade A, Level 2)
nonsuppressive levothyroxine therapy
indicated for young patients with subclinical hypothyroidism due to autoimmune
thyroiditis (AACE/ACE/AME Grade A, Level 2)
is option (in addition to or instead of iodine supplementation) in young patients living in
iodine-deficient regions with a small nodular goiter and high-normal serum TSH levels
radioiodine therapy
consider radioiodine therapy for hyperfunctioning and/or symptomatic goiters, especially for
patients with previous thyroid surgery or at surgical risk and in those who decline surgery
who decline surgery
who have had previous thyroid surgery or with high surgical risk
surgery
consider surgery in patients with either of (AACE/ACE/AME Grade B, Level 2)
local pressure symptoms that are clearly associated with nodule
appearance of suspicious ultrasound features, despite benign FNA findings
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preferred options for surgical excision (AACE/ACE/AME Grade A, Level 2)

lobectomy plus isthmectomy for benign uninodular goiter
total thyroidectomy for multinodular goiter (MNG)
consider surgery if higher-risk symptoms develop including any of neck pressure, dysphagia,
globus sensation, dyspnea (especially in supine position), dyspnea on exertion, or pain
perform surgical consultation as soon as possible if sudden and persistent dysphonia develops
percutaneous ethanol injection (PEI)
PEI safe and effective outpatient therapy indicated for benign thyroid cysts or complex nodules
with a large fluid component (AACE/ACE/AME Grade A, Level 1)
confirm benign status of complex lesions by sampling solid component before procedure
PEI is recommended as the first-line treatment for relapsing benign cystic lesions
consider PEI for hot nodules with compressive symptoms only if other treatments not available
PEI not recommended for either of (AACE/ACE/AME Grade A, Level 2)
solid nodules (whether hyperfunctioning or not)
multinodular goiters
ablation
consider laser or radiofrequency ablation for treatment of solid or complex thyroid nodules if ≥ 1
of (AACE/ACE/AME Grade C, Level 2)
progressive enlargement
symptoms
associated cosmetic concerns
consider confirmation of cytology with repeat FNA biopsy prior to thermal ablation therapy
have discussion with patient regarding alternative therapy options, efficacy, limitations, and
adverse effects (AACE/ACE/AME Grade B, Level 3)
American Thyroid Association (ATA) recommendations for management of benign nodules(2)
further immediate diagnostic studies or treatment are not necessary for most benign nodules (ATA
Strong recommendation, High-quality evidence)
routine thyrotropin (TSH) suppression therapy with levothyroxine is not recommended for benign
thyroid nodules in non-iodine-depleted patients (modest efficacy but benefit does not outweigh risk of
harm) (ATA Strong recommendation, High-quality evidence)
iodine 150 mcg/day supplement is recommended for patients with benign, solid, or mostly solid
nodules and possibly inadequate dietary intake (ATA Strong recommendation, Moderate-quality
evidence)
surgery may be reasonable option for nodules with any of (ATA Weak recommendation, Low-quality
evidence)
large size (> 4 cm)
compressive or structural symptoms
reason for clinical concern
monitor growing nodules regularly, but no intervention is necessary as long as asymptomatic (ATA
Strong recommendation, Low-quality evidence)
for recurrent cystic nodules of benign cytology (ATA Weak recommendation, Low-quality evidence)
consider surgical excision or PEI if compressive symptoms or cosmetic concerns
follow asymptomatic nodules conservatively
molecular testing with 7-gene molecular panel
not routinely performed in nodules with benign cytology but may be useful in select patients
with concerning ultrasound findings or high clinical suspicion for malignancy
American Thyroid Association (ATA) recommended management of benign nodules based on
results of 7-gene molecular panel if performed
if positive, perform initial oncologic thyroidectomy due to high likelihood of malignancy
if negative, manage nonoperatively unless other clinical reasons for surgery
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Atypia or Follicular lesions of undetermined significance (AUS/FLUS)
alternative terms to follicular lesions of undetermined significance (FLUS) include(3)

atypia of undetermined significance (AUS)
rule out neoplasm
atypical follicular lesion
cellular follicular lesion
estimated risk of malignancy 10%-30%(3, 4)
Bethesda criteria include(4)
focal nuclear atypia
predominance of Hurthle cells
microfollicular pattern in a hypocellular specimen
risk of malignancy 10-30%(4)
no clear-cut morphologic criteria to distinguish benign from malignant lesions(1)
specimens contain cells with architectural and/or nuclear atypia that is more pronounced than expected for
benign changes but not sufficient to be placed in one of the higher risk diagnostic categories(2)
expected frequency of nodules with AUS/FLUS cytology is about 7% (but 1%-27% of all thyroid FNA
samples may actually receive AUS/FLUS diagnosis)(2)
6%-48% overall risk of cancer reported in patients with AUS/FLUS nodules that were surgically removed
(mean 16%)(2)
rates of malignancy reported in nodules with AUS/FLUS cytology based on ultrasound findings(2)
8% of nodules with no or very low risk ultrasound findings
58% of nodules with low risk ultrasound findings
100% of nodules with high risk ultrasound findings
single ultrasound findings reported to have > 90% specificity and positive predictive value for malignancy
include(2)
taller than wide shape
irregular borders
marked hypoechogenicity
different systems of cytologic classification exist(1)
use cytology classification system such as Bethesda (or consistent with Bethesda) consisting of 5
categories with indeterminate cytology category made up of 2 subcategories (AACE/ACE/AME Grade
A, Level 2)
for the subcategories of indeterminate cytology in Bethesda
AUS/FLUS cytology is the lower risk category
follicular neoplasm (FN), also called suspicious for follicular neoplasm (SFN) is the higher risk
category
considerations for low risk indeterminate nodules(1)
called AUS/FLUS (by Bethesda), Thy 3a (by UK Royal College of Pathologists), TIR 3a (by Thyroid
Image Reporting system)
expected risk of malignancy is 5%-15%
repeat fine needle aspiration (FNA) biopsy reported to confirm a cytologic diagnosis of benign or
malignant in almost 50% of cases
core needle biopsy (CNB) as alternative to FNA biopsy
CNB may provide further information as it provides architectural findings and enables
comparison with surrounding normal thyroid tissue
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role of CNB in evaluation of indeterminate cytology nodules requires confirmation but may be
considered for its ability to provide microhistologic information
immunocytochemical analyses may improve cytologic diagnostic accuracy with inconsistent predictive
value but expensive and practical utility is limited to specialized centers
somatic mutation testing of indeterminate nodules may be useful in some cases and next-generation
sequencing assays are being used for rule-in diagnostic value
close observation/follow-up is a reasonable option for most AUS/FLUS nodules especially if
favorable clinical factors including personal and family history
small lesion size
relatively low observed incidence of malignancy in indeterminate nodules at institution
low-risk ultrasound features and elastography features (may be most important of all clinical
factors)
preferred treatment for AUS/FLUS nodules with suspicious clinical or ultrasound findings is surgery
usually lobectomy and isthmectomy is sufficient for most patients
total thyroidectomy may be considered based on clinical setting, coexisting contralateral nodules,
or patient preference
considerations for high-risk indeterminate nodules(1)
also called follicular neoplasm or suspicious for follicular neoplasm (FN/SFN by Bethesda), Thy 3f (by
UK Royal College of Pathologists), TIR 3b (by Thyroid Image Reporting system)
expected risk of malignancy is about 15% to 30%
repeat FNA of FN/SFN nodules is not typically performed
may not provide additional information and is generally not recommended in most cases
exception may exist with findings of atypical cells, where repeat FNA has been reported to
identify a possible follicular variant of papillary thyroid cancer
most FN/SFN nodules should be surgically removed for histologic examination
for evaluation of nodules of indeterminate cytology, consider all of the following factors(1)
cytologic subclassification
clinical data associated with moderately increased risk of malignancy; for example
personal or family history of thyroid cancer
lesion size
ultrasound and elastography findings
possibly mutational analyses (molecular diagnostics if performed)
Recommendations
Treatment of AUS/FLUS Nodules:

Management
AACE/ACE/AME ATA NCCN
Strategy
Low-risk indeterminate lesions
and favorable clinical criteria If repeat FNA
Minority of high-risk cytology, molecular If radiographic
Conservative
indeterminate lesions cases testing, or both are suspicion of
management
with both favorable clinical not performed or malignancy not high
and no high-risk ultrasound inconclusive
features
To supplement If radiographic
Molecular testing No recommendations for or against malignancy risk suspicion of
assessment malignancy not high
If radiographic
suspicion of
To supplement
malignancy not high;
Repeat FNA biopsy Low-risk indeterminate lesions malignancy risk
also consider second
assessment
opinion of pathologic
results
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Core needle biopsy Routine use not recommended Not discussed Not discussed
If repeat FNA
cytology, molecular If radiographic
Diagnostic surgery High-risk indeterminate lesions testing, or both are suspicion of
not performed or malignancy not high
inconclusive
If high clinical and/or
Therapeutic surgery NA NA radiographic suspicion
of malignancy
aspiration; NA, not available; NCCN, National Comprehensive Cancer Network.
Endocrinologi (AACE/ACE/AME) recommendations for the management of atypia or follicular lesions of
undetermined significance (AUS/FLUS) or follicular neoplasm/suspicious for follicular lesions (FN/SFN)
base the management of indeterminate thyroid nodules on the combination of (AACE/ACE/AME
Grade A, Level 2)
cytologic subclassification
clinical data
ultrasound features
consider elastography, when available, for additional information (AACE/ACE/AME Grade B, Level
2)
consider the available technical resources and patient preferences (AACE/ACE/AME Grade D, Level
4)
management based on subclasses of indeterminate cytologic findings
low-risk indeterminate lesions (AUS/FLUS, Thy 3a, or TIR 3A category nodules)
consider conservative management in the case of favorable clinical criteria, such as
personal or family history
lesion size
low-risk ultrasound and elastography features
repeat FNA for further cytologic assessment, and review the samples with an experienced
cytopathologist (AACE/ACE/AME Grade B, Level 3)
routine use of core needle biopsy not recommended (AACE/ACE/AME Grade D, Level 4)
no recommendations for or against routine use of molecular markers in this category
high-risk indeterminate lesions (FN/SFN, Thy 3f, or TIR 3B category nodules)
perform surgery for most nodules in this category (AACE/ACE/AME Grade A, Level 2)
thyroid lobectomy plus isthmectomy is recommended; total thyroidectomy may be
performed, depending on the clinical situation, coexistence of bilateral thyroid nodules, or
patient preference (AACE/ACE/AME Grade A, Level 2)
frozen sections are usually not useful in this group (AACE/ACE/AME Grade D, Level 3)
consider close clinical follow-up in a minority of cases with favorable clinical and
ultrasound features after multidisciplinary consultation and discussion of treatment options
with patient (AACE/ACE/AME Grade C, Level 4)
American Thyroid Association (ATA) recommendations for management of AUS/FLUS nodules(2)
instead of proceeding to surveillance strategy or diagnostic surgery, to further assess malignancy risk
consider either of
repeat FNA biopsy (ATA Weak recommendation, Moderate-quality evidence)
molecular testing (ATA Weak recommendation, Moderate-quality evidence)
management based on results of molecular diagnostics
7-gene molecular panel
if positive, perform initial oncologic thyroidectomy
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usually single-stage total thyroidectomy due to high risk of malignancy,

