Accepted Manuscript

Title: Thyroid nodules: null guide to assessment, treatment

and follow-up

Author: Stavroula null. Paschou Andromachi Vryonidou

Dimitrios G. Goulis

PII: S0378-5122(16)30256-0
DOI: http://dx.doi.org/doi:10.1016/j.maturitas.2016.11.002
Reference: MAT 6720

To appear in: Maturitas

Received date: 4-10-2016

Accepted date: 4-11-2016

Please cite this article as: Paschou Stavroula x391;, Vryonidou Andromachi, Goulis
Dimitrios G.Thyroid nodules: x391; guide to assessment, treatment and follow-
up.Maturitas http://dx.doi.org/10.1016/j.maturitas.2016.11.002

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 1

Thyroid nodules: Α guide to assessment, treatment and follow-up

Stavroula Α. Paschou (1, 2), Andromachi Vryonidou (2), Dimitrios G. Goulis (1)

(1) Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology,

Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

(2) Department of Endocrinology and Diabetes, Hellenic Red Cross Hospital, Athens,

Greece

Corresponding author: Prof. Dimitrios G. Goulis, MD, PhD, Unit of Reproductive

Endocrinology, First Department of Obstetrics and Gynecology, Aristotle University of

Thessaloniki, “Papageorgiou” General Hospital, Ring Road, 56403, Nea Efkarpia,

Thessaloniki, Greece, phone: +30 2310 233468, e-mail: dgg@auth.gr

Short Title: Thyroid nodules management

Highlights

 Thyroid nodules constitute by far the most common disorder of the endocrine

system, as by the age of 60 years about 50% of the general population is

considered to present at least one.

 Hosting of a thyroid carcinoma is the most worrisome, although not so common

 2

(7-15%), clinical implication.

 The endocrinologist facing a thyroid nodule has to answer two main clinical

questions: (i) the possibility of thyroid hormonal excess (hyperthyroidism) and

(ii) the risk of malignancy.

 TSH measurement, thyroid US and FNAC constitute the cornerstones of the

diagnostic algorithm.

 The answers to these two questions will guide management, which can vary

from simple follow-up to surgical resection.

Abstract

Thyroid nodules constitute by far the most common disorder of the endocrine system.

Epidemiological studies have indicated that approximately 5% of women and 1% of men

resident in iodine-sufficient areas have palpable thyroid nodules. However, by the age of 60

years about 50% of the general population is estimated to have at least one thyroid nodule.

Indeed, the reported prevalence of a “thyroid incidentaloma” is up to 70% when neck/carotid

artery ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) is

performed for other indications. Of those with a nodule, 7-15% will have a thyroid carcinoma.

The objective of this article is to present updated information on the definition, prevalence,

imaging and functional features of thyroid nodules and to provide guidance on the optimal

assessment, treatment and follow-up strategy. The endocrinologist dealing with a patient with

a thyroid nodule has to consider two main clinical issues: (i) the possibility of thyroid

hormonal excess (hyperthyroidism) and (ii) the risk of malignancy. The former is determined

by the assessment of the serum concentrations of thyroid stimulating hormone (TSH) as well

as of peripheral thyroid hormones, and a thyroid radionuclide scan, if necessary; the latter is

achieved by the use of thyroid ultrasonography, as well as fine needle aspiration cytology
 3

(FNAC) and serum calcitonin measurement, if necessary. These assessments will guide

management, which can vary from simple follow-up to surgical resection. The indications for

surgical management, simple follow-up, conservative therapy or treatment with radioactive

iodine are discussed.

Abbreviations: CT: computed tomography; MTC: medullary thyroid cancer; MEN: multiple

endocrine neoplasia; MRI: magnetic resonance imaging; FNAC: fine needle aspiration

cytology; FTC: follicular thyroid cancer; PTC: papillary thyroid cancer; PET: positron

emission tomography; RAI: radioactive iodine; TSH: thyroid stimulating hormone; Tg:

thyroglobulin

Keywords: thyroid, nodule, cancer, fine needle aspiration, hyperthyroidism

1. Introduction

Thyroid nodules constitute by far the most common abnormality of the endocrine system.

The reported prevalence is up to 70% when neck/carotid artery ultrasound (US), computed

tomography (CT) or magnetic resonance imaging (MRI) is performed for other indications

[1-2]. A thyroid carcinoma is the most worrisome type of nodule, and although it is not so

common it does have clinical implications [3-4]. The endocrinologist dealing with a patient

with a thyroid nodule has to consider two main clinical issues: (i) the possibility of thyroid

hormonal excess resulting from this lesion and (ii) the risk of malignancy. These issues guide

the patient’s management, which can vary from follow-up to surgical resection.

