THE MEDICAL BULLETIN OF

SISLI ETFAL HOSPITAL

DOI: 10.14744/SEMB.2023.06992
Med Bull Sisli Etfal Hosp 2023;57(3):287–304

Review Article

Management of Thyroid Nodules

Mehmet Uludag,1 Mehmet Taner Unlu,1 Mehmet Kostek,1 Nurcihan Aygun,1 Ozan Caliskan,1
Alper Ozel,2 Adnan Isgor3
1
Division of Endocrine Surgery, Department of General Surgery, University of Health Sciences Türkiye, Sisli Hamidiye Etfal Training and
Research Hospital, Istanbul, Türkiye
2
Department of Radiology, University of Health Sciences Türkiye, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Türkiye
3
Department of General Surgery, Sisli Memorial Hospital, Istanbul, Türkiye

ABSTRACT
Thyroid nodules are common and the prevalence varies between 4 and 7% by palpation and 19–68% by high-resolution USG. Most
thyroid nodules are benign, and the malignancy rate varies between 7 and 15% of patients. Thyroid nodules are detected inciden-
tally during clinical examination or, more often, during imaging studies performed for another reason. All detected thyroid nodules
should be evaluated clinically. The main test in evaluating thyroid function is thyroid stimulating hormone (TSH). If the serum TSH
level is below the normal reference range, a radionuclide thyroid scan should be performed to determine whether the nodule is
hyperfunctioning. If the serum TSH level is normal or high, ultrasonography (US) should be performed to evaluate the nodule. US
is the most sensitive imaging method in the evaluation of thyroid nodules. Computed tomography (CT) and magnetic resonance
imaging are not routinely used in the initial evaluation of thyroid nodules. There are many risk classification systems according
to the USG characteristics of thyroid nodules, and the most widely used in clinical practice are the American Thyroid Association
guideline and the American College of Radiology Thyroid Imaging Reporting and Data System. Fine needle aspiration biopsy
(FNAB) is the gold standard method in the evaluation of nodules with indication according to USG risk class. In the cytological
evaluation of FNAB, the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is the most frequently applied cytological
classification. TBSRTC is a simplified, 6-category reporting system and was updated in 2023. The application of molecular tests
to FNAB specimens, especially those diagnosed with Bethesda III and IV, is increasing to reduce the need for diagnostic surgery.
Especially in Bethesda III and IV nodules, different methods are applied in the treatment of nodules according to the malignancy
risk of each category, these are follow-up, surgical treatment, radioactive iodine treatment, and non-surgical ablation methods.
Keywords: Imaging, risk classification, thyroid nodule, treatment management
Please cite this article as ”Uludag M, Unlu MT, Kostek M, Aygun N, Caliskan O, Ozel A, et al. Management of Thyroid Nodules. Med Bull Sisli
Etfal Hosp 2023;57(3):287–304”

T he prevalence of thyroid nodules is common in pub-

lic population. Their prevalence varies according to
the method of detection and the selected population
roid nodules are benign. However, malignancy rate varies
between 7 and 15% depending on the factors associated
with patients.[1]
and is 4–7% by palpation, 19–68% by high-resolution
ultrasound (US) in randomly selected individuals, with a Along with the developments in imaging methods, an in-
higher frequency in women and the elderly. Most of thy- crease in both the detection of thyroid nodules and, as a

Address for correspondence: Mehmet Taner Unlu, MD. Division of Endocrine Surgery, Department of General Surgery, University of
Health Sciences Türkiye, Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Türkiye
Phone: +90 539 211 32 36 E-mail: m.taner.unlu@gmail.com
Submitted Date: September 11, 2023 Revised Date: September 13, 2023 Accepted Date: September 18, 2023 Available Online Date: September 29, 2023
©
Copyright 2023 by The Medical Bulletin of Sisli Etfal Hospital - Available online at www.sislietfaltip.org
OPEN ACCESS This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
288 The Medical Bulletin of Sisli Etfal Hospital

result, the detection of thyroid cancer has been remarkable

in the last 3–4 decades.[2] Detection of any mass in a patient
is one of the most worrisome situations that causes fear of
cancer in the patient.[2,3]
It is important to evaluate all thyroid nodules to identify
those that are clinically significant requiring follow-up or
treatment. Detailed further evaluation and surgical inter-
vention are not required in most nodules. The main rea-
sons leading to surgery in thyroid nodules are presence of
cancer, hyperfunctioning, and compression symptoms of a
nodule. Diagnosis and treatment of thyroid nodules is one
of the most controversial issues. In this section, approaches
to the diagnosis and treatment of thyroid nodules will be
evaluated.

Definitions
Thyroid Nodule: Thyroid nodule is defined as a lesion that
can be distinguished from the surrounding thyroid paren-
chyma by US examination or other sensitive imaging meth-
ods.[1,4]
If the thyroid is structurally and/or functionally character-
ized by nodules that develop with transformation in one or
more areas, it is defined as nodular goiter.[5] Nodular goiter
is defined as a solitary thyroid nodule if it originates from a
single nodule, and as a multinodular goiter (MNG) if there
is more than one nodule.[6,7]
In US examinations performed for palpable solitary thyroid
nodules, one or more extrathyroid nodules are detected
except for the palpable nodule at a rate of 20–48%.[4]
In other words, solitary or multiple nodules in the thyroid
may be palpable or non-palpable (Fig. 1). Knobel proposed Figure 1. Multiple nodules in thyroid gland. Black arrow shows a sol-
the term nodular thyroid disease to describe all thyroid id nodule, white arrows show cystic thyroid nodules with septae.
nodules, including clinically palpable and non-palpable
solitary and multiple nodules, and stated that this term Clinical Risk Factors for Thyroid Cancer
would be more descriptive and appropriate.[7]
Although thyroid cancers are the most common endo-
In the fifth edition of the WHO classification of thyroid neo- crine cancer, the malignancy rate in thyroid nodules is not
plasms published in 2022, the clinical entity known as MNG high. Although the etiology of many thyroid malignancies
was previously used as a pathological entity; however, it is not clear, it is known that there are some risk factors
was stated that this term is not appropriate as it includes for thyroid cancer. Exposure to ionizing radiation due to
many lesions such as thyroiditis, hyperplasia, or tumoral treatment or accident during childhood or adolescence,
lesions. effects of dietary iodine intake (increased or decreased di-
To solve this problem, the term “thyroid follicular nodular etary iodine intake), family history of thyroid cancer, and
disease” has been proposed in this edition to avoid describ- hereditary syndromes associated with thyroid cancer are
ing a lesion as hyperplastic, neoplastic, or contradictory these risk factors. Although genetic changes and geno-
“adenomatous hyperplasia.”[8] We think that it would be ap- type phenotype relationship in familial medullary cancers
propriate to use the term “nodular disease of the thyroid,” are well known, genetic factors in non-medullary thyroid
which is recommended in both clinical and pathological cancers (non-MTC) have not been fully revealed. Family
classification, instead of the term thyroid nodule, due to its history of non-MTC increases the risk of malignancy (RoM)
comprehensiveness. 5–10 times.[2,9]
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 289