especially if positive for BRAF, RET/PTC, and/or PAX8-PPARgamma
mutations
consider complete lobectomy for lower-risk cancer
if negative
consider diagnostic thyroidectomy (at least complete lobectomy) if high
institutional prevalence of malignancy in FLUS lesions, or if clinical
suspicion for malignancy
observation and/or repeat FNA are alternatives if low local prevalence
of malignancy in FLUS lesions, and clinical and ultrasound features
indicate very low risk for malignancy
gene expression classifier (GEC)
if GEC-suspicious, perform at least diagnostic thyroid lobectomy (total
thyroidectomy may be indicated based on other clinical conditions)
if GEC-benign, consider active surveillance, but perform diagnostic
thyroidectomy if otherwise clinically indicated or if high institutional
prevalence of malignancy in FLUS lesions
If repeat FNA cytology, molecular testing, or both are not performed or inconclusive, consider either of
surveillance or diagnostic surgical excision depending on (ATA Strong recommendation, Low-quality
evidence)
clinical risk factors
sonographic pattern
patient preference
National Comprehensive Cancer Network (NCCN) recommendations for management of AUS/FLUS
nodules(3)
if high clinical and/or radiographic suspicion of malignancy (based on rapid growth of nodule,
imaging, physical exam, age, clinical history of radiation, and family history), consider lobectomy or
total thyroidectomy for definitive diagnosis and treatment (NCCN Category 2A)
if radiographic suspicion of malignancy not high, other options include (NCCN Category 2A)
diagnostic lobectomy
molecular testing
repeat FNA
active surveillance
Evidence
vascularization may be more predictive of malignancy than other individual ultrasound features in
thyroid nodules with follicular lesions of undetermined significance (AUS/FLUS) cytology (level 2
based on systematic review of diagnostic studies limited by heterogeneity
systematic review of 14 cohort studies evaluating ultrasound in 2,405 thyroid nodules with follicular
lesions of undetermined significance (FLUS) cytology on biopsy
reference standards included surgery in all studies plus repeat fine needle aspiration (FNA) biopsies in
some studies
for detection of malignancy
any suspicious feature on ultrasound in pooled analysis of all studies had (results limited by
significant heterogeneity)
including increased vascularization as a suspicious feature in pooled analysis of 3 studies had
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Reference - Medicine (Baltimore) 2017 Apr;96(16):e6564 full-text
addition of GEC testing to ultrasound might correctly diagnose nodules of indeterminate cytology with
solid and hypoechoic features (level 2 [mid-level] evidence)
119 patients with thyroid nodules > 1 cm of indeterminate cytology (follicular lesions of undetermined
significance [FLUS]) after ultrasound and first fine needle aspiration [FNA] biopsy) were evaluated
52 nodules of FLUS cytology confirmed on second FNA biopsy had samples analyzed by gene
expression classifier (GEC) and ultrasound
67% of repeat biopsy samples were malignant by histologic confirmation after surgery
diagnostic performance for detection of malignancy after repeat biopsy
of ultrasound in FLUS nodules with both solid and hypoechoic features
sensitivity 71.8%
specificity 88.2%
of GEC in FLUS nodules
sensitivity 96.9%
specificity 81.2%
Reference - Endocr Pract 2016 Oct;22(10):1199
about one-third of thyroid nodules classified as FLUS on FNA may be malignant, but absence of
nuclear atypia may identify those at lower risk (level 2 [mid-level] evidence)
127 patients with thyroid nodule > 0.5 cm classified as atypia or follicular lesion of undetermined
significance (AUS/FLUS) on FNA biopsy and treated with surgical excision were assessed
43 nodules (34%) confirmed malignant by histology
features of nuclear cytology associated with malignancy included
pseudoinclusions (p = 0.0001)
overlap or crowding (p = 0.0006)
grooves or irregular nuclear membranes (p = 0.016)
enlargement (p = 0.021)
malignancy in 100% with all 4 features, and in 13.5% with 0 features
cytologic features independently associated with malignancy included
nuclear pseudoinclusions (adjusted odds ratio [OR] 7.8, 95% CI 1.5-39.8)
nuclear overlap or crowding (adjusted OR 3.1, 95% CI 1.4-7)
Reference - Diagn Cytopathol 2014 Jan;42(1):18
rates of malignancy in thyroid nodules with AUS/FLUS cytology could be higher in individual centers
review of 541 biopsy samples of thyroid nodules classified as AUS/FLUS cytology
follow-up histology available for 381 samples, including 96 samples after repeat FNA biopsy
surgically confirmed malignancy rates
39% overall
26.3% in 31 patients who had nodule resected after repeat FNA
Reference - Thyroid 2014 May;24(5):832 full-text
negative result on fluorodeoxyglucose-positron emission tomography (FDG-PET) may help rule out thyroid
cancer in patients with indeterminate FNA biopsy of thyroid nodule, especially in lesions > 15 mm (level 2
Follicular or Hurthle cell neoplasm
also called suspicious for follicular or Hurthle cell neoplasm(3)

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Bethesda criteria include crowded and overlapping follicular cells, some or most of which are arranged as
microfollicles(4)
risk of malignancy 25%-40%
Recommendations
lobectomy (plus isthmectomy), or total thyroidectomy (preferred if Hurthle cell, history of radiation, or
contralateral lobe lesions) is recommended for most patients, particularly if high clinical suspicion of
malignancy (AACE/ACE/AME Grade A, Level 2; ATA Strong recommendation, Low-quality evidence;
NCCN Category 2A)(1, 2, 3)
other options for evaluation of follicular or Hurthle cell neoplasm(2, 3)
consider molecular diagnostics
consider molecular testing before proceeding to diagnostic surgical excision (ATA Weak
American Thyroid Association (ATA) recommended management of follicular neoplasm based
on results of molecular diagnostics
usually single-stage total thyroidectomy due to high risk of malignancy
consider lobectomy for low-risk cancer
if negative, perform at least a diagnostic thyroid lobectomy (more extensive surgery
[including total thyroidectomy] may be indicated based on other clinical conditions)
gene expression classifier (GEC)
if GEC-suspicious, perform at least a diagnostic thyroid lobectomy (more extensive
surgery [including total thyroidectomy] may be indicated based on other clinical
conditions)
if GEC-benign, consider active surveillance, but perform diagnostic thyroid
lobectomy if otherwise clinically indicated or if high institutional prevalence of
malignancy in nodules with follicular neoplasm cytology
close clinical follow-up may be considered in highly select cases with favorable clinical and ultrasound
features after multidisciplinary consultation and discussion of treatment options with patient
(AACE/ACE/AME Grade C, Level 4; NCCN Category 2A)
intraoperative frozen sections not recommended (AACE/ACE/AME Grade D, Level 4)(1)
in pregnant women, surgery can be deferred until after delivery (AACE/ACE/AME Grade B, Level 3)(1)
Suspicious cytology
overview(1)
Bethesda criteria includes
samples with cellularity suspicious for
metastatic carcinoma
lymphoma
samples with inadequate cellularity but cellular features strongly suggestive of malignancy
risk of malignancy 50%-75 %, with papillary carcinoma being the most frequent histologic type
suspicious cytology category includes samples characterized by cytologic features that are suggestive
of but do not fulfill the criteria for a definite diagnosis of malignancy
recommendations(1, 2, 3)
surgery recommended (AACE/ACE/AME Grade A, Level 1; ATA Strong recommendation, Low-
quality evidence; NCCN Category 2A), consider intraoperative frozen section(AACE/ACE/AME
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Grade B, Level 3)
consider repeat of FNA biopsy if inadequate cellularity or requiring additional techniques for better
characterization (AACE/ACE/AME Grade B, Level 3)(1)
ATA recommendations for evaluation of suspicious thyroid nodules with molecular diagnostics(2)
molecular diagnostics (7-gene molecular panel or BRAF mutation) may be considered if
expected to alter extent of surgery (ATA Weak recommendation, Moderate-quality evidence)(2)
usually initial total thyroidectomy due to high risk of malignancy
consider lobectomy for low-risk cancer
if negative, perform at least a diagnostic thyroid lobectomy (more extensive surgery
[including total thyroidectomy] may be indicated based on other clinical conditions)
gene expression classifier not routinely recommended for suspicious cytology, but may be
requested if clinically indicated
Reference - ATA statement on surgical application of molecular profiling for thyroid nodules
(Thyroid 2015 Jul;25(7):760)
Malignant cytology
Bethesda criteria includes cellularity findings consistent with
poorly differentiated carcinoma
undifferentiated (anaplastic) carcinoma
squamous cell carcinoma
carcinoma with mixed features (to be described)
risk of malignancy 97-99%
recommendations(1, 2, 3)
surgery generally recommended for nodules with cytology diagnostic of differentiated thyroid
carcinoma, including papillary thyroid cancer (AACE/ACE/AME Grade A, Level 1; ATA Strong
recommendation, Moderate-quality evidence; NCCN Category 2A)(1, 2, 3)
further diagnostic workup recommended before surgery if anaplastic carcinoma, metastatic cancer, or
lymphoma (AACE/ACE/AME Grade A, Level 2; NCCN Category 2A)(1, 3)
American Thyroid Association (ATA) recommends initial oncologic thyroidectomy for nodules with
any cytology (including benign or nondiagnostic cytology) that tests positive on 7-gene molecular
panel (Thyroid 2015 Jul;25(7):760 full-text)
active surveillance may be considered as alternative to immediate surgery in select cases including
patients with very low risk tumors (for example, a papillary microcarcinoma with no evidence of
local invasion, metastases, or aggressive cytology)
patients with high surgical risk due to comorbid conditions
relatively short remaining life expectancy
concurrent medical or surgical needs to be addressed prior to surgery
for additional information, see
Papillary thyroid cancer
Follicular thyroid cancer
Medullary thyroid cancer
Anaplastic thyroid cancer
Management by modality
Conservative management
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American Thyroid Association (ATA) recommendations for monitoring nodules not meeting criteria for FNA
biopsy based on sonographic features and size(2)
consider repeat ultrasound after
6-12 months in nodules with high suspicion pattern (ATA Weak recommendation, Low-quality
evidence)
12-24 months in nodules with intermediate suspicion pattern (ATA Weak recommendation, Low-
quality evidence)
≥ 24 months in nodules with very low suspicion pattern and > 1 cm
nodules ≤ 1 cm with very low suspicion pattern (spongiform or purely cystic nodules) may not require
routine follow-up by ultrasound (ATA Weak recommendation, Low-quality evidence)
National Cancer Center Network (NCCN) recommendations for nodules not meeting criteria for fine needle
aspiration (FNA) biopsy, or nodules that appear benign by scan or FNA biopsy (NCCN Category 2A)(3)
repeat ultrasound every 6-12 months
if stable for 1-2 years, consider repeat ultrasound every 3-5 years
recommendations for monitoring nodules demonstrating non-diagnostic cytology on FNA(1)
consider clinical and ultrasound follow-up for
solid nodules with clearly favorable clinical and US features (AACE/ACE/AME Grade C, Level
3)
persistently nondiagnostic predominantly cystic (> 50%) nodules (AACE/ACE/AME Grade C,
Level 3)
recommendations for monitoring nodules demonstrating benign cytology on FNA(1)
Medici Endocrinologi (AACE/ACE/AME) recommendations for long-term follow-up of nodules with
benign cytology on FNA
consider repeating
clinical examination, ultrasound, and serum thyrotropin (TSH) after 12 months
if nodules are unchanged at first ultrasound, repeat the followup ultrasound at 24 months
consider repeat fine needle aspiration (FNA) biopsy in nodules with
suspicious clinical or ultrasound features (AACE/ACE/AME Grade B, Level 3)
> 50% increase in volume or symptoms (AACE/ACE/AME Grade A, Level 2)
asymptomatic nodules that have benign cytology on repeated FNA with no suspicious clinical or
ultrasound features may not need routine follow-up (AACE/ACE/AME Grade D, Level 3)
American Thyroid Association (ATA) recommendations for long-term follow-up of nodules with
benign cytology on FNA based on ultrasonographic features(2)
repeat ultrasound and ultrasound-guided FNA within 12 months in nodules with high suspicion
patterns (ATA Strong recommendation, Moderate-quality evidence)
consider repeat ultrasound at (ATA Weak recommendation, Low-quality evidence)
12-24 months in nodules with low to intermediate suspicion pattern
≥ 24 months or not at all in nodules with very low suspicion patterns
consider repeat FNA in nodules with (ATA Weak recommendation, Low-quality evidence)
20% increase in ≥ 2 dimensions with ≥ 2 mm total increase
> 50% change in volume
routine follow-up not necessary for asymptomatic nodules after 2 results of benign cytology on
ultrasound-guided FNA (AACE/ACE/AME Grade D, Level 3; ATA Strong recommendation,
Moderate-quality evidence)(1, 2)
factors associated with thyroid nodule growth include age < 45 years, ≤ 3 pregnancies in women, and
nodule volume
992 patients with 1,567 solid or mixed solid/cystic benign thyroid nodules treated at thyroid disease
centers in Italy were followed for 5 years
nodule size
remained stable in 69%
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spontaneously shrank in 18.5%