Although many guidelines and papers focus on the management of patients with thyroid

nodules [3-6], the optimal assessment and therapeutic strategies are still not clear. The
 4

objective of this review is to complete our trilogy on “endocrine incidentalomas” (after

adrenal and pituitary ones) [7-8]. Updated information on the definition, prevalence, imaging

and functional features of thyroid nodules is presented, in an attempt to provide a guide to the

optimal assessment, treatment and follow-up of these patients.

2. Methods

In order to identify publications on thyroid nodules, a literature search was conducted in three

electronic databases: PubMed, Cochrane and EMBASE. In addition, a manual search of key

journals and abstracts from the major annual meetings in the field of endocrinology and

thyroidology was conducted. Special attention was paid to guidelines and papers focusing on

the management of patients with thyroid nodules. The reviewers collected, analyzed and

qualitatively re-synthesized information regarding: (1) the definition and prevalence of

thyroid nodules, (2) the initial assessment of thyroid hormonal excess, (3) the initial

assessment of risk of malignancy, (4) the indications for surgical treatment, (5) the

indications for purely medical treatment or for radioactive iodine (RAI) treatment or for

simple follow-up and (6) the management of thyroid nodules during pregnancy.

3. Results and Discussion

3.1 Definition and prevalence of thyroid nodules

The term “thyroid nodule” refers to any lesion that is radiologically distinct from the normal

parenchyma of the thyroid gland. This strict definition does not include palpable thyroid

lesions that do not correspond to this radiological definition [6, 9]. Nodules that are

asymptomatic, non-palpable and detected during imaging for indications other than thyroid

pathology are defined as “thyroid incidentalomas” [1-2].

 5

Thyroid nodules constitute by far the most common abnormality of the endocrine system.

Epidemiological studies have indicated that approximately 5% of women and 1% of men

resident in iodine-sufficient areas have palpable thyroid nodules. However, the reported

prevalence reaches up to 70% when neck/carotid artery ultrasound (US), CT or MRI is

performed for other indications [3-4, 6]. The highest prevalence rates are reported in women

and the older population. Indeed, thyroid nodules can be detected in about 50% of the general

population aged over 60 years [1-2, 6].

From a pathophysiological point of view, a thyroid nodule represents abnormal growth of

cells (usually but not always thyroid cells), which form a lump within the thyroid gland.

Hashimoto’s autoimmune thyroiditis is associated with an increased risk of thyroid nodules.

Iodine deficiency is also known to cause thyroid nodules [5-6]. The vast majority of thyroid

nodules are benign, and 20% diminish in size during their natural course. Thyroid cancer is

the most common endocrine malignancy, but constitutes less than 1% of all human cancers.

A thyroid carcinoma is met in 7-15% of patients with thyroid nodules, depending on the age,

gender, family history and history of radiation exposure. In general, nodules >1 cm present

greater potential to be clinically significant cancers [3-4]. The possible etiologies of thyroid

nodules are shown in Table 1.

3.2 Assessment of thyroid hormonal excess

The first issue to be addressed at the initial assessment of a patient with thyroid nodules is the

possibility of thyroid hormonal excess. Apart from clinical evaluation for the symptoms and

signs of hyperthyroidism (palpitations, nervousness, anxiety, irritability, tremor, sweating,

increased sensitivity to heat, fatigue, muscle weakness, increased appetite, weight loss,

difficulty in sleeping, changes in menstrual and/or bowel patterns), the most essential tool for

this assessment is measurement of the patient’s serum level of thyroid stimulating hormone
 6

(TSH) [10]. If the TSH level is below normal (the normal reference range is 0.4-4.0 mU/L),

peripheral thyroid hormones [free thyroxine (FT4) and total (TT3) or free (FT3)

triiodothyronine] should also be assessed. Furthermore, a radionuclide (preferably 123I)

thyroid scan should be performed; if the TSH level is normal or elevated, there is no need for

such a scan. The thyroid scan will document whether the nodule is: (i) hyper-functioning

(‘hot’), with tracer uptake being greater in the nodule than in the surrounding normal thyroid

tissue, (ii) iso-functioning (‘warm’), with tracer uptake equal, or (iii) non-functioning

(‘cold’), with less tracer uptake by the nodule than by the surrounding thyroid tissue [5-6, 10-

11].