Familial non-MTC can be divided into two different groups follicular C cell-derived MTCs are less frequently tumors
as syndromic and non-syndromic cancers; and most of that play a role in the etiopathogenesis.
these cancers are not associated with syndromes. Syn- Sometimes lymphomas and metastatic cancers may in-
dromes associated with non-MTC; familial adenomatous volve the thyroid and present as a nodule. Rarely, malignant
polyposis and Gartner syndrome (both cribriform pattern or benign nodular growths may occur from the connective
papillary thyroid cancer [PTC]), Carney complex (PTC and and supporting tissue surrounding the thyroid follicles.[8]
Follicular thyroid cancer [FTC]), Cowden syndrome (PTC
[Classic and follicular variant] FTC), DICER 1 syndrome (dif- Clinical Diagnostic Approach in Thyroid Nodules
ferentiated thyroid cancer [DTC]), Werner syndrome (PTC, Thyroid nodules detected both clinically and incidentally
FTC, Anaplastic thyroid cancer [ATC]), PTEN hamartoma tu- on imaging performed for other reasons should be evaluat-
mor syndrome (FTC, PTC, follicular variant PTC, MNG); rarer ed regarding the cancer risk, presence of hyperfunctioning,
syndromes associated with non-MTC are Peutz- Jeghers compression symptoms and signs by history, physical ex-
syndrome (PTC, DTC), Pendred syndrome (PTC, FTC, ATC),
amination, biochemical tests, and imaging modalities (Figs.
Li-Fraumeni syndrome (PTC classic, follicular variant), atax-
2 and 3).[15,16]
ia telangiectasia syndrome (PTC), papillary renal neoplasia
(PTC), and McCune-Albright syndrome.[9] In present, with the widespread use of imaging methods,
most of the thyroid nodules are detected incidentally and
Familial MTCs are familial MTC and multiple endocrine neo-
these nodules are typically not palpable. Incidentally de-
plasia 2A/2B syndromes.[10,11] Recently, the intraglandular
tected thyroid nodule rate is 20–67% in extrathyroidal US
localization of the nodule has been demonstrated to be
examinations (evaluation of carotid artery, parathyroid,
an independent risk factor for malignancy. Nodules arising
from the isthmus show the highest risk for cancer diagno-
sis; whereas those in the lower third of the lobe have the
lowest risk compared to those in the middle or upper pole
of the lobe.[12]
The age at which the thyroid nodule is detected in a pa-
tient affects the cancer risk of the nodule; younger (<14)
and older (>70) age are associated with a higher RoM.[4]
Gender of the patient is another important factor for ma-
lignancy risk in thyroid nodule. Cancer development risk in
female gender is approximately 3 times higher than male
gender. The effect of hormonal factors that may explain the
mechanism of this risk factor is not clearly known.[2] Howev-
er, the RoM is higher in male patients with thyroid nodules.[13]

Ethiology and Pathogenesis

Many benign and malignant diseases can cause thyroid
nodules. Benign thyroid diseases that cause the most of
thyroid nodules are follicular nodular disease of the thy-
roid, follicular adenoma, oncocytic adenoma, simple or
hemorrhagic cyst, Hashimoto’s thyroiditis, and subacute
thyroiditis.[8,14] Non-invasive follicular thyroid neoplasm
with papillary-like nuclear features, thyroid tumors of un-
certain malignant potential, and hyalenized trabecular tu-
mor are classified as low-risk tumors (Low-risk neoplasms)
and these tumors also rarely present as nodules.[8]
Follicular cell-derived tumors constitute the majority of pri-
mary malignant thyroid tumors presenting with a thyroid
nodule; PTC, invasive encapsulated follicular variant pap- Figure 2. Clinical algorithm for evaluation of thyroid nodules (US: Ul-
illary carcinoma, FTC, oncocytic carcinoma of the thyroid, trasound examination, PE: Physical examination, TSH: Thyroid-stimu-
follicular-derived carcinomas, high-grade, and ATCs. Para- lating hormone).
290 The Medical Bulletin of Sisli Etfal Hospital

Figure 3. Clinical algorithm for thyroid nodules with patients who have high or normal Thyroid-stimulating Hormone levels.

Figure 4. (a) An incidental thyroid nodule (white arrow) causing tracheal deviation in computed tomography scan. (b) An incidental thyroid
nodule (white arrow) causing tracheal deviation in T1-weighted image in magnetic resonance imaging. (c) An incidental thyroid nodule (white
arrow) with increased 18-Fluoro-Deoxyglucose (FDG) uptake in FDG-Positron Emission Tomography/Computed Tomography.

cervical lymph node, internal jugular vein and other struc- ed in other nuclear medicine imaging studies. In small
tures of the neck), 9–25% in computerized tomography studies, especially in scintigraphies with technetium-99m
(CT) (Fig. 4a) and magnetic resonance imaging (MRI) (Fig. methoxyisobutilisonitrile (MIBI), the malignancy rate in
4b), and 1–4.3% in positron emission tomography/com- MIBI-enhancing thyroid nodules is 22–66%, and in PET/CT
with radio-labeled prostate-specific membrane antigen
puted tomography (PET/CT) (Fig. 4c).
(PSMA), the malignancy rate is 26% in PSMA-enhancing
Especially in PET/CT performed with 18-fluorodeoxyglu- thyroid nodules. The RoM in incidental nodules detected
cose (FDG), the RoM is high in active nodules and can on MR and CT varies between 0 and 11% (17). In addition to
reach 30%. Incidental thyroid nodules can also be detect- these, additional nodules are detected at a rate of 20–48%
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 291

in patients undergoing USG for palpable thyroid nodules.[4] Laboratory Examination