increased (defined as increase ≥ 20% across ≥ 2 diameters and increase ≥ 2 mm) in 11.1%
5 nodules (0.3%) developed into malignancy (2 nodules had increased in size)
factors associated with increased nodule growth
≤ 3 pregnancies in females (odds ratio [OR] 3, 95% CI 1.1-8.6)
volume of largest nodule ≥ 1 mL (OR 2.9, 95% CI 1.7-4.9)
2 nodules (OR 2.2, 95% CI 1.4-3.4)
male sex (OR 1.7, 95% CI 1.1-2.6)
factors associated with decreased nodule growth
age ≥ 60 years (OR 0.5, 95% CI 0.3-0.9)
body mass index (BMI) ≥ 25 m2 and < 27 m2 (OR 0.4, 95% CI 0.2-0.7)
Reference - JAMA 2015 Mar 3;313(9):926
follow-up ultrasound for assessment of growth of benign thyroid nodules may have limited utility for
prediction of thyroid cancer in patients without history of thyroid cancer (level 2 [mid-level] evidence)
based on systematic review of diagnostic cohort studies without blinding
systematic review of 7 studies evaluating growth of benign thyroid nodules during follow-up with
ultrasound in 2,438 patients with benign thyroid nodules but without history of thyroid cancer
reference standards were repeat fine needle aspiration biopsy (all studies) or surgical histopathology (4
studies)
in most studies, biopsy or histology performed only for suspicious nodules (based on ultrasound or
other modality)
definition of significant growth varied across studies (increase in volume > 50% and/or increase by >
20% plus 2 mm in 4 studies, increase in size ≥ 3 mm in 1 study, not defined in 2 studies)
follow-up ranged from 3 months to 5 years
pooled performance of significant growth for predicting thyroid cancer
using repeat fine needle aspiration biopsy reference standard
positive likelihood ratio 1.8 (95% CI 0.48-6.4), results limited by significant heterogeneity
diagnostic odds ratio 2.2 (95% CI 0.26-18), results limited by significant heterogeneity
using surgical histopathology reference standard
diagnostic odds ratio 0.58 (95% CI 0.26-1.3)
Reference - Clin Endocrinol (Oxf) 2016 Jul;85(1):122
malignant nodules may be more likely to grow ≥ 2 mm per year among nodules monitored by
ultrasound (level 2 [mid-level] evidence)
1,489 thyroid nodules ≥ 1 cm were evaluated by ultrasound at median 21- to 22-month intervals over
20-year period
all nodules included in analysis were evaluated by ≥ 2 ultrasounds
for malignant nodules ≥ 6 months apart before surgical resection
for benign nodules ≥ 1 year apart
8.5% (126 nodules) malignant by surgical histopathology
increased rate of nodule growth associated with increased risk of malignancy
> 8 mm/year (relative risk [RR] 5.05, 95% CI 2.02-12.65)
> 6-8 mm/year (RR 4.49, 95% CI 2.13-9.45)
> 4-6 mm/year (RR 2.48, 95% CI 1.23-5)
> 2-4 mm/year (RR 1.85, 95% CI 1.15-2.98)
malignancy types associated with growth > 2 mm/year include
high-risk thyroid cancer, including medullary thyroid cancer, tall-cell and columnar variants of
PTC, and poorly differentiated thyroid cancer (adjusted odds ratio [OR] 8.69, 95% CI 1.78-
42.34)
intermediate-risk thyroid cancer, including classical papillary thyroid cancer (PTC) and most
PTC variants or minimally invasive follicular or Hurthle cell carcinoma (adjusted odds ratio
[OR] 2.99, 95% CI 1.2-7.47)
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Reference - J Clin Endocrinol Metab 2017 Dec 1;102(12):4642

no significant difference in growth of malignant nodules compared to benign nodules monitored by
ultrasound (level 2 [mid-level] evidence)
263 patients with benign thyroid nodule on FNA biopsy had either immediate thyroidectomy or
ultrasound follow-up
48 patients had immediate thyroidectomy; malignancy confirmed in 2
215 patients followed by ultrasound (most annually) for median 3.3 years
81 patients had thyroidectomy; malignancy confirmed in 11 (5.1% of 215)
89 patients had repeat FNA biopsy; 87% due to increased size of nodule; malignancy confirmed
in 8
comparing malignant nodules vs. benign nodules
preoperative size of nodule 4.14 cm vs. 3.83 cm (not significant)
mean increase in size of nodule during follow-up 0.57 cm vs. 0.48 cm (not significant)
time between initial FNA biopsy and thyroidectomy 4.3 years vs. 3 years (not significant)
Reference - J Am Coll Surg 2015 Jun;220(6):987, editorial can be found in J Am Coll Surg 2015
Jun;220(6):992
Medications
Levothyroxine
routine suppression of serum thyrotropin (TSH) with levothyroxine not recommended for benign nodules in
iodine-sufficient population (AACE/ACE/AME Grade A, Level 1; ATA Strong recommendation, Moderate-
quality evidence)(1, 2)
consider levothyroxine replacement in young patients with (1)
subclinical hypothyroidism and autoimmune thyroiditis (AACE/ACE/AME Grade A, Level 2)
small nodular goiter and high-normal thyrotropin (TSH) levels who live in iodine-deficient regions,
with or without iodine supplementation (AACE/ACE/AME Grade B, Level 2)
levothyroxine not recommended for(1)
thyroid nodules or goiter during pregnancy (AACE/ACE/AME Grade B, Level 3)
preventing recurrence after lobectomy if TSH remains normal (AACE/ACE/AME Grade A, Level 2)
levothyroxine may reduce volume of thyroid nodules (level 3 [lacking direct] evidence)
based on nonclinical outcome in Cochrane review
systematic review of 31 randomized trials evaluating levothyroxine or minimally invasive therapies in
2,952 patients with benign thyroid nodules
16 trials evaluated levothyroxine
comparing levothyroxine to no treatment or placebo
levothyroxine associated with increase in > 50% nodule volume reduction at 6-24 months in
analysis of 10 trials with 958 patients
risk ratio 1.57 (95% CI 1.04-2.38)
NNT 8-250 with > 50% nodule volume reduction at 6-24 months in 10% of control group
levothyroxine significantly increased hyperthyroidism in 1 of 3 trials
4 trials reported no adverse effects, levothyroxine described as generally well tolerated
pressure symptoms and cosmetic complaints not reported
Reference - Cochrane Database Syst Rev 2014 Jun 18;(6):CD004098
levothyroxine plus potassium iodide may be superior to either monotherapy for reducing nodule
volume in euthyroid patients with 1 or more nodules (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes
1,020 euthyroid patients (aged 18-65 years) with ≥ 1 thyroid nodule ≥ 10 mm randomized to 1 of 4
groups for 1 year
potassium iodide 150 mcg/day
levothyroxine 75 mcg/day
levothyroxine 75 mcg/day plus potassium iodide 150 mcg/day
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placebo
nodule volume reduction
-17.3% with levothyroxine plus potassium iodide (p < 0.05 vs. placebo, levothyroxine, and
potassium iodide)
-7.3% with levothyroxine (not significant vs. placebo)
-4% with potassium iodide (not significant vs. placebo)
thyroid volume reduction
-7.9% with levothyroxine plus potassium iodide (p < 0.05 vs. placebo and potassium iodide)
-5.2% with levothyroxine (p = 0.024 vs. placebo)
-2.5% with potassium iodide (not significant vs. placebo)
Reference - LISA trial (J Clin Endocrinol Metab 2011 Sep;96(9):2786 full-text)
Iodine supplementation
iodine supplementation (150 mcg/day) recommended for all patients with benign, solid, or mostly solid
nodules if dietary intake is found or suspected to be inadequate (ATA Strong recommendation, Moderate-
quality evidence)(2)
Radioactive iodine
overview of radioiodine therapy(1)

goals of radioiodine treatment include
ablation of the autonomously functioning areas
restoration of euthyroidism
reduction of goiter size
general info
reported to normalize thyroid function in 85%-100% of patients with hyperfunctioning thyroid
nodules or toxic multinodular goiters
is reported to reduce thyroid/goiter volume, but extent of reduction may vary
40%-50% decrease in thyroid size has been reported after 1 year (50% of reduction in 3
months)
50%-60% decrease in thyroid size has been reported after 3-5 years
about 20% of patients may not respond
effects of radioiodine on thyroid function
euthyroidism often can be restored in many patients due to functioning of residual normal
thyroid tissue
post-radioiodine hypothyroidism
reported to develop in up to 60% of patients after 20 years
may depend on factors such as dose of radioiodine used, follow-up of thyroid function, and
possible autoimmune thyroiditis
immunogenic hyperthyroidism reported to develop in up to 5% of patients receiving radioiodine
treatment for toxic or nontoxic nodular goiter; typically occurs 3-6 months post-treatment due to
induction of thyroid receptor antibodies (TRAbs)
prior to radioiodine administration
ingestion of drugs with high iodine content (for example, amiodarone, which is made from a
saturated solution of potassium iodide) may impair radioiodine uptake by thyroid and should be
avoided
antithyroid drugs (for example, propylthiouracil or methimazole) should be discontinued ≥ 1
week before treatment if feasible
discontinuation helps to prevent radioiodine uptake by normal thyroid tissue and increase
uptake in hot, hyperfunctioning, thyroid tissue
antithyroid drugs may also decrease treatment efficacy during first week after therapy
radioiodine treatment may be best suited for patient populations including
those with small- to medium-sized benign goiters
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those with previously treated surgically