If hyperthyroidism is diagnosed, it should be managed appropriately. The main causes of

hyperthyroidism that are associated with thyroid nodules are toxic multinodular goiter,

Graves’ disease and toxic adenoma. The therapeutic options include anti-thyroid drugs,

surgery and radioactive iodine (RAI). Each type of treatment presents advantages and

disadvantages, so the therapeutic strategy should be individualized according to the cause of

hyperthyroidism, the clinical characteristics, the age, personality and preference of the

patient, as well as the experience of the medical team [12]. Anti-thyroid drugs (preferably

methimazole at a starting daily dose of 10-30 mg to restore euthyroidism and then a

maintenance dose of 5-10 mg) are the first-line therapeutic option for patients with

hyperthyroidism. For Graves’ disease, treatment should be continued for at least 18 months,

after which complete remission is recorded in 30% of patients. Lobectomy is the treatment of

choice for patients with toxic adenoma. Total thyroidectomy is preferred in cases of toxic

multinodular goiter, especially when cancer is also suspected or where the large size of the

goiter causes pressure problems, and in patients with Graves’ disease when relapse, large size

of goiter or moderate to severe ophthalmopathy are present [10-12]. RAI (in therapeutic

doses of 12-20 mCi 131I) is often used in the USA (up to 69% of cases) for the management
 7

of hyperthyroidism, while in Europe it is not usually the treatment approach of choice [13].

Even when surgical or RAI treatment is decided, anti-thyroid drugs should be used first, in

order to render the patient euthyroid before further treatment [10-13].

If the serum TSH level is high (>4.0 mU/L), additional evaluation for subclinical or clinical

hypothyroidism with free thyroxine (FT4) and anti-TPO (anti-thyroid peroxidase antibody)

measurement is recommended. Higher TSH levels, even within the upper part of the

reference range, have been associated with an increased risk of malignancy for a thyroid

nodule [14-15].

3.3 Assessment of the risk of malignancy

The majority of thyroid nodules are benign; only 7-15% are malignant. Nonetheless, the

most important question to be answered at the initial assessment of a patient with one or more

thyroid nodules is whether they are malignant [3-4]. Apart from detailed clinical evaluation,

personal and family history, the most essential tool for this assessment is thyroid imaging.

Τhe diagnostic technique of choice is thyroid US, while fine needle aspiration cytology

(FNAC) should follow, according to the nodule’s ultrasonography characteristics and greatest

dimension. Thyroid incidentalomas that are detected by other imaging techniques should

always be evaluated by thyroid US. Thyroid incidentalomas that are detected by positron

emission tomography (PET) have a high malignancy risk (especially when focal uptake is

present) and should be evaluated by US and FNAC. Routine assessment of serum calcitonin

levels is not broadly recommended by current guidelines; however, it is used by many

endocrinologists at initial assessment. Thyroglobulin (Tg) measurement is not recommended

in the initial evaluation of thyroid nodules. The value of ultrasound elastography in predicting

thyroid malignancy is limited, especially in centers with good diagnostic conventional

thyroid US [5-6].
 8

3.3.1 Clinical evaluation

Physical and clinical characteristics associated with a higher risk of malignancy are young

age and male gender of the patient, solid and firm nodule(s) on palpation, as well as vocal

cord paralysis and presence of firm lymph nodes or even distant metastases. Recent and

significant growth of the nodule(s) (especially while the patient is on thyroxine treatment),

dysphagia, air obstruction or hoarseness, as well as past radiation of the head or neck are also

associated with a higher risk of malignancy. The presence of other cases of papillary or

medullary thyroid cancer within the family (uncovered in a detailed patient history) increases

the risk of malignancy. On the other hand, a family history of goiter or residence in an area

with known iodine deficiency are more suggestive of a benign nature of the nodule(s) [3-6].

3.3.2 Ultrasonography

3.3.2.1 Thyroid US

Thyroid US should evaluate and report details regarding the following [5-6, 16-18]:

 Thyroid gland size (total, each lobe and isthmus). A normal adult thyroid lobe is around 4

cm in length, 2 cm in width and 1 cm in thickness.

 Thyroid parenchyma (homogeneous, heterogeneous). Normally, the thyroid parenchyma

is homogeneous.

 Number, location, size (in 3 dimensions), shape (taller or wider), margins (smooth,

infiltrative, microlobulated) and additional US characteristics of any nodule, such as: a)

echogenicity, b) composition (solid, cystic, spongiform: the aggregation of multiple

micro-cystic components in > 50% of the nodule volume), c) calcifications (presence and

type: micro- or macro-) and d) vascularity.

 9

 Presence and characteristics of cervical lymph nodes in the central (VI) or lateral

compartments.