These nodules detected other than palpable nodules can Symptomatology and physical examination findings are
also be considered as incidental thyroid nodules.[17] not sufficient for the evaluation of thyroid function, and
Patient’s History, Symptoms, and Clinical Findings biochemical evaluation should also be performed for the
diagnosis. The main test giving information about the
Although patient history and physical examination alone
function of the thyroid gland is the serum thyroid stimu-
cannot determine the nature and composition of the thyroid
lating hormone (TSH) level. TSH measurement should be
nodule, there are some clinical features that may cause suspi-
performed first in all patients suspected of having a thyroid
cion of malignancy.[18] The risk factors listed above for malig-
nodule (Fig. 2). Normal serum TSH level indicates that the
nancy such as history of familial thyroid cancer or syndroms
function of the thyroid gland is normal in almost all pa-
related to thyroid cancer, and radiation to head and neck
tients.[28,29]
should be evaluated. The patient’s age and gender should be
considered in the risk assessment for malignancy.[19] TSH measurement is usually sufficient in the evaluation of
many patients with thyroid nodules, most tests other than
Patients may range from asymptomatic to patients exhib-
TSH are not necessary. If the serum TSH level is below the
iting symptoms of compression, hyperthyroidism, or hy-
normal reference range, a radionuclide thyroid scan should
pothyroidism. Symptoms may develop depending on the
be performed to determine whether the nodule is hyper-
size and function of the nodules, or the total volume and
functional (Fig. 2). If the serum TSH level is normal or high,
location of the thyroid gland.[20] In symptomatic patients,
radionuclide scanning should not be performed as the ini-
a detailed history and complete physical examination can
tial imaging evaluation (Fig. 3).[1,23]
guide the selection of appropriate clinical and laboratory in-
vestigations.[21,22] Furthermore, in symptomatic patients; the Since hyperfunctional nodules rarely contain malignancy,
duration of complaints, whether they have been evaluated cytological evaluation is not necessary. If there is overt or
before or are under follow-up, and growth or any changes subclinical hyperthyroidism, additional evaluation is neces-
in nodule should be evaluated.[19] Local symptoms do not sary. High serum TSH level is associated with an increased
occur in most of thyroid malignancies which rarely develop RoM in the thyroid nodule, as well as with more advanced
compression symptoms, vocal cord paralysis, or esophagus thyroid cancer.[1]
symptoms.[23] Compression-related symptoms and signs If the TSH level is outside the reference range (high or low);
such as cough and dysphonia may also suggest the risk of free T4 (fT4), total T3 or free T3 (fT3), and thyroid antibod-
an underlying malignant lesion. Therefore, surgical treat- ies such as antithyroid peroxidase antibody (anti-TPO), an-
ment should be considered in patients with an enlarged tithyroglobulin antibody (anti-Tg), TSH receptor antibody
thyroid mass and vocal cord paresis, although cytological (TSHRab) can be examined for the confirmation of thyroid
results are not compatible with malignancy.[23-25] The growth dysfunction and diagnosis of the disease, respectively.[28,29]
rate in the size of a nodule is not a reliable feature in distin- Thyroglobulin Measurement: Although serum thyroglobu-
guishing between benign and malignant nodules.[26] In be- lin (Tg) levels are typically high in unoperated thyroid can-
nign nodules, slow growth can be seen over the years.[21,22]
cer patients, they can also be markedly elevated in patients
Progressive nodule growth seen within weeks or months in
with benign MNG.[30-32]
a stable or recently noticed nodule may suggest malignan-
cy.[23,24] The appearance of a sudden development of swell- Tg is a biomarker that is frequently used in the monitoring
ing in the thyroid region accompanied by pain is usually of recurrence in patients with thyroidectomized for follicle
due to bleeding from the cystic nodule.[27] However, in the cell-derived thyroid cancer. However, thyroglobulin (Tg)
case of progressive and painful enlargement of the thyroid measurement is not recommended routinely in the evalu-
nodule in patients; anaplastic thyroid carcinoma, rare forms ation of thyroid nodules, as serum Tg levels are insensitive
of chronic thyroiditis (e.g., Riedel’s disease), and primary and nonspecific for thyroid cancer.[1]
lymphoma should be considered.[23,24] Calsitonin Measurement: Calcitonin is a sensitive and spe-
Despite the low predictive value of palpation, careful ex- cific biomarker used in the diagnosis and follow-up of para-
amination, and palpation of the thyroid gland, anterior and follicular C cell-derived MTC. In addition, MTC is a rare form
lateral lymph node compartments should be performed. and its incidence in thyroid nodules is 0.14–0.4%.[33,34]
[4]
The presence of solid, firm nodules fixed to surrounding Routine measurement of calcitonin in the evaluation of
structures such as trachea and strep muscles, enlarged re- thyroid nodules is controversial.[35] Serum calcitonin mea-
gional lymph nodes, or vocal cord paralysis by palpation surement is recommended in selected patients with nod-
increases the RoM over 70%.[18] ules who have a family history and clinical suspicion of
292 The Medical Bulletin of Sisli Etfal Hospital

familial MTC. In addition, calcitonin level should be mea- (Fig. 5 and Table 1) The size, shape, localization, echogenicity,
sured when MTC is suspected in US findings or uncertain vascular pattern, calcification, and/or cystic change of cervi-
cytology.[4] cal lymph nodes should be specified if there is (Fig. 6).[18]
The pattern of sonographic features associated with the
Imaging Methods nodule indicates the RoM and, combined with the nodule
size, guides the decision-making process for fine needle as-
Thyroid Ultrasonography (US)
piration biopsy (FNAB).[36,37]
High-resolution US is the most sensitive method available
and superior to other imaging methods in detecting thy- Should US be Performed in a Toxic Nodule?
roid nodules, measuring the size of the nodule, determin- In the patient group with low serum TSH levels and nod-
ing its shape, borders, localization and number, echoge- ules detected on thyroid scintigraphy, US should be per-
nicity, content, and evaluate any associated changes in the formed to evaluate both the presence of nodules that do
thyroid gland.[28] It is a non-invasive, inexpensive, and ioniz- not require FNAB compatible with hyperfunctional areas
ing radiation-free imaging method, and it is important that on scintigraphy and other non-functional nodules that
it should be performed by experienced physicians. Cervical meet the sonographic criteria for FNAB.[38] Since the malig-
lymph node examination with US should be performed in nancy rate is low in hyperactive nodules on scintigraphy,
all patients with or suspected of having a thyroid nodule. it is suggested that FNAB and cytological evaluation are
[1,28]
not necessary.[1] However, this proposal is still a controver-
Sonographic features; thyroid parenchyma (homogeneous sial issue in the literature. In a recent meta-analysis, Lau
or heterogeneous) and gland size; the size (in three dimen- et al. [39] reported that although the malignancy rate was
sions) and location of the nodule (e.g., right upper lobe), as reduced by 55% in hot nodules, it was not zero and the in-
well as the composition of the nodule (solid, cystic, or spon- cidence was higher than expected. In another recent study
giform), echogenicity (hypoechoic, isoechoic, hyperechoic, by Rosario et al., [40] although the malignancy rate is lower
and heterogeneous), marginal features, presence and type than that of the non-autonomous nodules, it is 14.6% in
of calcifications, shape (wider than tall or taller than wide), nodules with autonomous function. Researchers recom-
and vascularity of nodule should be included in US report mend performing FNAB in autonomous nodules larger

Figure 5. (a1): A taller-than-wide and markedly hypoechoic thyroid nodule (white arrow) with irregular margin and punctate echogenic foci
on background parenchyma. (a2): A thyroid nodule with irregular margin (white arrows). Post-operative pathology result was papillary carci-
noma on autoimmune thyroiditis background. (b): A hypoechoic thyroid nodule with punctate echogenic foci (White arrows). (c): A thyroid
nodule with taller-than-wide shape. (d): A thyroid nodule showing rim calcification (White continuous arrows show calcified margins and
white dashed arrows show non-calcified margins) (e): A hyperechoic thyroid nodule with multiple punctate echogenic foci (White arrows).
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 293

Table 1. Comparison of ATA and ACR TI-RADS systems

VARIABLES THAT SHOULD BE INCLUDED IN THE THYROID US REPORT

Thyroid Dimensions, volume, vascularity Neck level
Dimensions*, shape Dimensions, shape
Location, composition (includes echogenicity) Cortical thickness, echogenicity
Lymph node(s)
Nodule Margins Calcifications / cystic areas
Calcifications: macro/micro/peripheral Soft tissue relationship
Vascularity Vascular patern