those with serious comorbid conditions
those who decline surgery
patient populations for which radioiodine is not well-suited include
those with large nodules (more likely to require high doses of radioiodine or not respond to
treatment)
those for whom immediate reversal of hyperthyroidism is preferred
radioiodine therapies are contraindicated for use during pregnancy or breastfeeding; pregnancy should
be excluded by pregnancy test before planning treatment
lower age limit for radioiodine therapy has not been established
adverse effects
early adverse effects of radioiodine are generally mild and transient; they include
radiation thyroiditis in approximately 3% of cases
transient thyrotoxicosis in 5%
occasionally an increase in thyroid size of up to 25%
late adverse effects
hypothyroidism is reported in 22 to 58% of cases within 5 to 8 years post-therapy
increased risk of malignancy is not established (no large-scale studies have been
conducted)
no studies which compare radioiodine vs. surgery have been conducted and few studies report on
quality-of-life measures
recommendations for radioiodine therapy(1)
radioiodine therapy recommended for hyperfunctioning or symptomatic goiter, especially in patients
(AACE/ACE/AME Grade A, Level 2)(1)
with previous thyroid surgery
at high risk with surgery
who decline surgery
radioactive agents are contraindicated in pregnancy(1)
do NOT use radioiodine therapy in pregnant or breastfeeding women (AACE/ACE/AME Grade
A, Level 2)
perform pregnancy test before starting radioiodine therapy in women of childbearing age
treatment considerations(1)
perform ultrasound-guided fine needle aspiration (FNA) biopsy on coexisting cold nodules
before starting treatment in cases of nontoxic multinodular goiter (AACE/ACE/AME Grade B,
Level 3)
do not use iodine contrast agent or iodinated drugs before radioiodine therapy
stop antithyroid drugs 4-7 days before radioiodine treatment and consider resuming 1 week after
after treatment(1)
monitor thyroid function regularly (AACE/ACE/AME Grade A, Level 2)
treatment may be repeated after 3-6 months if persistent or recurrent hyperthyroidism or if
inadequate size reduction (AACE/ACE/AME Grade B, Level 3)
Surgery and surgical procedures
Surgical resection
Overview of surgical resection
primary goal of thyroid surgery for a thyroid nodule that is cytologically indeterminate (AUS/FLUS or
FN/SFN or SUSP) is(2)
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to establish a histological diagnosis and definitive removal

reducing the risks associated with remedial surgery in the previously operated field if the nodule proves
to be malignant
surgical options include(2)
lobectomy (hemithyroidectomy) with or without isthmectomy
provides histologic data for definitive diagnosis and complete tumor removal for cytologically
indeterminate nodules
risk of complications reported to be lower than total thyroidectomy
about 22% of cases associated with postoperative hypothyroidism (4% of surgeries associated
with overt or clinical hypothyroidism)
increased risk of hypothyroidism has been reported with findings including
thyroid peroxidase antibodies (TPOAbs) (indicating autoimmune thyroid disease)
high normal or elevated thyrotropin (TSH)
near-total thyroidectomy
described as removal of all grossly visible thyroid tissue
leaves < 1 g of tissue adjacent to the recurrent laryngeal nerve near the ligament of Berry
total thyroidectomy (removal of all grossly visible thyroid tissue)
necessitates thyroid hormone replacement
comparing total thyroidectomy vs. lobectomy, thyroidectomy reported to have higher risks of
complications including
recurrent laryngeal nerve injury (transient relative risk [RR] 1.7, permanent RR 1.9)
hypocalcemia (transient RR 10.7, permanent RR 3.2)
hemorrhage or hematoma (RR 2.6)
bilateral recurrent laryngeal nerve injury (necessitating tracheostomy) has been rarely reported
with total thyroidectomy
hypothyroidism does not necessarily preclude doing a lobectomy, and decision to perform total
thyroidectomy over lobectomy should be balanced with the higher risk
practices which should be avoided include(2)
removal of the nodule alone
partial lobectomy
subtotal thyroidectomy
leaving > 1 g of tissue with the posterior capsule on the uninvolved side
considerations during thyroid surgery
both general and locoregional anesthesia can be used for thyroidectomy, and there is limited evidence
to support the use of any anesthetic technique over another
perioperative use of antiemetics (such as dexamethasone 8-10 mg IV) help prevent postoperative
nausea and vomiting
intraoperative nerve monitoring with a dual-channel electromyographic endotracheal tube can be used
during thyroid surgery to monitor the laryngeal nerves
despite lack of definitive evidence that laryngeal nerve monitoring prevents nerve injuries, it may
be useful for patients having outpatient thyroidectomy
may help identify recurrent laryngeal nerve complications, but does not appear to prevent vocal
cord injury except potentially in high-risk patients having surgery for cancer
hemostasis
use of LigaSure vessel-sealing device for thyroidectomy may reduce operation time compared to
conventional ligation (level 2 [mid-level] evidence)
harmonic scalpel for hemostasis associated with decreased operation time and blood loss
compared with other hemostatic techniques in patients having thyroid surgery (level 2 [mid-
level] evidence)
using drains in patients having thyroid surgery does not appear to improve outcomes and may increase
length of hospital stay (level 2 [mid-level] evidence)
transoral thyroidectomy is a minimally invasive approach to the thyroid gland that avoids the physical
and psychological effects of postoperative scarring
video-assisted thyroidectomy may reduce risk of early post-thyroidectomy voice and swallowing
symptoms (level 2 [mid-level] evidence)
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see Thyroid surgery considerations for details
Preoperative preparation
perioperative assessments(1)
preoperative evaluation should include (AACE/ACE/AME Grade A, Level 2)
review ultrasound and cytologic results with the patient; discuss treatment options and consult
with surgeon who has experience with endocrine surgery
perform ultrasound of neck to evaluate any neck adenopathy for surgical planning and perform
fine needle aspiration (FNA) biopsy of any additional suspicious nodule or lymph node
if there are suspicious ultrasound features, confirm metastatic involvement of lymph nodes by
measuring thyroglobulin or calcitonin on washout of FNA biopsy
perform vocal cord assessment with laryngoscopy
consider magnetic resonance imaging (MRI), computed tomography (CT), and/or positron emission
tomography (PET) scan in select cases for more accurate preoperative staging of malignant nodules
with aggressive features (AACE/ACE/AME Grade B, Level 3)
Recommendations for surgical resection
consider surgical excision for histopathologic diagnosis of persistently nondiagnostic nodules

that are solid and hypoechoic (AACE/ACE/AME Grade B, Level 3)
with high suspicion pattern on ultrasound, rapid growth (> 20% in 2 dimensions), or clinical risk
factors for malignancy are present (ATA Weak recommendation, Low-quality evidence)
without high suspicion pattern on ultrasound as alternative to close observation (ATA Weak
indications for surgery of benign nodules include(1, 2)
rapid growth (defined as > 50% increase in volume or 20% increase in 2 dimensions and > 2 mm) and
> 4 cm in size (ATA Weak recommendation, Low-quality evidence; NCCN Category 2A)
causing compressive or structural symptoms (AACE/ACE/AME Grade B, Level 2; ATA Weak
development of suspicious ultrasound features despite benign FNA findings (AACE/ACE/AME Grade
B, Level 2)
indications for surgery of indeterminate nodules(1, 2)
Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME)
surgery is recommended for most high-risk indeterminate thyroid nodules (AACE/ACE/AME
Grade A, Level 2)
thyroid lobectomy plus isthmectomy is recommended; total thyroidectomy may be performed,
depending on the clinical situation, coexistence of bilateral thyroid nodules, or patient preference
frozen sections may not be useful (AACE/ACE/AME Grade D, Level 3)
diagnostic surgical excision is an option for atypia of undetermined significance (AUS/FLUS)
thyroid nodules if (ATA Strong recommendation, Low-quality evidence)
appropriate based on clinical risk factors, sonographic pattern, and patient preference
repeat FNA cytology and/or molecular testing are not performed or inconclusive
thyroid lobectomy is the preferred method but may be modified based on clinical or ultrasound
features, patient preference, and/or molecular testing (ATA Strong recommendation, Moderate-
quality evidence)
because of increased risk for malignancy, total thyroidectomy is preferred in patients with
indeterminate nodules and ≥ 1 of (ATA Strong recommendation, Moderate-quality evidence)
cytologically suspicious for malignancy
positive for known mutations specific for carcinoma
sonographically suspicious
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large (> 4 cm)

familial thyroid carcinoma or history of radiation exposure
patients with indeterminate nodules may opt for total or near-total thyroidectomy if ≥ 1 of (ATA
Weak recommendation, Low-quality evidence)
bilateral nodular disease
significant medical comorbidities
desire to avoid a future surgery
indications for surgery of nodules with suspicious for malignancy cytology(1, 2)
according to AACE/ACE/AME
surgical management of nodules with suspicious cytology is recommended (AACE/ACE/AME
Grade A, Level 1)
if inadequate cellularity on biopsy, consider repeat FNA to obtain improved characterization
intraoperative frozen sections may be considered (AACE/ACE/AME Grade B, Level 3)
according to ATA
surgical management of thyroid nodules with suspicious cytology should be similar to
management with malignant cytology but may depend on clinical risk factors, ultrasound
findings, patient preference, and mutational testing (if performed) (ATA Strong recommendation,
consider mutational testing for BRAF or 7-panel gene testing if would alter surgical decision-
making (ATA Weak recommendation, Moderate-quality evidence)
indications for surgery of nodules with malignant cytology(1, 2)
according to AACE/ACE/AME
surgery is recommended for differentiated thyroid carcinoma, including papillary thyroid cancer
and follicular thyroid cancer (AACE/ACE/AME Grade A, Level 1)
further diagnostic work-up before surgery recommended for anaplastic thyroid cancer, metastatic
lesions, or thyroid lymphoma (AACE/ACE/AME Grade B, Level 3)
according to ATA
surgery recommended for nodules of malignant cytology (ATA Strong recommendation,
completion thyroidectomy should be offered to patients for whom a bilateral
thyroidectomy would have been recommended if diagnosis had been available before
initial surgery
include therapeutic lymph node dissection if lymph nodes are clinically involved
consider thyroid lobectomy for treatment of low-risk papillary thyroid cancer or follicular
thyroid cancer
radioactive iodine ablation therapy should not routinely be substituted for thyroidectomy but may
be used to ablate the remnant lobe in some cases (ATA Weak recommendation, Moderate-quality
evidence)
type of surgery(1, 2)
perform thyroid lobectomy on most cytologically indeterminate nodules without high risk features
(ATA Strong recommendation, Moderate-quality evidence)
assuming that complete thyroidectomy would be recommended if proven malignancy following
lobectomy, total thyroidectomy may be preferred for nodules with indeterminate cytology with
characteristics including
nodules with carcinoma-specific mutations (ATA Strong recommendation, Moderate-quality
evidence)
nodules with suspicious sonographic features (ATA Strong recommendation, Moderate-quality
evidence)
nodule of large size (> 4 cm) (ATA Strong recommendation, Moderate-quality evidence)
nodules in patients with familial thyroid carcinoma or history of radiation exposure (ATA Strong
bilateral nodular disease, significant comorbidities, or patient preference to avoid possible future
surgeries (ATA Weak recommendation, Low-quality evidence)
extent of resection for goiters (AACE/ACE/AME Grade A, Level 2)
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lobectomy plus isthmectomy for benign uninodular goiter