In patients with low serum TSH concentrations who have undergone a radionuclide thyroid

scan, US should also be performed. In this case, the thyroid US will evaluate both the

presence of nodules concordant with the hyper-functioning areas and the possibility of the

presence of non-functioning or iso-functioning nodules [10, 19]. In the case of multiple

nodules, details for all nodules should be given rather than for the largest nodule only.

Nodules >1 cm have a greater potential to be clinically significant cancers. As there may be

nodules <1 cm with suspicious US findings, each nodule should be evaluated separately in

detail, regardless of its size and the total number of nodules present [5-6].

The information provided by the thyroid US should be used to stratify the risk of malignancy

for each separate nodule. Many characteristics consistent with malignancy have been

reported, with micro-calcifications, irregular margins and a vertical orientation (“taller-than-

wide”) measured on a transverse view giving the higher specificities (>90%) [18, 20-26].

Vascularity does not seem to have any independent predictive value for malignancy [23-24].

Patients with papillary thyroid carcinomas (PTC) mainly have an increased peripheral

vascularity, while patients with follicular thyroid cancers (FTC) have intra-nodular or mixed

increased vascularity [23, 27]. Indeed, FTC exhibit different US characteristics: they are

more likely to be iso-echoic or hyper-echoic, without calcifications, to have increased

vascularity and to be round, with regular smooth margins [27]. Medullary thyroid cancer

(MTC) does not present greatly different US characteristics from PTC [28]. In any case,

malignant characteristics are not “black or white”; they should be considered in total and not

as single features. Then, each nodule should be assigned a position on a continuum, graded

1–5, from benign to high suspicion for malignancy [5-6, 18, 20-28], according to Table 2.
 10

The five categories have their own specific risk ranges for malignancy based on the nodule

characteristics (rather than collectively covering the 0–100% risk range as a whole).

3.3.2.2 Cervical lymph nodes US

Ultrasonography assessment of cervical lymph nodes has the highest sensitivity in detecting

malignancy. Cervical lymph nodes in the central compartment, the most common site of

nodal metastases (Level VI), or lateral compartments (Level I-V) should be evaluated in

detail. Micro-calcifications, cystic parts, peripheral or mixed vascularity, hyper-echogenicity

and round rather than oval shape are the most suggestive characteristics of thyroid metastatic

lymph node involvement [5, 29].

3.3.3 FNAC

3.3.3.1 Thyroid nodule FNAC

FNAC is a very accurate method of thyroid nodule evaluation. Retrospective studies have

reported lower rates of both non-diagnostic and false-negative cytology from FNAC

performed under US-guidance compared with palpation; therefore, US-guided FNA should

be preferred [30-31]. The indication for FNAC depends on two parameters: (a) the position of

the thyroid nodule on the malignancy risk continuum (1-5) (Table 2); and (b) the thyroid

nodule’s greatest dimension (Figure 1), as follows:

1. Benign (malignancy risk <1%): FNAC not recommended for diagnostic purposes.

2. Very low suspicion (malignancy risk <3%): FNAC recommended for nodules >2 cm in

greatest dimension.

3. Low suspicion (malignancy risk 5-10%): FNAC recommended for nodules >1.5 cm in

greatest dimension.
 11

4. Intermediate suspicion (malignancy risk 10-20%): FNAC recommended for nodules >1

cm in greatest dimension.

5. High suspicion (malignancy risk >70-90%): FNAC recommended for nodules >1 cm in

greatest dimension. Nodules of this category with greatest dimension 0.5 to 1 cm can also

present an indication for FNAC.

Patients with nodules with a greatest dimension <0.5 cm should not undergo FNAC

irrespective of the sonographic characteristics, due to the very low clinical risk [5-6, 20-28].

In the subset of patients with decreased serum TSH concentrations, FNAC should not be

performed in hyper-functioning (hot) nodules after thyroid scan. In the case of multiple

nodules, the selection for FNAC should be performed one-by-one, on the basis of the

previously described criteria. In vast majority, no more than 2 nodules in the same patient

present characteristics and size indicative of FNAC [5-6, 19].