CLASSIFICATIONS
ATA ACR TI-RADS
TIRADS US PATTERNS Point
ROM Total
Group US PATTERNS Group (TR)
(%) Score
Class COMPOSITION
(Choose one)
Spongiform 0
Cystic1 0
Pure cystic Mixed2 1
Benign <1
(no solid component) Solid 2
Cannot be 2
determined3
Benign TR 1 0
Spongiform ECHOGENITY4
Partially cystic (Choose one)
Very Low Anechoic 0
<3 Iso/hyper echoic 1
Risk Without features consistent
with the following groups Hypoechoic 2
Very hypoechoic 3
Iso / hyperechoic solid SHAPE: Diameter5
Not
Cystic + eccentric solid area TR 2 2 Choose one
Suspicious
Wider than tall5 Wider than tall 0
Low Risk 5-10 Taller than wide 3
Microcalcifications
Mildly
No Irregular margin TR 3 3
Suspicious
ETE MARGIN
Choose one
Hypoechoic solid
Smooth 0
Smooth margins Ill-defined 0
Intermediate Moderately
Wider than tall 5 10-20 TR 4 4-6 Lobulated6 / irregular7 2
Risk Suspicious
ETE ETE 3
No
Microcalcifications
Hypoechoic solid
ECHOGENIC FOCI
Partially cystic+ Hypoechoic
Choose all that apply
solid areas
PLUS one or more features
None 0
- Irregular margin 7 Highly
High Risk % 70-90 TR 5 ≥7 Comet like artifact8 0
(infiltrative, microlobulated) Suspicious
Macrocalcification9 1
- Microcalcifications
Rim calcification10 2
- Rim Calcifications10
Small echogenic foci 3
- Taller than wide5
(microcalcification)
- ETE

1: More than 50% of the spongiform nodule contains small cystic areas. 2: Mixed: Contains cystic and solid areas. The component that occupies more than
50% of the nodule determines the type of nodule. 3: If the composition of the nodule cannot be determined due to dense calcifications, 2 points. are given. 4:
Hypoechoic nodule: If nodule echogenicity is lower than that of intact thyroid parenchyma; very hypoechoic nodule: If nodule echogenicity is lower than that
of strap muscle. 1 point is given for a nodule whose echogenicity cannot be determined exactly. 5: When the ultrasound probe is held in the transverse plane,
the measurement parallel to the direction of the sound waves (beam) is recorded as depth (tallness!) or antero-posterior diameter, and the measurement
perpendicular to the sound waves is recorded as width. 6: Lobulation: Protrusion into adjacent tissue. 7: Irregular margin: It is defined as the margin of the
nodule being rough or having spiky protrusions or sharp corners. 8: A "V"-shaped flare, usually greater than 1 mm, in the cystic component of the nodule
is defined as a comet-like appearance. 9: Macrocalcification: Coarse calcification causing acoustic shadowing. 10: Complete (eggshell-like) or incoplete thin
calcifications along margin of the nodule, and may cause acoustic shadowing.)(Table 1 is established using the ATA and ACR TI-RADS guidelines (1,4)
294 The Medical Bulletin of Sisli Etfal Hospital

Figure 6. (a) A hypoechoic metastatic cervical lymph node (white arrow) with peripheric penetrating vascular structures. (b) A metastatic
cervical lymph node (white arrow) with cystic components. (c) A hyperechoic metastatic cervical lymph node (white arrow).

than 1 cm with ultrasonographic findings suspicious for In the ATA guideline, biopsy is recommended for nodules
malignancy. FNAB is also recommended in other studies of >1 cm in moderately and highly suspicious nodules,
in selected patients particularly with suspicious features and >1.5 cm with low risk. In very low-risk nodules, biopsy
on US in autonomous functioning nodules.[41-43] Although is recommended for nodules of > 2 cm, and it is stated
there is still a need for extensive studies on this subject, that nodules of <2 cm can be followed without biopsy.
it strengthens the idea that suspicious US features of the Biopsy is not recommended for nodules with benign pat-
hyperfunctional nodule should be taken into account in terns (Table 2).[1,26]
terms of malignancy and FNAB should be performed in In the ATA guideline, irregular margins (infiltrative and mi-
selected patients. crolobulated), microcalcifications, taller than wide shape,
Ultrasonographic Risk Classification rim calcifications with small extrusive soft-tissue compo-
nent, and evidence of ETE are listed as suspicious features
Multiple risk classification systems based on the above-men-
in US (Fig. 5 and Table 1). Solid hypoechoic or partial cys-
tioned sonographic features of thyroid nodules have been
tic nodules with solid hypoechoic component containing
established to develop a common language for identifying
one or more of these features are categorized as highly
and classifying the nodules at greatest risk for morbidity,
suspicious. However, solid or partial cystic hyper/isoechoic
and preventing unnecessary biopsies performed on be-
nodules containing one or more of these features are not
nign nodules (Table 1).[1,4,26,44-48]
categorized.
Risk classification systems are used for dividing thyroid
In a meta-analysis of 16 studies including 21,000 nodules
nodules into categories based on their composite sono-
which have not been categorized in the ATA guideline, the
graphic features associated with malignancy risk and this
pooled prevalence was 7.8% (1872 nodules; [confidence
classification can guide surveillance strategies and per-
interval; CI 5.1–11.1]), with a pooled RoM 20.3% (CI 13.0–
forming US-guided FNAB. One of the two most widely
used systems in clinical practice is the American College 28.7), which was found to be comparable with the nodules
of Radiology Thyroid Imaging Reporting and Data System of intermediate suspicious risk category in the ATA guide-
(ACR TI-RADS) used by many radiologists, and the other is line. However, there was significant heterogeneity be-
the American Thyroid Association (ATA) guidelines used tween studies (I2=92.8%, p<0.001); a significant difference
by many endocrinologists (Table 1). ACR TI-RADS sums was found between single center and multicentric studies
it up by assigning points for each of the five ultrasound (24.8% vs. 12.3%, respectively, p=0.031) and also between
characteristics and identifies risk categories from TR1 (be- retrospective and prospective studies (25.1% vs. 8.5%, re-
nign) to TR5 (highly suspicious). In the ATA guideline, the spectively, p=0.003).[49]
US features were combined and the nodules were divided In the ACR TI-RADS classification, the composition, echo-
into five categories as highly suspicious, moderately sus- genicity, shape, border features, and echogenic foci of the
picious, low suspicious, very low suspicious, and benign nodule were scored on US and divided into five categories
patterns. Biopsy and follow-up criteria according to ATA according to the sum of these scores (Table 1). Nodules not
and ACR TI-RADS are summarized in Table 2. In all guide- categorized by ATA are categorized by ACR TI-RADS (TR)
lines, FNAB is recommended considering the nodule size with this scoring system. In addition, FNAB recommended
and RoM in the categories to avoid unnecessary biopsies. nodule diameter is larger in ACR TI-RADS than that is in the
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 295

Table 2. Comparison of recommendations for follow-up and biopsy timing in ATA and ACR TI-RADS classifications