(near) total thyroidectomy for multinodular goiter
Radiofrequency and laser ablation
overview of radiofrequency and laser ablation(1)

nonsurgical, outpatient procedures may serve as alternative to surgery for solid or complex thyroid
nodules that have excessive growth, symptoms, or are associated with cosmetic concerns
radiofrequency ablation (RFA)
radiofrequency ablation induces thermal injury to the nodule through a high frequency
alternating electric current
procedure requires conscious sedation of patient (with IV diazepam) and local anesthesia (with
lidocaine or ropivacaine delivered by subcutaneous pericapsular infiltration)
2 types of electrodes are used for RFA of thyroid nodules
a multi-tined expandable electrode (14-gauge with 4-9 expandable hooks)
straight, internally cooled electrode (17- or 18-gauge)
radiofrequency ablation methods
18-gauge electrode needle that is straight, internally cooled, short (7 centimeters) and with
active tips of various sizes is typically used for thyroid nodule ablation
performed using "moving shot" technique, where the nodule is divided into multiple
virtual areas and each unit of nodule is ablated; maneuver is repeated (without retreating
from nodule) until all areas are ablated
ablation may be confirmed by appearance of a hyperechogenic area (created due to
microbubble production) and an abrupt increase in impedance on radiofrequency generator
monitor
adverse effects or major complications, such as severe pain or recurrent nerve palsy, reported to
be rare and transient
ultrasound-guided laser thermal ablation (LTA)
performed with local anesthesia as an outpatient procedure
method
fine (21-gauge) spinal needle is inserted into the target nodule
300-nm optical fibers from a neodymium-doped yttrium aluminum garnet (NdYAG) or
diode laser deliver energy to the nodule for about 10 minutes
single treatment with 1-2 fibers reported to decrease nodule volume and alleviate local symptoms
reported to be well-tolerated and efficacious for persistent reduction of large, benign nodules
recommendations for radiofrequency and laser ablation(1)
consider laser or radiofrequency ablation for the treatment of solid or complex thyroid nodules that
progressively enlarge, are symptomatic, or cause cosmetic concern (AACE/ACE/AME Grade C, Level
2)
repeat FNA for cytologic confirmation before ablative treatments (AACE/ACE/AME Grade B, Level
3)
discuss alternative therapy options and their efficacy, limitations, and adverse effects with the patient
consider laser or radiofrequency ablation for treatment of solid or complex thyroid nodule with ≥ 1 of
progressive increase in size
pressure symptoms
cosmetic concerns
consider repeating FNA for cytologic confirmation prior to thermal ablation treatment
evidence for radiofrequency ablation
radiofrequency ablation for benign thyroid nodules has limited evidence for improving pressure
symptoms in randomized trials
based on Cochrane review
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systematic review of 31 randomized trials evaluating levothyroxine or minimally invasive

therapies in 2,952 patients with benign thyroid nodules
3 trials evaluated radiofrequency ablation
radiofrequency ablation significantly improved pressure symptoms and reduced nodule volume
compared to no treatment in 1 trial with 40 patients
2 sessions of radiofrequency ablation nonsignificantly reduced nodule volume compared to 1
session in 1 trial with 30 patients
no significant difference in ≥ 50% reduction in nodule volume comparing radiofrequency
ablation compared to percutaneous ethanol injection in 1 trial with 42 patients (event rate was
100% in both groups)
radiofrequency ablation described as generally well tolerated
radiofrequency ablation reported to decrease nodular volume, pressure symptoms, and cosmetic
concerns in patients with benign thyroid nodules (level 3 [lacking direct] evidence)
based on systematic review of mostly observational studies
systematic review of 20 studies (1 randomized trial and 19 cohort studies) evaluating
radiofrequency ablation in 1,090 patients with 1,406 benign thyroid nodules
compared to baseline, radiofrequency ablation associated with (all limited by significant
heterogeneity)
decrease in nodular volume at
6 months (standard mean difference [SMD] 1.25, 95% CI 0.9-1.59) in analysis of 15
studies
12 months (SMD 4.16, 95% CI 2.25-6.07) in analysis of 6 studies
decrease in symptoms (SMD 3.11, 95% CI 2.28-3.94) in analysis of 16 studies
improved cosmetic concerns (SMD 2.77, 95% CI 2.18-3.36) in analysis of 12 studies
Reference - Medicine (Baltimore) 2016 Aug;95(34):e4659 full-text
radiofrequency ablation may reduce nodule volume more than laser ablation in patients with
benign solid thyroid nodules (level 3 [lacking direct] evidence)
based on systematic review of studies with nonclinical outcomes
systematic review of 10 studies (8 trials and 2 case series) evaluating radiofrequency ablation
and/or laser ablation in 184 patients with benign solid thyroid nodules
all trials compared ablation to control or 1 vs. 2 treatment sessions with same ablation technique
(no trials directly compared radiofrequency ablation to laser ablation)
pooled mean decrease in nodule volume from baseline at 6 months
76.1% (95% CI 70.1%-82.1%) with radiofrequency ablation in pooled analysis of 4 studies
with 65 patients
49% (95% CI 41.1%-58.5%) with laser ablation in pooled analysis of 8 studies with 119
patients
compared to laser ablation, radiofrequency ablation associated with greater decrease in nodule
volume at 6 months (mean difference 28.3%, 95% CI 3.4%-53.3%) in pooled analysis of 7 trials
1 session of radiofrequency ablation may relieve pressure symptoms as effectively as 2 sessions in
patients with benign solid thyroid nodules (level 2 [mid-level] evidence)
based on small randomized trial
30 patients with benign solid thyroid nodules randomized to radiofrequency ablation in 1 vs. 2
sessions and followed up to 6 months
radiofrequency ablation performed with 18-gauge internally cooled electrode with
ultrasonographic guidance
both groups improved from baseline in nodule volume reduction, pressure symptom scores, and
cosmetic scores (p < 0.001 for all)
no significant differences between groups
2 sessions of radiofrequency ablation associated with nonsignificant decrease in nodule volume
(p = 0.078)
Reference - Radiology 2012 Jun;263(3):909
evidence for laser ablation
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laser photocoagulation may reduce pressure symptoms in patients with benign thyroid nodules
based on Cochrane review of small trials
therapies 2,952 patients with benign thyroid nodules
5 trials evaluated laser photocoagulation
comparing laser photocoagulation to no treatment
laser photocoagulation associated with improvement in pressure symptoms at 6-12 months
(risk ratio 26.65, 95% CI 5.47-129.72) in analysis of 3 trials with 92 patients (no patients
in no treatment group reported improvement)
no significant difference in cervical pain lasting ≥ 48 hours in 2 trials with 71 patients
decreased thyroid nodule volume with
addition of laser photocoagulation to aspiration in 1 trial with 44 patients
3 sessions of laser photocoagulation vs. 1 session in 1 trial with 30 patients
laser photocoagulation described as generally well tolerated
ultrasound-guided laser ablation reported to reduce nodule volume in patients with benign solid
thyroid nodules (level 3 [lacking direct] evidence)
based on randomized trial without direct comparison of groups as randomized
200 patients with benign solid thyroid nodules with volume 6-17 mL were randomized to
ultrasound-guided laser ablation for one session vs. no treatment and followed for 36 months
all patients had normal thyroid function, no autoimmunity, and no prior thyroid treatment
mean change in nodule volume -57% with ultrasound-guided laser ablation vs. +25% with no
treatment (no p value reported for pairwise comparison)
ultrasound-guided laser ablation associated with significant reduction in nodule volume and local
pressure symptoms from baseline
Reference - J Clin Endocrinol Metab 2014 Oct;99(10):3653
interstitial laser photocoagulation following aspiration of benign cystic thyroid nodule may
reduce pressure symptoms and recurrence (level 2 [mid-level] evidence)
based on small randomized trial
44 patients with symptomatic, recurrent, benign cystic thyroid nodule (volume ≥ 2 mL)
randomized to ultrasound-guided single aspiration followed by interstitial laser photocoagulation
(ILP) vs. aspiration only and followed for 6 months
baseline median pressure symptom scores (on visual analog scale [0-10] with higher scores
indicating more severe symptoms) 3 in ILP group and 4 in no ILP group
comparing ILP vs. no ILP
median pressure symptom scores decreased by 3 vs. 0.5 (p = 0.006)
recurrence (cyst volume > 1 mL) in 32% vs. 82% (p = 0.002)
no major adverse events occurred
Reference - J Clin Endocrinol Metab 2013 Jul;98(7):E1213
no randomized trials found evaluating high-intensity focused ultrasound for benign thyroid
nodules
no randomized trials found evaluating microwave ablation for benign thyroid nodules
Percutaneous ethanol injection (PEI)
overview of PEI for thyroid nodules(1)

PEI is considered first-line therapy for relapsing benign cystic nodules
may be especially well-suited for medium-sized relapsing lesions which can be treated with a single or
a few sessions
requires no posttreatment observation, monitoring, or medical support
71/85
procedure does not affect thyroid function (unlike some others) so no risk of developing thyroid
autoimmunity
PEI should not be used to treat
solid nodules, whether hyperfunctioning or not
multinodular goiters (MNGs)
hot nodules
recommendations for treatment of thyroid nodules with PEI(1, 2)
percutaneous ethanol injection recommended for benign cystic or complex thyroid nodules that have a
large fluid component particularly if (AACE/ACE/AME Grade A, Level 1; ATA Weak
recurrent or relapsing
causing pressure symptoms or cosmetic concerns
percutaneous ethanol injection not recommended for treatment of (AACE/ACE/AME Grade A, Level
2)
solitary solid nodules (whether hyperfunctioning or not)
multinodular goiters
hot nodules unless there are compressive symptoms and alternative treatments are not possible
sample any solid component of complex lesions to confirm benign status before performing procedure
evidence for PEI treatment of thyroid nodules
percutaneous ethanol injection may reduce volume of thyroid nodules compared to cyst
aspiration or levothyroxine (level 3 [lacking direct] evidence)
based on nonclinical outcome in Cochrane review
therapies in 2,952 patients with benign thyroid nodules
7 trials evaluated percutaneous ethanol injection (PEI)
comparing PEI to cyst aspiration
PEI associated with
increase in > 50% nodule volume reduction at 1-24 months in analysis of 3 trials
with 105 patients
risk ratio 1.83 (95% CI 1.32-2.54)
NNT 2-7 with > 50% nodule volume reduction at 1-24 months in 44% of cyst
aspiration group
improved neck compression symptoms in 1 trial with 266 patients
no significant difference in slight-to-moderate pain in analysis of 3 trials with 104 patients
PEI significantly increased > 50% nodule volume reduction and nonsignificantly increased
pressure symptom improvement vs. levothyroxine in 1 trial with 50 patients
no significant difference in > 50% nodule volume reduction comparing PEI vs. radiofrequency
ablation in 1 trial with 42 patients (all patients had > 50% reduction nodule volume in both
groups)
Additional Populations
Multinodular thyroid glands
overview of management of multiple nodules(2)

in general, the risk of malignancy with multiple nodules is the same as risk with a solitary nodule
solitary nodules have been reported to have higher likelihood of malignancy per nodule
compared to nonsolitary nodules, but the risk of malignancy per patient is likely the same
slightly higher risk of malignancy in solitary nodules may be limited to areas with high
prevalence of iodine deficiency outside of the United States
multiple nodules ≥ 1 cm may require FNA biopsy as biopsy of solely the largest nodule may miss a
potential malignancy
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practices to choose most appropriate nodules to biopsy include