When FNAC is performed, the cytology report should use the standard international

classification systems (Italian Consensus [32], Bethesda System for Reporting Thyroid

Cytopathology [33], UK-Royal College of Pathologists [34]). We recommend the Bethesda

System for Reporting Thyroid Cytopathology (BSRTC) [33], as it is the most commonly

used system worldwide in both clinical practice and research studies. The BSRTC recognizes

six categories (Table 3):

1. Non-diagnostic or Unsatisfactory (malignancy risk 1-4%): These are FNA cytology

reports which fail to meet the established criteria for adequacy: presence of at least six

groups of well-visualized follicular cells, with each group containing at least 10 well-

preserved epithelial cells, preferably on a single slide [33, 35-37]. The actual risk of

malignancy in nodules from this category surgically excised is higher (median 20%).
 12

[38]. When FNA cytology is insufficient but consistent with a benign cystic lesion, this

should be mentioned in the report.

2. Benign (malignancy risk 0-3%)

3. Atypia of Undetermined Significance or Follicular Lesion of Undetermined Significance

(AUS/FLUS) (malignancy risk 5-15%): Specimens from this category have been

associated with the highest discordance rates. Some studies suggest that this category

should be further sub-divided into AUS with cell nuclear atypia (high risk for

malignancy) and FLUS with architectural atypia (low risk for malignancy) [33, 35, 39].

4. Follicular Neoplasm or Suspicious for a Follicular Neoplasm (FN/SFN) (malignancy risk

15-30%): This category also encompasses the diagnosis of Hürthle cell

neoplasm/suspicious for Hürthle cell neoplasm [33, 35].

5. Suspicious for malignancy (SUSP) (malignancy risk 60-75%): Even if most cases in this

category are suspicious for papillary carcinoma, descriptive comments should further

classify the type of suspected malignancy [33].

6. Malignant (malignancy risk 97-99%): The general term ‘malignant’ is used whenever the

FNAC results are conclusive for malignancy, but descriptive comments should further

classify the type of malignancy (papillary thyroid carcinoma, medullary thyroid

carcinoma, etc.) [33].

3.3.3.2 Cervical lymph nodes FNA

Suspicious lymph nodes larger than 0.8-1 cm in the smallest diameter can also be biopsied by

FNA in order to confirm nodular metastases. Of course, this procedure should be followed

only if it might change the treatment approach. Furthermore, Tg measurement from cervical
 13

lymph node FNA washout could also be helpful; however, interpretation can be difficult in

pre-operative procedures, when patients have an intact thyroid gland [5-6, 40].

3.3.4 Calcitonin

A series of prospective, non-randomized studies have shown that the measurement of serum

calcitonin may detect early-stage C-cell hyperplasia and medullary thyroid cancer (MTC);

however, most of these studies did not rely on basal calcitonin concentrations but on

pentagastrin stimulation tests for diagnosis [41-45]. Therefore, issues regarding sensitivity,

specificity, and thresholds are still a matter of debate. Recent guidelines from both the

American Thyroid Association (ATA) [5, 46] and the American Association of Clinical

Endocrinologists (AACE) [6] make no recommendation regarding the routine measurement

of serum calcitonin in patients with thyroid nodules. However, routine calcitonin

measurement will detect MTC in one in 200–300 patients presenting with thyroid nodules

and no suspicion of MTC (a greater sensitivity than FNAC), while the overall survival of

patients with MTC is improved when the condition is detected earlier [47-49]. Furthermore, a

cost-effectiveness and decision analysis measured in dollars per life years saved (LYS) in the

United States showed that routine serum calcitonin screening is cost-effective indeed,

comparable to the measurement of thyroid stimulating hormone, colonoscopy and

mammography screening [50]. Thus, we would recommend calcitonin measurement at the

initial diagnostic evaluation of thyroid nodules in all patients. Of course, endocrinologists

should be aware of other causes of elevated concentrations of calcitonin, such as

hypercalcemia, chronic kidney disease, pancreatitis, lung disease, sepsis, use of medications

such as proton pump-inhibitors and glucagon-like peptide (GLP1)-receptor antagonists, as

well as smoking. High-risk subgroups are patients with a family history or clinical suspicion

of MTC or multiple endocrine neoplasia type 2 (MEN2). Serum calcitonin concentrations

 14

>50 pg/mL make the diagnosis of MTC possible. When concentrations are high, but still

lower than 100 pg/mL, a calcium stimulation test will increase the diagnostic accuracy, while

the pentagastrin stimulation test is not recommended [46-49]. The addition of FNA calcitonin

washout in the pre-operative evaluation of patients with modestly elevated basal serum

calcitonin concentrations (20-100 pg/mL) may also be helpful but remains to be routinely

incorporated in everyday clinical practice [51]. If MTC is suspected, total thyroidectomy

along with resection of the central neck lymph node compartment (Level VI) is the surgical

approach of choice [46].