ATA ACR TI-RADS

First
Recommendation Follow-up FNA: Benign Follow-up Recommendation
GROUP CLASS
for FNAB with US with US for FNAB
Not recommended
No routine
Benign (Diameter ≥ 4cm *
follow up
aspiration)
Diameter
If FNAB was
1
No routine Not TR 1
Diameter ≥ 2cm ≥ 1cm
performed, follow-up recommended Benign
Very low FNAB After 2 years
if there is
risk or < 1cm growth2/change
follow No routine consider FNA
Follow up
No routine
Not TR 2
Follow up
recommended Not Suspicious
Diameter ≥ 1.5cm After 2 years
Low 12–24 month if there is
FNAB Diameter
risk intervals growth2/change in TR 3
≥ 1.5cm Diameter ≥ 2.5cm
the nodule Mildly
In 1–2 & 5 FNAB
consider FNA Suspicious
years
Intermediate Diameter ≥ 1cm 12–24 months Diameter
TR 4
Risk FNAB at intervals > 1 cm Diameter ≥1.5 cm
Moderately
Diameter ≥ 1cm In 1-2-3 & 5. FNAB
Suspicious
FNAB years
US and
High FNAB Diameter
3

Annual > 0.5cm TR 5

Risk Diameter < 1cm within 12 In 12 Diameter ≥ 1cm
months 6-12 months Highly
Follow months FNAB
interval for 5 Suspicious
years
*: Since there is no need for biopsy in these nodules after the first ultrasound, it can be decided whether to follow up according to clinical findings. 1: While
ATA recommends FNAB for nodules ≥ 2 cm in diameter in very low risk group, ACR TI-RADS does not recommend FNAB or even follow-up with US for TR 1 and
TR 2 corresponding to this class. 2: A 50% increase in nodule volume or 20% increase in 2 dimensions of the nodule in 12-18 months is considered as nodule
enlargement (growth) 3: FNAB can be performed in nodules with a diameter of 0.5-1 cm, taking into account the history of exposure to ionizing radiation, a
strong family history of thyroid cancer, suspicion of lymph node/distant metastasis, or the patient's preference.) (Table 2 is established using the ATA and ACR
TI-RADS guidelines (1,4).

ATA guideline. TR1 (0 points) is categorized as benign, TR2 ported that it was not a predictive factor for malignancy in
as not suspicious, and biopsy is not recommended in these subsequent studies.[50-52]
nodules. FNAB is recommended in TR3- mildly suspicious In the meta-analysis by Khadra et al., [53] there was no sig-
(3 points) nodule of ≥2.5 cm, TR4- moderately suspicious nificant difference between benign and malignant nodules
(4–6 points) nodule of ≥1.5 cm, and TR5-highly suspicious in terms of vascular flow, peripheral vascular flow, and in-
(≥7 points) nodule of ≥1 cm.[26] ternal vascularity in color Doppler US. It is stated that in-
Although the malignancy risk ratios are given in the ATA creased nodular vascularity cannot predict malignancy.
guideline table, the malignancy risks are not given in the
Intranodular vascularity is more common in follicular vari-
ACR TI-RADS table (Table 1). Different rates can be seen in
ant papillary carcinoma and follicular carcinoma compared
various studies in the literature. In the literature, malignan-
to classic papillary thyroid carcinoma. It is depicted that in-
cy rates of <2% in ACR TI-RADS TR1 and TR2, 2.1–5% in TR3,
tranodular vascularity is also common in medullary thyroid
5–20% in TR4, and >20% in TR5 are noteworthy.[19]
carcinoma.[52,54]
Intranodular Vascularity Color Doppler or power Doppler US is widely used to de-
Although intranodular vascularity has been identified as termine vascular flow in thyroid nodules, but new methods
a risk factor for malignancy in previous studies, it was re- have been developed recently to evaluate vascular flow
296 The Medical Bulletin of Sisli Etfal Hospital

because it is a nonspecific feature for malignancy and not should not be used completely instead of US, but it can be
of high diagnostic value. Superb microvascular imaging used as a complementary method to US and may contrib-
(SMI), one of which views low-velocity blood flow, has been ute to reduce unnecessary FNAB.[62]
started to be used in clinical practice for evaluating thyroid
nodules after liver and breast. In the last metaanalysis; for Thyroid US Findings in Non-PTCs
malignant thyroid nodules, SMI was found superior to col- The suspicious US findings such as taller than wide shape,
or Doppler US in providing significantly more information microcalcifications, and hypoechogenicity are well-pre-
about vascularity and its diagnostic efficiency was found dictive factors for papillary thyroid carcinoma but less fre-
to be better than color Doppler US. It has been concluded quently associated with other thyroid cancers.[18]
that SMI had better clinical application value.[55] In general, US features of FTC are different from classical
Another developing technique is contrast-enhanced US PTC. Tumors associated with FTC are more likely to have in-
which was firstly used for imaging liver lesions. Afterward, tranodular vascularity, iso or hyperechogenic composition,
it has been used for imaging the thyroid and many organs. absence of calcifications on sonography, and nodules with
Angiogenesis is the basis of neoplastic growth, and con- regular margins and round shape (width greater than AP di-
trast-enhanced ultrasound (CEUS) is considered an effec- ameter). The US image in follicular variant PTC has the same
tive technique to assess microvascularization.[56] In a recent US features as FTC rather than PTC. Since distant metastases
meta-analysis, the sensitivity of CEUS was found slightly are rare in folliculary cancers smaller than 2 cm, the diameter
higher than that of conventional US in distinguishing be- cutoff for FNAB is higher for the hypoechoic nodules.[1]
tween benign and malignant nodules (0.87; [95% CI: 0.82– The tall cell variant of PTC usually shows the classic signs
0.90] vs. 0.84 [95% CI: 0.75–0.90]).[57] The perfusion type of of malignancy on US including significantly hypoechoic
CEUS has good diagnostic performance for cervical lymph nodules with lobulated contours and microcalcifications.
node metastasis in PTC.[58] Lymph node metastasis and extrathyroidal extension may
Some features of CEUS overlap in the differentiation of ma- be evident.
lignant and benign nodules, and further studies are need- The diffuse sclerosing variant of PTC may pose a diagnostic
ed for reliable standardization.[59] challenge on US examination, as the gland may appear en-
larged and widely hypoechoic, as in Hashimoto’s thyroid-
Elastography
itis. Numerous fine and scattered hyperechoic microcalci-
Clinically firm thyroid nodule is associated with malignancy fications might be visualized as a “starry night” appearance
risk. Elastography is a dynamic technique evaluating tissue in wide areas of the thyroid.[4]
elasticity through US. At present, two different techniques
Oncocytic cell neoplasms have a heterogeneous US ap-
are used for elastography during real-time US evaluation
pearance; echogenicity is usually reduced, but hypere-
of palpable and non-palpable thyroid nodules. Strain elas-
tography evaluates the degree of deformation in the tissue choic tumors are not uncommon. Vascular organization is
due to the pressure applied with the US probe. A special variable. A large, irregularly circumscribed, and inhomoge-
software evaluates the degree of displacement of the tis- neous solid structure surrounded by an irregularly thick-
sue under compression, and this parameter is reflected ened halo is common in these tumors.[4]
on a colored scale according to the stiffness of the nodu- US findings of MTC are variable. Although they show US
lar and extranodular tissue. The other is shear wave speed features similar to PTC such as marked hypoechogenicity
measurement, which measures the speed of shear waves and coarse calcifications, they are more likely to be round-
propagating perpendicular to the direction of tissue dis- ed (not long, but wide), have regular borders, mixed echo-
placement. The speed of shear waves is generally higher in genicity, and intranodular vascularity than PTC.[54,63,64]
malignant thyroid nodules than in benign nodules.[60] While
Examination of Lymph Node
elastography shows promise as a technique for noninvasive
assessment of cancer risk, its performance is highly vari- Evaluation of central and lateral compartments of the neck
able and operator-dependent. It is also not a standardized with US in terms of lymph node metastases is important. Sus-
method for data reporting. Moreover, cystic lesions, nod- picious non-palpable lymph nodes detected on US increase
ules with microcalcifications, MNGs with deep-seated co- the RoM in the nodule and may affect the surgical plan.[18]
alescent nodules, microcarcinomas, and nodules in chronic There is no single sensitive sonographic feature for detect-
thyroiditis are less suitable for elastographic evaluation.[61] ing metastatic lymph nodes in thyroid cancer. Enlargement
In the last meta-analysis, it was stated that diagnostic value of lymph node, loss of fatty hilum, rounded shape rather
of elastography in malignant thyroid nodules is limited. It than oval, hyperechogenity, cystic transformation, calcifi-
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 297