performing a diagnostic ultrasound to evaluate the sonographic risk pattern of each nodule
individually
radionuclide scanning in patients with low or low-normal TSH to exclude hyperfunctioning
nodules
recommendations for multiple nodules(2)
patients with multiple nodules should be evaluated in similar way as patients with solitary nodules;
since each nodule > 1 cm is at increased risk of malignancy, multiple nodules may require FNA biopsy
(ATA Strong recommendation, Moderate-quality evidence)
perform FNA biopsy of nodules with higher risk ultrasound patterns and/or larger size (ATA Strong
for multiple nodules with low or very low suspicion ultrasound pattern which coalesce with no
intervening normal parenchymal tissue, consider FNA biopsy of any large nodules (> 2 cm) or continue
ultrasound surveillance without FNA (ATA Weak recommendation, Low-quality evidence)
in patients with a low or low-normal serum TSH
multiple nodules suggests presence of ≥ 1 autonomous nodule
consider radionuclide (preferably 123I) scan and directly compare results to ultrasound images to
determine functionality of each nodule ≥ 1 cm
perform FNA biopsy for isofunctioning or nonfunctioning nodules with preference for higher
suspicion patterns on ultrasound
Pregnant women
Endocrinologi recommendations for evaluation and management of pregnant women with thyroid nodules(1)
thyroid nodules in pregnant women should be evaluated and managed similarly to nodules in
nonpregnant patients (AACE/ACE/AME Grade A, Level 2)
for women with suspicious clinical findings or ultrasound results, perform fine needle aspiration (FNA)
since diagnostic criteria are not overly influenced by pregnancy (AACE/ACE/AME Grade A, Level 2)
for nodules that grow substantially or become symptomatic, perform followup ultrasound and FNA if
appropriate (AACE/ACE/AME Grade A, Level 2)
avoid use of radioactive agents for diagnostic or therapeutic purposes during pregnancy or while
breastfeeding (AACE/ACE/AME Grade A, Level 2)
in patients with low TSH levels during second half of pregnancy, postpone radionuclide scanning until
after both delivery and cessation of breastfeeding (AACE/ACE/AME Grade A, Level 2)
thyrotropin (TSH)-suppressive levothyroxine therapy not routinely recommended (AACE/ACE/AME
Grade B, Level 3)
consider iodine supplementation for pregnant women who live in iodine-deficient areas
in pregnant women with thyroid nodules with indeterminate cytology, consider postponing surgery
until after delivery (AACE/ACE/AME Grade B, Level 3)
American Thyroid Association recommendations for evaluation and management of pregnant women with
thyroid nodules(2)
FNA reported to be safe in pregnant women and can be performed in any trimester
decision to perform FNA in pregnant women with thyroid nodule depends on serum TSH level
if TSH levels are suppressed and persisting beyond 16 weeks, FNA may be deferred until after
pregnancy at which time a radionuclide scan can also be performed if TSH remains suppressed
and patient is not breastfeeding (ATA Strong recommendation, Low-quality evidence)
if TSH levels are not suppressed, FNA generally recommended (ATA Strong recommendation,
select nodules for FNA based on nodule's sonographic pattern
clinical assessment of cancer risk or patient preference may influence decision to perform
FNA or delay until after pregnancy
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for patients with indeterminate or malignant cytology (ATA Weak recommendation, Low-quality
evidence)
papillary thyroid cancer in early pregnancy should be monitored by ultrasound
if nodule grows substantially before 24-26 weeks gestation, or if ultrasound reveals cervical
lymph nodes that are suspicious for metastatic disease, consider surgery during pregnancy
if nodule remains stable by midgestation, or if it is diagnosed in the second half of pregnancy,
consider deferring surgery until after delivery
management of malignant nodules during pregnancy(1, 2)
Medici Endocrinologi recommendations for pregnant women with malignant cytology
thyroidectomy may be performed in second trimester if thyroid malignancy discovered during
first or second trimester (AACE/ACE/AME Grade B, Level 3)
if extracapsular growth or lymph nodes metastases, consider surgery during the second trimester
if no evidence of aggressive thyroid cancer, surgical treatment performed soon after delivery is
option unlikely to adversely affect prognosis; clinical and ultrasound monitoring should be
considered (AACE/ACE/AME Grade B, Level 3)
if thyroid malignancy with no aggressive findings discovered during the third trimester, surgical
treatment can be deferred until immediate postpartum period (AACE/ACE/AME Grade C, Level
3)
if surgery is postponed until after delivery in patients with suspicious or malignant nodules,
consider maintaining thyrotropin (TSH) at low-normal levels (for example, 0.5-1.0 milliunits/L)
American Thyroid Association (ATA) expert panels recommendations for pregnant women with
cytology indicating papillary thyroid cancer
monitor nodule by ultrasound and if substantial growth by 24-26 weeks, or lymph nodes suggest
metastatic disease, consider surgery (ATA Weak recommendation, Low-quality evidence)
if nodule is stable at midgestation or discovered in second half of pregnancy, surgery can be
performed after delivery (ATA Weak recommendation, Low-quality evidence)
avoid surgery after 24 weeks gestation to minimize risk of miscarriage if possible
consider administering levothyroxine to keep thyrotropin (TSH) levels in the 0.3-2 milliunits/L
range
see also Thyroid disease in pregnancy
Children
overview of thyroid nodules in children
thyroid nodules are generally uncommon in children, but may have greater risk of malignancy (Thyroid
2015 Jul;25(7):716 full-text)
incidence/prevalence in children
new cases of thyroid cancer in those aged < 20 years represent 1.8% of all thyroid malignancies
diagnosed in the United States
among adolescents aged 15-19 years, thyroid cancer reported to be 8th most frequently
diagnosed cancer and 2nd most common cancer among girls
adolescents reported to have a 10-fold greater incidence of thyroid cancer compared to younger
children
thyroid nodules reported to develop in 5 times as many females as males during adolescence
from ultrasound and postmortem examinations, 1%-1.5% of children and up to 13% of older
adolescents/young adults reported to have thyroid nodules, but unknown if these nodules would
have become clinically apparent
cystic lesions (detected by high resolution ultrasound) were reported in 57% of Japanese children
and adolescents but unclear if other regions may have similar prevalence
References - Thyroid 2015 Jul;25(7):716 full-text
rates of malignancy in thyroid nodules in children exceed comparable rates in adults
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historical rates of malignancy may have been as high as 40% (J Ultrasound Med 2018
Oct;37(10):2311)
more recently, malignancy reported in about 22%-26% of nodules
References - Thyroid 2015 Jul;25(7):716 full-text
risk factors for thyroid nodule in children include
iodine deficiency
history of antecedent thyroid disease
genetic syndromes or conditions
variety of genetic disorders predispose children to neoplasias of thyroid
both benign and malignant thyroid nodules may develop in patients with APC-associated
polyposis, Carney complex, DICER1 syndrome, PTEN hamartoma tumor syndrome, and
Werner syndrome
cases of differentiated thyroid cancer have been reported in Beckwith-Wiedermann
syndrome, familial paraganglioma syndromes, Li-Fraumeni syndrome, McCune-Albright
syndrome, Peutz-Jeghers syndrome
children from families with familial nonmedullary thyroid cancer may be at higher risk of
tumor development
prior radiation exposure, especially in childhood survivors of Hodgkin lymphoma, leukemia, and
central nervous system tumors
thyroid nodules reported to develop at rate of 2% annually and reach peak incidence 15-25
years after exposure to radiation therapy
risk is greatest among those who received radiation therapy at a younger age and with
doses up to 20-29 Gy
general considerations
adult guidelines indicate that FNA is not warranted for evaluation of a nodule < 1 cm in size
unless patient is considered high-risk, most commonly with history of exposure to ionizing
radiation or with regional lymph node pathology
size criteria may not be as useful in children due to age-related changes in volume of the thyroid
ultrasound characteristics and overall clinical context should be used to identify nodules in
children which should have FNA biopsy
ultrasound features such as hypoechogenicity, irregular margins, increased intranodular blood
flow, microcalcifications, and/or abnormal cervical lymph nodes may suggest malignancy
in children with a suspicious nodule, ultrasound evaluation of the cervical lymph nodes should
be performed
FNA biopsy not necessary for hyperfunctioning nodules in children (as with adults) due to
assumption that they will always be surgically removed
FNA biopsy should always be performed with ultrasound guidance especially in children
consider, in particular, for complex cystic lesions which require aspiration of solid portion
of nodule
may reduce the need for repeat FNA in a population in which obtaining repeat samples
could be difficult
no recommendation for measurement of serum calcitonin in children, mainly due to
very low prevalence of sporadic (non-familial) medullary thyroid cancer in children and
adolescents
cost-effectiveness of testing serum calcitonin unknown
papillary thyroid cancer may present differently in children
may present as diffusely infiltrating disease that results in diffuse enlargement of a lobe or
the entire gland
diffuse infiltrating forms of papillary thyroid cancer almost always have
microcalcifications
thus, if there is diffuse thyroid enlargement, especially with palpable cervical lymph nodes,
imaging should be performed
for children with nodules of indeterminate cytology
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this includes any indeterminate cytology (atypia of undetermined significance

[AUS/FLUS] through suspicious categories)
children with nodules of indeterminate cytology are at increased risk of malignancy
thus, definitive surgery (lobectomy plus isthmectomy) is recommended for children
recommendations for thyroid nodules in children
Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME)(1)
evaluation and management of thyroid nodules in children may be similar to adults
consider surgical management of both cold and hot nodules due to greater prevalence of
malignancy in children (AACE/ACE/AME Grade C, Level 3)
the evaluation and treatment of thyroid nodules in children should be the same as in adults,
except that (ATA Grade B)
clinical context and ultrasound characteristics should be used in addition to size in decision
to perform FNA biopsy
consider performing FNA biopsy under ultrasound guidance
preoperative FNA biopsy of a hyperfunctioning nodule in a child is not warranted as long
as the lesion is removed
a diffusely infiltrative form of papillary thyroid cancer may occur in children and should
be considered in a clinically suspicious gland
surgery (lobectomy plus isthmectomy) is favored over repeat FNA biopsy for most
nodules with indeterminate cytology
no recommendation for or against routine use of levothyroxine therapy for children with benign
nodules (ATA Grade I)
in general, evidence supports the efficacy of levothyroxine therapy to reduce size/risk of
subsequent nodules
no evidence supports the potential benefit against the risks of long-term suppression
therapy
in patients with compressive symptoms or a history of radiation exposure, levothyroxine
may be useful
benign lesions should be followed by serial ultrasound (ATA Grade B)
consider repeat FNA if suspicious features develop or if nodule continues to grow
consider lobectomy in children with
compressive symptoms and cosmetic concerns
nodules > 4 cm
nodules demonstrating significant growth
other clinical concerns for malignancy
parental preference for lobectomy
for children with thyroid nodule and a suppressed serum thyrotropin (TSH) level (ATA Grade A)
thyroid scintigraphy should be performed
increased uptake within the nodule suggests autonomous nodular function
surgical resection, usually lobectomy, is recommended for most autonomous nodules in
children and adolescents
Reference - American Thyroid Association guideline for management of thyroid nodule and
differentiated thyroid cancer in children (Thyroid 2015 Jul;25(7):716 full-text)
Screening
ultrasound not suggested for screening general population or in patients with normal thyroid exam who have
low risk of thyroid disease (AACE/ACE/AME Grade C, Level 4)(1)
perform thyroid ultrasound in individuals at increased risk of thyroid cancer including (AACE/ACE/AME
Grade A, Level 2)(1)
76/85
history of head and neck irradiation

family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, or papillary
thyroid carcinoma
United States Preventive Task Force (USPSTF) recommends against screening for thyroid cancer in
asymptomatic adults (USPSTF Grade D, Moderate evidence) (JAMA 2017 May 9;317(18):1882), editorial
can be found in JAMA 2017 May 9;317(18):1840
screening for thyroid nodules associated with low rate of carcinoma detection in patients with Graves
disease
315 consecutive outpatients with Graves hyperthyroidism not previously treated with surgery or
radioiodine therapy were screened with thyroid ultrasonography annually with mean follow-up of 7
years
fine needle aspiration (FNA) performed in patients with nodules and repeated at intervals ≤ 2 years
106 patients (34%) had thyroid nodules ≥ 8 mm
49 patients had nodules at initial exam
57 patients developed nodules during follow-up
FNA cytology results revealed features of carcinoma in 1 patient (0.3%)
Reference - Arch Intern Med 1999 Aug 9-23;159(15):1705, commentary can be found in Arch Intern
Med 2000 May 22;160(10):1540
Quality Improvement
Physician Quality Reporting System Quality Measures
406. Appropriate Follow-Up Imaging for Incidental Thyroid Nodules in Patients