3.3.5 Thyroglobulin

Serum Tg concentrations are elevated in most thyroid diseases. Thyroglobulin measurement

is therefore a non-specific test for the assessment of risk for malignancy and should not be

performed in patients with thyroid nodule(s) [5-6, 52].

3.3.6 Elastography

Ultrasound elastography (USE) is a technique to determine tissue stiffness; it involves the use

of a separate computational module added to the US. The stiffer the nodule is, the higher is

the risk of malignancy. USE may prove a helpful tool in the future; however, recent trials

have reported inferior positive and negative predictive values compared with US. Therefore,

its inclusion in the malignancy risk assessment is not suggested, and there is no reason for it

to be a substitute for the detailed thyroid and cervical lymph node US evaluation [53-54].

3.4 Management according to FNAC results

3.4.1 Non-diagnostic or Unsatisfactory (malignancy risk 1-4%)

 15

For any nodule of this category, FNA should be repeated under US guidance for a new

cytologic evaluation. It had been proposed that repeat FNAC should be performed no sooner

than 3 months [55], but recent studies question the necessity of such a waiting period,

especially when the suspicion of malignancy is higher [56-57]. When non-diagnostic or

unsatisfactory results are found again in repeat FNAC, the US nodule’s characteristics along

with the individual features of each patient should guide the endocrinologist to the decision

for surgical excision or close observation. Surgical excision will provide the final

histopathologic diagnosis [5-6]. Molecular testing for BRAF single mutation or a panel of

mutations (see details in AUS/FLUS category) could also facilitate the appropriate

management of these patients. However, the cost, the availability and the true impact on the

possible alteration of the surgical decision-making should be always considered before such

testing [58-59].

3.4.2 Benign (malignancy risk 0-3%)

For any nodule in this category, no further immediate diagnostic or treatment action is

generally required. However, benign FNA cytology for nodules >4 cm cannot guarantee a

zero cancer risk. It is still unclear whether these nodules should be managed differently; the

treatment decision should be individualized in the context of US characteristics of the nodule,

as well as the age, general health status and preference of the patient [5-6]. According to the

Nodule Malignancy Risk Continuum, thyroid US and FNA should then repeated in 12

months for Category 5, while thyroid US should be repeated in 12-24 months for categories 3

and 4. If US indicates >20% increase in two dimensions or >50% in total volume, FNA

should be repeated. After two benign FNAC results, further US observation for this nodule is

not recommended [60-62].

 16

3.4.3 Atypia of Undetermined Significance or Follicular Lesion of Undetermined

Significance (AUS/FLUS) (malignancy risk 5-15%)

For nodules in this category, repeat FNAC and molecular testing or surgery are the decisions

of choice, depending on the patient’s clinical features and the nodule’s US characteristics [5-

6]. There is no single optimal type of molecular testing that can reliably rule out the presence

of malignancy. The largest studies so far have evaluated: a) a genetic panel of 7 mutations

and rearrangements (BRAF, NRAS, HRAS, KRAS, RET/PTC1, RET/PTC3, PAX8/PPARγ),

b) mRNA expression of 167 genes (167 GEC) and c) cell blocks for galectin-3 expression by

immunohistochemistry. The BRAF V600E single mutation test has a very high specificity

(approximately 99%), but its sensitivity is too low to rule out the possibility of malignancy

[58-59, 63-64]. Molecular profiling of such nodules is very helpful in decision making for

both the need of surgical excision and the extent of initial resection. However, the cost of this

testing renders it unfeasible in most countries. Again, the true impact in relation to any

possible change of the therapeutic decision should be always considered before such testing.

If repeat FNA cytology and/or molecular testing are not performed or are inconclusive,

diagnostic surgical excision or active surveillance should be decided in the context of the US

characteristics of the nodule, as well as the age, general health status and the preference of

the patient. Nodules characterized by FNAC as AUS with nuclear atypia present a higher risk

of malignancy than FLUS with architectural atypia [5-6, 33, 35, 39].

3.4.4 Follicular Neoplasm or Suspicious for a Follicular Neoplasm (FN/SFN) (malignancy

risk 15-30%)

Surgical excision is generally recommended for removal and definitive diagnosis of an

FN/SFN thyroid nodule. However, depending on the clinical features of the patient and the

US characteristics of the nodule, molecular testing could also be considered in the same
 17

context as for the AUS/FLUS category (above) before the surgical procedure [5-6, 58-59, 63-

66].

3.4.5 Suspicious for malignancy (SUSP) (malignancy risk 60-75%)

For any nodule which is suspicious for malignancy, the management approach should, in

general, be similar to that for the malignant cytology category (below). If molecular testing is

available and such data would be expected to alter surgical decision-making, the BRAF or 7-

gene marker panel may be considered before surgical excision [5-6, 58-59, 63-66].