cations, and peripheral vascularity are abnormal US find- take is low.[4] Although there is no radioactive iodine up-
ings that suggest metastatic lymph nodes (Fig. 6).[1] take in 3–8% of the nodules, 99mTc-pertechnetate may
Artificial intelligence studies, which are also being evaluat- be uptaken and cause false positive results. In addition,
ed in medicine recently, are promising to improve thyroid 99mTc-pertechnetate uptake in the esophagus and vascu-
cancer risk estimation. Future studies using artificial intel- lar structures may also cause false positive imaging.[65]
ligence should focus on improving patient outcomes and When there is low thyroid uptake, better imaging can be
use rigorous scientific methods.[13] obtained with I-123 providing better visualization of the
retrosternal region, and also true iodine clearance can be
Other Cross-sectional Imaging Methods measured. However, it is much more expensive and diffi-
Computed Tomography (CT) and Magnetic Reso- cult to obtain. The imaging time is generally longer, often
nance Imaging (MRI) using delayed 24th h imaging.[4]

CT and MRI have no routine use in the initial evaluation of Fine Needle Aspiration Biopsy
thyroid nodules and do not have reliable findings for the FNAB is still the gold standard method for evaluating the
differentiation of benign and malignant thyroid nodules. In thyroid nodules.[14] FNAB is an outpatient method that is
case of situations such as the need of thyroid volume eval- easily applied, generally well tolerated, and can be per-
uation, compression on the trachea, retrosternal extension formed with low complication rates. It is a fast and safe
of the nodular goiter and evaluation of its relation to other method that has high sensitivity, specificity, and precision
intrathoracic vascular structures, prediction of invasion to and also can distinguish between benign and malignant
surrounding tissues, and presence of conglomerate lymph nodules with high accuracy.[18,66]
node metastasis or pathological lymph node that cannot
be detected through US; CT and MRI should be performed Cytological evaluation of FNAB
in addition to US (Fig. 4a and b).[4,20] At present, The Bethesda System for Reporting Thyroid
Iodinated contrast material is used in CT and its use should Cytopathology (TBSRTC) is the most commonly used clas-
be avoided since it may cause Jod-Basedow phenomenon. sification system for the cytological evaluation of FNAB.
In centers where nodular goiter is evaluated, the role of MRI TBSRTC is a simplified, 6-category-based reporting system,
in evaluating the volume and characteristics of nodules is and its first 2 editions (2010 and 2017) significantly achieved
limited. There are no comparative studies with reliable re- its goal of standardizing thyroid cytopathology reporting.
sults regarding the use of MRI and CT methods.[7] This classification system was updated as the third edition
in 2023 in accordance with the terminology of the classifi-
18-FDG-PET/CT cation of thyroid neoplasms updated by the World Health
FDG-PET/CT has no place in the initial evaluation of a thy- Organization in 2022.[66] In this edition, alternative names
roid nodule.[17] Many DTC and MTCs do not uptake FDG. from the three diagnostic categories that may have caused
Therefore, PET/CT can be considered only in the pre-opera- some confusion in previous editions (the terms “unsatisfac-
tive staging of aggressive malignant nodules (Fig. 4c).[4] tory” for Bethesda 1, “follicular lesion of undetermined sig-
nificance” for Bethesda 3, “suspicious for follicular neoplasm”
Scintigraphic Methods for Bethesda 4) have been removed by giving each category
If TSH value is below the lower limit of normal range in lab- a unique name.[67] The RoM rates for adults have been up-
oratory evaluation, scintigraphic imaging should be per- dated for each category based on the results of the prospec-
formed to evaluate the functional status of the nodule. By tively analyzed large series published since 2017.[67]
scintigraphy, it can be evaluated whether the nodule is hy- Although thyroid nodules are less common in childhood
peractive (hot), normoactive (warm), or hypoactive (cold). than adults, the rate of malignancy for thyroid nodules in
Scintigraphic imaging can be performed using radioactive children is higher than in adults. It is essential to ensure
iodine (I-123 or I-131) or 99mTc-pertechnetate. Use of I123 that the Bethesda system is also used by children.[68] In
is recommended preferably. Diagnostic testing with I131 is this edition, ROM rates for childhood thyroid cancers were
not recommended unless low-uptake thyrotoxicosis is sus- calculated according to six categories, associated with fre-
pected.[1,4] quently used practical guidelines, and treatment recom-
99mTc-pertechnetat is cheaper, more accessible, and has mendations are given separately.[67]
a shorter shooting time. Although 99mTc-pertechnetate is Non-diagnostic (Bethesda I): Approximately 15% of FNABs
uptaken, it is not organificated, so it can cause false posi- are in the non-diagnostic category.[14] It is difficult to calcu-
tive and negative results. Image quality is poor when up- late the malignancy risk in this category, since most of the
298 The Medical Bulletin of Sisli Etfal Hospital