Percentage of final reports for computed tomography (CT) or magnetic resonance imaging (MRI)
studies of the chest or neck or ultrasound of the neck for patients ≥ 18 years old with no known thyroid
disease with a thyroid nodule < 1.0 cm noted incidentally with follow-up imaging recommended
see Physician Quality Reporting System Quality Measures for additional information
Choosing Wisely
American College of Radiology recommends against ultrasound for incidental thyroid nodules found on CT,
magnetic resonance imaging (MRI) or non-thyroid-focused neck ultrasound in low-risk patients unless the
nodule meets age-based size criteria or has suspicious features. (Choosing Wisely 2017 Oct 16)
Society of Nuclear Medicine and Molecular Imaging recommends against using nuclear medicine thyroid
scans to evaluate thyroid nodules in patients with normal thyroid gland function (Choosing Wisely 2013 Feb
21)
Choosing Wisely Canada

Canadian Association of Nuclear Medicine recommends against nuclear medicine thyroid scans to evaluate
thyroid nodules in patients with normal thyroid gland function (Choosing Wisely Canada 2015 Jun 2)
Choosing Wisely Italy
Italian Association of Medical Endocrinologists (AME) recommends against L-thyroxine treatment in

patients with thyroid nodules except in selected cases. (Choosing Wisely Italy 2015 Apr PDF, Choosing
Wisely Italy 2015 Apr PDF [Italian])
Guidelines and Resources
77/85
Guidelines
International guidelines

Endocrinologi (AACE/ACE/AME) guideline on diagnosis and management of thyroid nodules can be found
in Endocr Pract 2016 May;22(5):622 PDF
Society of Nuclear Medicine and Molecular Imaging (SNMMI) practice guideline on therapy of thyroid
disease with iodine 131 (131I) can be found at SNMMI 2012 Oct PDF or in J Nucl Med 2012
Oct;53(10):1633 full-text, commentary can be found in J Nucl Med 2013 Feb;54(2):327
United States guidelines
American Thyroid Association (ATA)

ATA management guideline on children with thyroid nodules and differentiated thyroid cancer can be
found in Thyroid 2015 Jul;25(7):716
ATA management guideline on adult patients with thyroid nodules and differentiated thyroid cancer
can be found in Thyroid 2016 Jan;26(1):1 full-text, commentary can be found in Thyroid 2016
Feb;26(2):319
ATA statement on surgical application of molecular profiling for thyroid nodules: current impact on
perioperative decision-making can be found in Thyroid 2015 Jul;25(7):760 full-text
American Association of Clinical Endocrinologists/American Thyroid Association (AACE/ATA) clinical

practice guideline on hypothyroidism in adults can be found in Thyroid 2012 Dec;22(12):1200, corrections
can be found in Thyroid 2013 Jan;23(1):129 and Thyroid 2013 Feb;23(2):251, commentary can be found in
Thyroid 2012 Dec;22(12):1197
National Comprehensive Cancer Network (NCCN) guideline on evaluation and management of thyroid
carcinoma can be found at NCCN website (free registration required)
Endocrine Society clinical practice guideline on management of thyroid dysfunction during pregnancy and
post partum can be found in J Clin Endocrinol Metab 2012 Aug;97(8):2543, editorial can be found in J Clin
Endocrinol Metab 2012 Aug;97(8):2632, commentary can be found in Nat Rev Endocrinol 2012
Nov;8(11):624
American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guideline on
improving voice outcomes after thyroid surgery can be found in Otolaryngol Head Neck Surg 2013 Jun;148(6
Suppl):S1
European guidelines
Sociedad Española de Endocrinología y Nutrición (SEEN)

SEEN guía clínica para el manejo del nódulo tiroideo y cáncer de tiroides durante el embarazo se
puede encontrar en SEEN 2013 PDF [Spanish]
SEEN toma de posición en relación con el protocolo de tratamiento actual del nódulo y cáncer tiroideo
se puede encontrar en SEEN 2010 PDF [Spanish]
SEEN documento de consenso: ecografia tiroidea se puede encontrar en SEEN PDF [Spanish]
Italian Association of Clinical Endocrinologists/Italian Thyroid Association (AME/AIT) joint statement on
clinical practice on thyroid nodule and differentiated thyroid cancer management in pregnancy can be found
in J Endocrinol Invest 2010 Sep;33(8):579
European Association of Nuclear Medicine (EANM) procedure guideline on therapy of benign thyroid
disease can be found in Eur J Nucl Med Mol Imaging 2010 Nov;37(11):2218
78/85
Société Française d'Endocrinologie (French Society of Endocrinology [SFE]) recommendations on

management of thyroid nodules can be found in Ann Endocrinol (Paris) 2011 Sep;72(4):251 [English], Presse
Med 2011 Sep;40(9 Pt 1):793 [French]
Croatian Society for Clinical Cytology (Hrvatsko Društvo za Kliničku Citologiju) guideline on thyroid
cytology can be found in Lijec Vjesn 2012 Jul-Aug;134(7-8):203 [Croatian]
German Association of Endocrine Surgeons (Chirurgischen Arbeitsgemeinschaft für Endokrinologie

[CAEK]) practice guideline on surgical treatment of benign thyroid disease can be found in Langenbecks
Arch Surg 2011 Jun;396(5):639
Spanish guideline on management of thyroid nodules and differentiated thyroid cancer can be found in
Minerva Endocrinol 2011 Mar;36(1):7
Asian guidelines
Korean Society of Thyroid Radiology (KSThR) consensus statement and recommendations on ultrasound
diagnosis and ultrasound-based management of thyroid nodules can be found in Korean J Radiol 2016 May-
Jun;17(3):370 full-text
Central and South American guidelines
Latin American Thyroid Society guideline on management of thyroid nodules can be found in Arq Bras
Endocrinol Metabol 2009 Dec;53(9):1167 full-text
Review articles
general reviews of thyroid nodules

review of diagnosis and management of thyroid nodules can be found in JAMA 2018 Mar
6;319(9):914
review can be found in N Engl J Med 2015 Dec 10;373(24):2347, commentary can be found in N Engl
J Med 2016 Mar 31;374(13):1294
review of evaluation and management of thyroid nodules can be found in Maturitas 2017 Feb;96:1
review of diagnosis and management of thyroid nodules can be found in Clin Diabetes Endocrinol
2016;2:17 full-text
review can be found in Am Fam Physician 2013 Aug 1;88(3):193 full-text
reviews of testing
review of evaluation of a thyroid nodule can be found in Otolaryngol Clin North Am 2010
Apr;43(2):229 full-text
review on Bethesda System for classification of thyroid cytopathology can be found in Thyroid 2017
Nov;27(11):1341
review of investigating the thyroid nodule can be found in BMJ 2009 Mar 13;338:b733, commentary
can be found in BMJ 2009 Apr 7;338:b1370
review on molecular profiling of thyroid nodule can be found in Nat Rev Endocrinol 2017
Jul;13(7):415
review of molecular markers for malignant potential in thyroid nodules can be found in World J Surg
2008 Jul;32(7):1237, commentary can be found in World J Surg 2008 Dec;32(12):2744
review of role of ultrasonographic evaluation and management of benign nodules can be found in
World J Surg 2008 Jul;32(7):1253
review of evaluation of thyroid nodules by core needle biopsy can be found in Endocrinol Metab
(Seoul) 2017 Dec;32(4):407 full-text
review of fine needle aspiration of benign thyroid nodules can be found in World J Surg 2008
Jul;32(7):1247
reviews of treatment and management
79/85
review of minimally invasive video-assisted thyroidectomy for benign thyroid disease can be found in
World J Surg 2008 Jul;32(7):1333
review of endoscopic thyroidectomy can be found in World J Surg 2008 Jul;32(7):1349
review of endoscopic thyroidectomy in management of benign thyroid disease can be found in World J
Surg 2008 Jul;32(7):1325 full-text
review of intraoperative monitoring of recurrent laryngeal nerve palsy in thyroid surgery can be found
in World J Surg 2008 Jul;32(7):1358
review of lateral mini-incision technique can be found in World J Surg 2008 Jul;32(7):1341,
commentary can be found in World J Surg 2009 Feb;33(2):365
reviews of thyroid conditions in children
review of evaluation and management of thyroid nodules in children can be found in Curr Opin Pediatr
2016 Aug;28(4):536
review of thyroid nodules in children can be found in Pediatric Surgery Update 2009 Jan;32(1):1
brief 'what you should do' review of thyroid swellings can be found in BMJ 2009 Jul 13;339:b2563,
commentary can be found in BMJ 2009 Aug 18;339:b3346
case presentation of imaging for incidental thyroid nodule can be found in BMJ 2009 Mar 4;338:b611
MEDLINE search
to search MEDLINE for (Thyroid nodule) with targeted search (Clinical Queries), click therapy, diagnosis, or
prognosis
Patient Information
handout from American Academy of Family Physicians or in Spanish
handout from Hormone Health Network PDF or in Spanish PDF
handout from American Thyroid Association PDF
handout from American Association of Clinical Endocrinologists PDF
ICD Codes
ICD-10 codes
E04.1 nontoxic single thyroid nodule

E04.2 nontoxic multinodular goitre
E04.9 nontoxic goitre, unspecified [use for nodular goitre]
E05.1 thyrotoxicosis with toxic single thyroid nodule
E05.2 thyrotoxicosis with toxic multinodular goitre
E05.3 thyrotoxicosis from ectopic thyroid tissue
References
General references used
1. Gharib H, Papini E, Garber JR, et al. AACE/ACE/AME Task Force on Thyroid Nodules. American
Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici
Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid
Nodules--2016 update. Endocr Pract. 2016 May;22(5):622-39
2. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines
for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid
Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016
Jan;26(1):1-133 full-text, commentary can be found in Eur J Nucl Med Mol Imaging 2016 Feb;43(2):221
80/85
3. Haddad RI, Hoh C, Ridge JA, et al. Version 2.2017. In: National Comprehensive Cancer Network (NCCN)
Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN 2017 May 17 NCCN website (free
registration required)
4. Durante C, Grani G, Lamartina L, Filetti S, Mandel SJ, Cooper DS. The Diagnosis and Management of
Thyroid Nodules: A Review. JAMA. 2018 Mar 6;319(9):914-924, correction can be found in JAMA 2018
Apr 17;319(15):1622
Recommendation grading systems used

American Thyroid Association (ATA) grading system (adapted from United States Preventive Services Task
Force)
recommendations
Grade A - strongly recommend, based on good evidence that service or intervention can improve
important health outcomes; evidence from well-designed, well-conducted studies in
representative populations that assess effects on health outcomes
Grade B - recommend, based on fair evidence that service or intervention can improve important
health outcomes; evidence sufficient to determine effects on health outcomes, strength of
evidence is limited
Grade C - recommend, based on expert opinion
Grade D - recommend against, based on expert opinion
Grade E - recommend against, based on fair evidence that service or intervention does not
improve important health outcomes or that harms outweigh benefits
Grade F - strongly recommend against, based on good evidence that service or intervention does
not improve important health outcomes or that harms outweigh benefits
Grade I - recommends neither for nor against, poor quality or conflicting evidence; balance of
benefits and harms cannot be determined
Reference - ATA management guidelines for children with thyroid nodules and differentiated thyroid
cancer (Thyroid 2015 Jul;25(7):716 full-text)
National Comprehensive Cancer Network (NCCN) categories of evidence and consensus
Category 1 - based on high-level evidence, there is uniform NCCN consensus that the intervention is
appropriate
Category 2A - based on lower-level evidence, there is uniform NCCN consensus that the intervention
is appropriate
Category 2B - based on lower-level evidence, there is NCCN consensus that the intervention is
appropriate
Category 3 - based on any level of evidence, there is major NCCN disagreement that the intervention is
appropriate
Endocrinologi/ (AACE/ACE/AME) guideline grading system
grades of recommendation
Grade A - ≥ 1 conclusive level 1 publications demonstrating benefit greater than risk
Grade B
no conclusive level 1 publication
≥ 1 conclusive level 2 publications demonstrating benefit greater than risk
Grade C
no conclusive level 1 or 2 publication
≥ 1 conclusive level 3 publications demonstrating benefit greater than risk or no risk at all
and no benefit at all
Grade D
no conclusive level 1, 2, or 3 publication demonstrating benefit greater than risk, or
conclusive level 1, 2, or 3 publication demonstrating risk greater than benefit
levels of evidence
Level 1 - prospective, randomized, controlled trials - large
Level 2 - prospective with or without randomization - limited body of outcome data
Level 3 - other experimental outcome data and nonexperimental data
81/85
Level 4 - expert opinion