3.4.6 Malignant (malignancy risk 97-99%)

For any nodule of this category, surgery is generally recommended. However, active

surveillance can be an alternative approach in the case of patients with very low-risk tumors

(as for micro-PTCs <1 cm) [67], patients with high surgical risk because of co-morbidity or

concurrent issues that need to be addressed prior to thyroid surgery, or patients with a

relatively short expected life span [5-6] (Table 4).

3.5 Management of thyroid nodules that do not meet criteria for FNAC at initial assessment

For patients with nodules that do not meet criteria for FNAC according to sonographic

characteristics and size, surveillance with repeat thyroid US is the approach of choice. For

nodules in category 5 on the Malignancy Risk Continuum, thyroid US should be repeated in

6-12 months, for nodules of categories 3 and 4 in 12-24 months, while for the rest thyroid US

should be repeated in more than 24 months and only if they are >1 cm in size [5-6, 68].

TSH suppression therapy with exogenous levothyroxine for benign thyroid nodules has no

indication at all. It has been broadly used in the past, but the potential harm to bone and heart

health outweighs the possible benefit for most patients [69-70].

 18

Of course, adequate iodine intake is essential and if this cannot be achieved by dietary intake,

daily supplementation with 150 μg iodine is recommended [71].

For large (>4 cm) or growing thyroid nodules, surgical treatment can be also an alternative

management option [72-73]. Recurrent cystic nodules can be managed by surgery too,

despite the minimal risk of malignancy. Percutaneous ethanol injection is another therapeutic

approach for this category of cystic benign nodules [5, 74].

3.6 The management of thyroid nodules during pregnancy

In the case of thyroid nodules that are discovered during pregnancy, FNAC should be

performed according to the same indications described (Figure 1), but only for women with

normal or elevated TSH levels. If TSH levels are subnormal beyond the 16th week of

gestation, FNAC should be postponed until after pregnancy and cessation of lactation, when a

radionuclide thyroid scan can be performed. If thyroid cancer is diagnosed or suspected by

cytology, the management approach of choice is suppression therapy with exogenous

levothyroxine (to keep serum TSH concentrations in the range 0.1-1.0 mU/L) and US

monitoring, until surgery after delivery. However, if the thyroid nodule(s) grow(s)

substantially or if US reveals cervical lymph nodes that are suspicious for metastatic disease,

surgery could be considered during the second trimester of pregnancy [75-77].

4. Conclusion

Thyroid nodules constitute by far the most common endocrine clinical problem and both

diagnostic and treatment procedures should be aligned to the optimal benefit of each

individual patient. TSH measurement, thyroid US and FNAC constitute the cornerstones of

the diagnostic algorithm, which then guide the appropriate therapeutic management, which

can vary from simple follow-up to surgical resection (Figure 2).

 19

Contributors

SAP contributed to the conception, design and drafting the paper.

AV contributed to revising the paper critically for important intellectual content.

DGG contributed to the conception, design and revising the paper critically for important

intellectual content.

Conflict of interest

The authors declare that they have no conflict of interest.

Funding

No funding was received for this review.

Provenance and peer review

This article has undergone peer review.

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 31

Figure 1. Indications for FNAC according to: (a) the position of the thyroid nodule on the
malignancy risk continuum (1-5), and (b) the thyroid nodule greatest dimension.

Nodules with greatest dimension <0.5 cm should not be biopsied irrespectively of the sonographic

characteristics. Nodules of high suspicion (5) with greatest dimension 0.5 to 1 cm sometimes present

an indication for FNAC. Nodules of intermediate or high suspicion (4-5) present an indication for

FNAC, when they are >1 cm in greatest dimension. Nodules of low suspicion (3) present an

indication for FNAC, when they are >1.5 cm in greatest dimension. Nodules of very low suspicion (2)

present an indication for FNAC, when they are >2 cm in greatest dimension. FNAC is not

recommended for diagnostic purposes in the case of benign nodules (1) [5-6].
 32

Figure 2. Diagnostic and therapeutic algorithm for thyroid nodules management.