nodules whose initial FNAB results have been non-diagnos- In this category, the ROM differs according to the cytomor-
tic were not resected. The ROM is 13% in resected nodules phological features considered as atypia. The ROM in nu-
whose initial biopsy is reported as non-diagnostic. This rate clear atypia is higher than other atypical features (such as
is higher compared to the entire non-diagnostic cohort.[67] cellular structural atypia, oncocytic atypia, and lymphocyt-
FNAB should be reperformed in a nodule with an initial ic atypia).[70,71]
biopsy result of non-diagnostic.[14] In nodules with non-di- In the latest update of the Bethesda classification, it has
agnostic FNAB results and especially including small cystic been suggested that the Bethesda III category be divided
components, US-guided second FNAB results in a diag- into two subclasses: Nuclear and other atypia. In particular,
nostic cytology with a rate of 60–80%. Thus, the treatment the presence of nuclear atypia is important for the cyto-
should be decided according to the recommendations in pathologist to warn the clinician that the ROM is higher.[67]
the relevant category.[67] Making this distinction can make a significant contribution
If the second FNAB result is Bethesda I again, surgical resec- to the selection for the application of molecular tests, espe-
tion should be considered (Table 3).[69] cially in the nuclear atypia group.[71]
Benign (Bethesda 2): Approximately 70% of FNABs result In this category, the decision should be made according to
in benign cytology.[14] The ROM is low in nodules with be- the patient’s clinical risk factors, US characteristics of the
nign cytology. Although it is 4% in resected nodules with nodule, available facilities, and the patient’s preference.
benign cytology, the rate is around 1–2% when long-term FNAB is repeated considering the factors related to the
follow-up nodules are taken into account.[67] US findings of patient and the nodule. If FNAB result is still in the unde-
the nodule are important in the follow-up of patients with termined group or there are nodules with high risk factors,
benign cytology, and this issue is evaluated in the treat- diagnostic lobectomy should be performed. Nodules with
ment section (Table 3). low-risk features can be followed by US.[14] After the patient
is informed regarding the characteristics of the nodule and
Atypia of Undetermined Significance (Bethesta III) Nodules:
treatment options, diagnostic lobectomy can be considered
Bethesda III and IV account for 10–15% of FNAB results.[14]
in case the patient is unwilling to be followed up (Table 3).
In these nodules, the latest Bethesda classification update
recommends FNAB repeat, molecular tests, lobectomy, and Follicular Neoplasm (Bethesda IV): The ROM is 30% in adults
clinical follow-up options in adults. The ROM in this catego- and 50% in children in this category. Molecular tests can be
ry averages 22% in adults according to data based on sur- used for risk assessment in adults.[72]
gical resection materials. Considering all Bethesda III FNAB Surgical resection is recommended in children since the ma-
results, this rate is likely higher than expected. The mean lignancy rate is higher. Surgical resection, often hemithyroid-
ROM is slightly higher in children (28%), and repeat FNAB ectomy or lobectomy, is recommended for the treatment of
or lobectomy is recommended.[67] nodules diagnosed with follicular neoplasia (Table 3).[67]

Table 3. The 2023 Bethesda System for Reporting Thyroid Cytopathology (This table is established using The 2023 Bethesda System for
Reporting Thyroid Cytopathology guideline (67))

Adult Pediatric
Diagnostic Category ROM Usual Management ROM Usual Management
%Mean (min-max) %Mean (min-max)
Nondiagnostic Bethesda I %13 (5-20) Repeat FNA with %14 (0-33) Repeat FNA with
ultrasound guidance ultrasound guidance
Benign Bethesda II %4 (2-7) Clinical and ultrasound %6 (0-27) Clinical and ultrasound
follow-up follow-up
Atypia of undetermined Bethesda III %22 (13-30) Repeat FNA, molecular %28 (11-54) Repeat FNA, lobectomy
significance testing, lobectomy,
surveillance
Follicular Neoplasm Bethesda IV %30 (23-34) Molecular testing, %50 (%58-100) Surgical resection
diagnostic lobectomy
Suspicious for Bethesda V %74 (67-83) Molecular testing, %81 (40-100) Surgical resection
malignancy lobectomy or near-total
thyroidectomy
Malignant Bethesda VI %97 (97-100) Lobectomy or near-total %98 (86-100) Surgical resection
thyroidectomy
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 299

Suspicious for Malignancy (Bethesda V): In this category, ThyraMIR (MPTX) and Thyroseqv3 (TSv3). Molecular tests
the ROM is reported as 74%. Molecular tests can be used to can be classified as “rule in” and “rule out” based on their
determine the extent of surgery.[67] ability to confirm or exclude malignancy.[74]
In these patients, lobectomy or total or near-total thyroid- Vargas-Salas et al. [75] reported that a robust “rule out” test
ectomy can be performed (Table 3).[67] with a thyroid cancer prevalence value of 20–40% requires
Malignant (Bethesda VI): This category includes malignant a minimum negative predictive value of 94% and a mini-
results of different tumor types diagnosed according to the mum sensitivity of 90%; however, they found that a “rule
cytomorphological features in FNAB. The average ROM is in” test for malignancy required a positive predictive value
97%. The type of surgery should be determined according of at least 60% and a specificity >80%. MPTX, Afirma GSC,
to the type and characteristics of the tumor. In metastatic and TSv3 all demonstrated to perform well as undiagnosed
tumors, necessary investigations should be made about (Bethesda III and IV) “exclusion” tests based on their rela-
the primary tumor. Depending on the type of primary tu- tively high sensitivity and negative predictive values. How-
mor, there may not be an indication for surgery of the thy- ever, their diagnostic confirmatory performance for malig-
roid (Table 3).[67] nancy is still limited (Table 3).[74]
Molecular testing for thyroid nodules and thyroid cancer in-
Number of nodules to be biopsied creases the diagnostic accuracy of indeterminate thyroid nod-
FNAB may be indicated for more than one nodule accord- ules. Although the use of molecular tests is increasing, the cost
ing to US features of the thyroid. Biopsy of three or more of molecular tests varies between 3000 and 5000 dollars and
nodules is not well tolerated by patients. Cost increases the most important problem is still the cost of testing.
without significant a benefit, and there are some addition-
al risks. If FNAB is indicated in three or more nodules con- Tru-cut biopsy
sidering the ACR TI-RADS classification, it is recommended FNAB is the first-line diagnostic tool in thyroid nodules, and
to biopsy two of the most suspicious nodules according to there is no difference in diagnostic performance between
their total scores.[26] FNAB and thick needle biopsy.[76] Although FNAB is suffi-
cient for the evaluation of many nodules, tru-cut biopsy
Immunohistochemical studies in FNAB (with 18–21 gauge needle) is recommended in some rare
Immunohistochemical method is a good method for de- cases. In recent years, the use of tru-cut biopsy has been
tecting malignancy in paraffin block tissue. CD56 negativi- increasing as an alternative, especially in non-diagnostic
ty, CK19, HBME-1, and galectin-3 positivity are some of the (Bethesta I, III, and IV) biopsied thyroid nodules.[68] Tru-cut
most appropriate markers in the differential diagnosis of biopsy has low non-diagnostic outcome rates and high
malignant and benign lesions of the thyroid.[68] Although the specificity for the diagnosis of malignancy in thyroid nod-
use of these immunohistochemical markers in FNAB speci- ules whose initial FNAB is non-diagnostic. Tru-cut biopsy
mens has been limited to date, some studies have reported is indicated as a safe diagnostic technique with higher di-
that a single or a combination of two or three may contrib- agnostic efficiency and low complication rate, especially
ute to the detection of malignancy in FNAB specimens. In in cases where molecular testing is not available or FNAB
the latest meta-analysis, Galectin-3, HBME-1, CK-19, CD-56, cannot obtain enough cells for molecular testing.[77]
and TPO are stated as high-confidence marker candidates Tru-cut biopsy may be considered in second biopsies, es-
whose efficacy should be confirmed in thyroid cytology.[73] pecially in selected patients for whom it is difficult to ob-
Although immunohistochemical analysis of FNAB smears tain sufficient samples in FNAB. In addition, in fast-growing
increases the overall diagnostic accuracy, more studies are thyroid masses with suspected ATC or thyroid lymphoma,
needed to determine the best immune panel. it is more appropriate to prefer tru-cut biopsy instead of
FNAB as the first diagnostic tool.
Molecular tests in FNAB
There have been rapid developments in the past 15–20 Treatment and Follow-up
years in cytomolecular tests, which are used to reduce the Follow-up in Benign (Bethesta II) Nodules: There is no con-
need for diagnostic surgery, especially in FNAB samples di- sensus in the guidelines regarding the follow-up period.
agnosed with Bethesda III and IV.[74] According to the guidelines of the American Association
The three molecular tests most commonly used in the Unit- of Endocrinologists, nodules with benign cytological find-
ed States today, each using different methods, are Afirma ings and no clinical and US risk factors can be followed up
Genomic Sequencing Classifier (Afirma GSC), ThyGeNEXT/ if they are asymptomatic.
300 The Medical Bulletin of Sisli Etfal Hospital