Reference - AACE/ACE/AME 2016 guideline update for clinical practice for the diagnosis and
management of thyroid nodules (Endocr Pract 2016 May;22(5):622)
American Thyroid Association (ATA) grades of recommendation
grades of recommendation
Strong recommendation, High-quality evidence - can be offered to most patients in most
applicable circumstances without reservation
Strong recommendation, Moderate-quality evidence - can be offered to most patients in most
applicable circumstances without reservation
Strong recommendation, Low-quality evidence - can be offered to most patients in most
applicable circumstances; may change when higher-quality evidence becomes available
Weak recommendation, High-quality evidence - best action may differ based on circumstances or
patients’ values
Weak recommendation, Moderate-quality evidence - best action may differ based on
circumstances or patients’ values
Weak recommendation, Low-quality evidence - alternative options may be equally reasonable
Insufficient - insufficient evidence to recommend for or against
levels of evidence
for therapeutic interventions
High-quality evidence - RCT without important limitations or overwhelming evidence
from observational studies
Moderate-quality evidence - RCT with important limitations or strong evidence from
observational studies
Low-quality evidence - observational studies/case studies
Insufficient - evidence is conflicting, of poor quality, or lacking
for diagnostic interventions
High-quality evidence - evidence from ≥ 1 well-designed nonrandomized diagnostic
accuracy studies or systematic reviews/meta-analyses of such observational studies with
no concern about internal validity or external generalizability of the results
Moderate-quality evidence - evidence from nonrandomized diagnostic accuracy studies
with ≥ 1 possible limitations causing minor concern about internal validity or external
generalizability of the results
Low-quality evidence - evidence from nonrandomized diagnostic accuracy studies with ≥
1 important limitations causing serious concern about internal validity or external
generalizability of the results
Insufficient - evidence may be of such poor quality, conflicting, lacking, or not externally
generalizable to the target clinical population such that the estimate of the true effect of the
test is uncertain and does not permit a reasonable conclusion to be made
Reference - ATA guidelines for adult patients with thyroid nodules and differentiated thyroid cancer
(Thyroid 2016 Jan;26(1):1 full-text)
United States Preventive Services Task Force (USPSTF) grades of recommendation (after July 2012)
Grade A - USPSTF recommends the service with high certainty of substantial net benefit
Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate
certainty of moderate-to-substantial net benefit
Grade C - USPSTF recommends selectively offering or providing the service (based on professional
judgment and patient preference) with at least moderate certainty of small net benefit
Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no
net benefit or harms outweighing benefits
Grade I - insufficient evidence to assess balance of benefits and harms
Reference - USPSTF Grade Definitions
Synthesized Recommendation Grading System for DynaMed Plus
82/85
DynaMed systematically monitors clinical evidence to continuously provide a synthesis of the most valid
relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology).
Guideline recommendations summarized in the body of a DynaMed topic are provided with the
recommendation grading system used in the original guideline(s), and allow DynaMed users to quickly see
where guidelines agree and where guidelines differ from each other and from the current evidence.
In DynaMed Plus (DMP), we synthesize the current evidence, current guidelines from leading authorities,
and clinical expertise to provide recommendations to support clinical decision-making in the Overview &
Recommendations section.
We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify
synthesized recommendations as Strong or Weak.
Strong recommendations are used when, based on the available evidence, clinicians (without
conflicts of interest) consistently have a high degree of confidence that the desirable consequences
(health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs,
burdens).
Weak recommendations are used when, based on the available evidence, clinicians believe that
desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the
magnitude of expected consequences (benefits and harms). Weak recommendations are used when
clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their
judgments. Weak recommendations are also used when the range of patient values and preferences
suggests that informed patients are likely to make different choices.
DynaMed Plus (DMP) synthesized recommendations (in the Overview & Recommendations section) are
determined with a systematic methodology:
Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise
and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and
the recommendations from guidelines.
Recommendations are phrased to match the strength of recommendation. Strong recommendations
use "should do" phrasing, or phrasing implying an expectation to perform the recommended action for
most patients. Weak recommendations use "consider" or "suggested" phrasing.
Recommendations are explicitly labeled as Strong recommendations or Weak recommendations
when a qualified group has explicitly deliberated on making such a recommendation. Group
deliberation may occur during guideline development. When group deliberation occurs through
DynaMed-initiated groups:
Clinical questions will be formulated using the PICO (Population, Intervention, Comparison,
Outcome) framework for all outcomes of interest specific to the recommendation to be
developed.
Systematic searches will be conducted for any clinical questions where systematic searches were
not already completed through DynaMed content development.
Evidence will be summarized for recommendation panel review including for each outcome, the
relative importance of the outcome, the estimated effects comparing intervention and
comparison, the sample size, and the overall quality rating for the body of evidence.
Recommendation panel members will be selected to include at least 3 members that together
have sufficient clinical expertise for the subject(s) pertinent to the recommendation,
methodological expertise for the evidence being considered, and experience with guideline
development.
All recommendation panel members must disclose any potential conflicts of interest
(professional, intellectual, and financial), and will not be included for the specific panel if a
significant conflict exists for the recommendation in question.
Panel members will make Strong recommendations if and only if there is consistent agreement
in a high confidence in the likelihood that desirable consequences outweigh undesirable
consequences across the majority of expected patient values and preferences. Panel members
will make Weak recommendationsif there is limited confidence (or inconsistent assessment or
dissenting opinions) that desirable consequences outweigh undesirable consequences across the
majority of expected patient values and preferences. No recommendation will be made if there is
insufficient confidence to make a recommendation.
83/85
All steps in this process (including evidence summaries which were shared with the panel, and
identification of panel members) will be transparent and accessible in support of the
recommendation.
Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in
recommendation drafting or development, with explicit confirmation that Strong recommendations are
adequately supported.
Recommendations are published only after consensus is established with agreement in phrasing and
strength of recommendation by all editors.
If consensus cannot be reached then the recommendation can be published with a notation of
"dissenting commentary" and the dissenting commentary is included in the topic details.
If recommendations are questioned during peer review or post publication by a qualified individual, or
reevaluation is warranted based on new information detected through systematic literature surveillance,
the recommendation is subject to additional internal review.
DynaMed Editorial Process

DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
All editorial team members and reviewers have declared that they have no financial or other competing
interests related to this topic, unless otherwise indicated.
DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster
University and F1000.
Special acknowledgements
Runhua Hou, MD (Assistant Professor of Medicine, Division of Endocrinology, Harvard Medical School;
Beth Israel Deaconess Medical Center; Massachusetts, United States)
Zbys Fedorowicz, MSc, DPH, BDS, LDSRCS (Director of Bahrain Branch of the United Kingdom Cochrane
Center, The Cochrane Collaboration; Awali, Bahrain)
Dr. Fedorowicz declares no relevant financial conflicts of interest.
William Aird, MD (Deputy Editor of Hematology, Endocrinology, and Nephrology; Professor of Medicine,
Harvard Medical School; Massachusetts, United States)
Dr. Aird declares no relevant financial conflicts of interest.
The Canadian Association of Nuclear Medicine provides review for the incorporation of Choosing Wisely
Canada recommendations.
Choosing Wisely Canada acknowledges dissemination of their recommendations through DynaMed Plus to
reach the point of clinical decision-making.
DynaMed Plus topics are written and edited through the collaborative efforts of the above individuals.
Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice.
Recommendations Editors are actively involved in development and/or evaluation of guidelines.
Editorial Team role definitions

Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and
suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic
Editors also serve as consultants for the internal DynaMed Plus Editorial Team during the writing and
editing process, and review the final topic drafts prior to publication.
Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review
of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.
Recommendations Editors provide explicit review of DynaMed Plus Overview and Recommendations
sections to ensure that all recommendations are sound, supported, and evidence-based. This process is
described in "Synthesized Recommendation Grading."
84/85
Deputy Editors are employees of DynaMed and oversee DynaMed Plus internal publishing groups. Each is
responsible for all content published within that group, including supervising topic development at all stages
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team.
How to cite
National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
DynaMed Plus [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T115781,
Thyroid nodule; [updated 2018 Nov 30, cited place cited date here]. Available from
https://www.dynamed.com/topics/dmp~AN~T115781. Registration and login required.
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women (reported to be 4 times more common in women than in men)(3)

contrast-enhanced CT scan detected by CT

Risk for malignancy

overall rate of malignancy in thyroid nodules reported to be about 10%(4)

Etiology and Pathogenesis

thyroid nodules may be caused by

thyroid nodules detected by ultrasound reported in 31.1% of patients with

originates from thyroid follicular epithelial cells

normal - normal uptake on scintiscan (about 40% of all nodules)

development of nodular thyroid disease(2)

History and Physical

thyroid nodules may be discovered

vocal cord paralysis

History of present illness (HPI)

ask about (AACE/ACE/AME Grade B, Level 2)(1, 4)

Past medical history (PMH)

Family history (FH)

check for common signs of

check for ocular signs of hyperthyroidism including

check for signs of hyperthyroidism including

check for signs of hypothyroidism including

check for signs of hyperthyroidism including

check for signs of hyperthyroidism including

thyroid nodule is diagnosed by ultrasound or other anatomic imaging studies(2)

other causes of neck masses include

Thyroid-stimulating hormone, thyroid hormone, and thyroid antibody testing

Other blood tests

determine type, frequency, and the need for follow up

Indications for thyroid ultrasound

indications for thyroid ultrasound vary slightly between guideline organizations(1, 2, 3)

American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici

vascular features of the nodule

isoechoic or mildly hypoechoic homogeneous appearance with intranodular vascularization and

negative likelihood ratio 0.6 (95% CI 0.5-0.8)

Risk stratification systems

classification of risk by ultrasound features varies according to different organizations(1, 2, 3)

Enhanced ultrasound techniques

ultrasound with elastography(1, 2)

Thyroid scintigraphy (radionuclide scanning)

overview of thyroid scintigraphy(1, 2)

recommendations for radionuclide scanning of thyroid nodules

Fluorodeoxyglucose positron emission tomography (FDG-PET)

18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan of thyroid nodules(1, 2)

negative predictive value 93%

Magnetic resonance imaging (MRI) or computed tomography (CT) scan

magnetic resonance imaging (MRI) or computed tomography (CT) scan(1, 2)

Fine needle aspiration (FNA) biopsy

FNA used to obtain

Recommendations for fine needle aspiration biopsy

indications for fine needle aspiration (FNA) biopsy vary by organization(1, 2, 3)

Indications for FNA Biopsy:

scintigraphy (AACE/ACE/AME Grade B,

Efficacy of FNA biopsy for detecting malignancy

Classification and malignancy risk (based on histopathologic analysis)

VI. Malignancy confirmed; examples include 97%-99% 99% (range

African 20% of 5 2% of 99 32% of 28 33% of 15 100% of 2 100% of 6

decoloration of previous stain

general considerations for molecular testing of thyroid nodules

no recommendation for or against the use of(1)

diagnostic performance of presence of ≥ 1 mutation for detection of malignancies over 3-year

pooled prevalence of malignancy 31%

Reference - Thyroid 2015 Nov;25(11):1217 full-text