TSH

< 0.4 mU/L 0.4 - 4.0 mU/L > 4.0 mU/L

- FT4, T3 - No thyroid - FT4, anti-TPO

- Thyroid scan hormones - No thyroid scan
- No thyroid scan
- Thyroid US - Thyroid US
- Thyroid US

Management of
hypethyroidism, if No Thyroglobulin
present, and FNAC measurement
considered only for iso- or
non-functioning nodules
FNAC according
to thyroid US
(see Fig. 1)

Yes No
Calcitonin
measurement at
initial assessment

Bethesda categories Repeat thyroid US according to

nodule malignancy risk continuum:
1 to 6
5: in 6-12 months
If MTC suspected, 3-4: in 12-24 months
total thyroidectomy 2: in >24 months
with central lymph
node resection is
indicated (after
5-6: Total thyroidectomy
exclusion of false
3-4: Surgical excision *
positives)
2: No further immediate action **
1: Repeat FNAC ***
If Bethesda 2, management according
* For decision consider also: age, to nodule malignancy risk continuum:
general health status, patient’s 5: Thyroid US and FNAC in 12 months
preference, nodule’s US
characteristics. 3-4: Thyroid US in 12-24 months, if
** Surgery can be an alternative >20% increase in two dimensions or
approach for nodules >4 cm. >50% in volume: repeat FNAC
*** If Bethesda 1 again after repeat STOP after two benign FNAC
FNAC, consider surgical excision or
close observation.
 33

Table 1. Categories of thyroid nodules.

Benign (85-93%)  Focal thyroiditis (mainly autoimmune)

 Dominant nodule(s) in multinodular goiter

 Follicular adenoma

 Hürthle cell adenoma

 Parathyroid adenoma

 Cyst (thyroid, parathyroid, thyroglossal)

 Thyroid lobe agenesis

 Post-surgical hyperplasia of remnant thyroid tissue

 Post-radioactive iodine hyperplasia of remnant thyroid tissue

Very rarely:

 Teratoma

 Lipoma

 Hemangioma

 Infiltrative disease

Malignant (7-15%)  Papillary carcinoma

 Follicular carcinoma

 Medullary carcinoma

Very rarely:

 Anaplastic carcinoma

 Parathyroid carcinoma

 Lymphoma

 Fibrosarcoma

 Metastases
 34

Table 2. Thyroid nodule malignancy risk continuum.

Category Type Nodule characteristics Malignancy

risk

1 Benign Purely cystic <1%

2 Very low suspicion Partially cystic with no characteristics of <3%

categories 3-5 or spongiform

3 Low suspicion Partially cystic with eccentric uniformly 5-10%

solid areas with no characteristics of

categories 4-5 or isoechoic or

hyperechoic solid

4 Intermediate Hypoechoic solid with no characteristics 10-20%

suspicion of category 5

5 High suspicion Hypoechoic solid or partially cystic, >70-90%

presenting at least one of the following

characteristics: micro-calcifications,

irregular margins, orientation “taller-

than-wide”, disrupted rim calcifications

or extra-thyroidal extension

Malignant characteristics do not constitute “black or white” situations; they should be considered in
total and not as single features. Each thyroid nodule should take its position on this continuum (1-5),
from benign to high suspicion for malignancy [5-6, 18, 20-27].
 35

Table 3. Bethesda system for reporting thyroid cytopathology (BSRTC).

Category Type Malignancy risk

1 Non-diagnostic or Unsatisfactory 1-4% *

2 Benign 0-3%

3 Atypia of Undetermined Significance or Follicular Lesion 5-15%

of Undetermined Significance (AUS/FLUS)

4 Follicular Neoplasm or Suspicious for a Follicular 15-30%

Neoplasm (FN/SFN)

5 Suspicious for Malignancy (SUSP) 60-75%

6 Malignant 9-99%

* The actual risk of malignancy in nodules from this category surgically excised is higher (median

20%)
 36

Table 4. Indications and types of surgical treatment for thyroid nodules.

Absolute indications 1. Bethesda Category 6 - Malignant (total thyroidectomy) *

2. Bethesda Category 5 - SUSP (total thyroidectomy) *

Relative indications 1. Bethesda Category 4 - FN/SFN **

2. Bethesda Category 3 - AUS/FLUS **

3. Bethesda Category 2 - Benign, when size >4 cm **

4. Bethesda Category 1 - Non-diagnostic or Unsatisfactory, after

repeat FNA **

5. Toxic adenoma (lobectomy)

6. Toxic nodular goiter (total thyroidectomy)

7. Graves’ disease (total thyroidectomy)

8. Non-toxic nodular goiter (total thyroidectomy)

* In the case of MTC, total thyroidectomy with central lymph node resection is indicated

** The type of surgical treatment should be individualized and can vary from lobectomy to total
thyroidectomy, according to nodule’s characteristics, molecular testing (if performed), as well as
patient’s features and preference