The follow-up of nodules with benign FNAB is defined in Follow-up is not recommended for benign (TIRADS 1) and
the ATA guideline and these follow-up criteria are written not suspicious nodules (TIRADS 2).[1,26] If the ACR TI-RADS
in next sections. Since the false negative rate in FNAB is score increases in follow-up nodules compared to the pre-
low, it is common practice to follow up most of the nodules vious control, a repeat US control should be performed 1
with benign FNAB results with US. Since US nodule features year later, regardless of the initial TIRADS score. The Amer-
rather than enlargement are associated with high missed ican Radiology Association guideline stated that the ab-
malignancy, it is recommended to follow-up thyroid nod- sence of any change in the size of a nodule under follow
ules with benign cytology according to the risk classifica- up period of 5-years can safely indicate that the nodule is
tion in US.[1,4,46] benign, and US follow-up of these nodules can be termi-
US control and repeat FNAB within 6–12 months are rec- nated.[26]
ommended for nodules with highly suspected US features FNAB should be repeated in nodules with a 20% (2 mm
and benign FNAB results. If they are benign in the second and above) increase in at least 2 diameters of the nodule
FNAB, these nodules can be followed by US.[1,4] US should or more than 50% increase in the nodule volume or in case
be repeated within 12–24 months in nodules with low and new suspicious US features are detected in the follow-up.[1]
moderate suspicious US features. If there is enlargement on Routine US follow-up is not required in very low-risk nod-
US (20% increase in at least two nodule dimensions with ules and cysts smaller than 1 cm due to the ATA guideline.
a minimal increase of 2 mm or more than a 50% change However, in very low-risk nodules or cysts larger than 1 cm,
in volume) or new suspicious US features develop, FNAB US follow-up and time interval are unknown. If follow-up is
should be repeated or follow-up with repeated USs should to be carried out, US should be repeated at intervals longer
be continued. If growth continues in US follow-up, FNAB than at least 24 months.[1]
should be repeated.[1]
Medical Treatment
The use of US in the follow-up of very low suspicious nod-
ules (including spongioform nodules) and the evaluation L-thyroxine suppression therapy is not recommended for
of nodule enlargement as an indicator in repeat biopsy are benign nodules. L-thyroxine therapy is not recommended
limited in detecting missed malignancy. If US is to be re- to prevent recurrence in individuals with normal serum TSH
levels after lobectomy. Appropriate iodine intake should be
peated, it should be performed after 24 months.[1]
provided in young patients with a follow-up nodule, iodine
If the repeated US-guided FNAB of the nodule is benign, support can be given in followed-up patients who are not
then US follow-up is not required for the continuation thought to have adequate iodine intake. L-thyroxine re-
of the malignancy risk.[1] To exclude this nodule from fol- placement therapy is recommended in young patients with
low-up, it is important that it is asymptomatic and has no subclinical hypothyroidism due to autoimmune thyroiditis.[4]
suspicious US features.[4] This method can be applied for
solitary nodules. However, in MNG, long-term follow-up is Surgical Treatment
usually required.[18] Surgical treatment may be required for nodules that cause
The follow-up of nodules that do not meet the FNAB crite- symptoms such as breathing and swallowing difficulties
ria in the initial evaluation is going to be decided according due to compression on the trachea and esophagus or for
to the recommendations of the ATA guideline and ACR TI- cosmetic reasons.[11,19,78]
RADS guideline.[1,26] It is recommended to repeat US in 6–12 Progressive nodule enlargement can be an indication for
months for nodules <1 cm with highly suspicious USG fea- thyroidectomy.[1] Although there is no exact nodule diam-
tures, and annual US control for 5 years for nodules >×0.5 eter established for the surgery, some researchers recom-
cm in ACR TI-RADS 5 is recommended.[1,26] mend thyroidectomy for Bethesda II-diagnosed nodules
For nodules of <1 cm with moderate suspicious US fea- larger than 3 or 4 cm because of the higher false-negative
tures, ATA recommends follow-up with US at 12–24-month FNAB rate and higher RoM.[79-81]
intervals. American Radiology Association recommends However, in some other studies, it has been reported that
follow-up with US in TIRADS 4 >1 cm nodules at 1st, 2nd, 3rd, the malignancy rates are not higher in nodules larger than
and 5th years. 4 cm compared to nodules smaller than 4 cm, and nodules
In nodules with low suspicious US features, ATA recom- larger than 4 cm should be individualized according to clin-
mends follow-up with US at 12–24-month intervals, and ical, ultrasonographic, and cytological characteristics rath-
very low-risk nodules at intervals longer than 24 months er than routine surgical resection based on size alone.[82,83]
and in TIRADS 3 for >1.5 cm nodules at 1st, 3rd, and 5th years. While making a decision in these patients, it would be ap-
Uludag et al., Management of Thyroid Nodules / doi: 10.14744/SEMB.2023.06992 301

propriate to share the nodule characteristics and different Since the morphological features of nodules treated with
recommendations with the patient, and to choose the ablative methods may change over time, they should be fol-
treatment method specifically with the patient. In undeter- lowed clinically and ultrasonographically. If regrowth occurs
mined categories (Bethesda I, III, and IV) diagnostic lobec- at follow-up, evaluation with a new FNAB is required to con-
tomy can be performed.[67] tinue follow-up or before re-ablation. Appropriate patient
Although there are benign FNAB findings, surgery can be selection and an experienced practitioner are the main fac-
considered in nodules with suspicious US features for ma- tors that increase the success rate while minimizing the risk
lignancy. Thyroidectomy may be required in hyperfunc- of complications for all these ablative procedures.[11,85]
tional nodules (solitary nodule or toxic MNG).[11] Disclosures
When surgery is needed, the extent of the resection (lo- Peer-review: Externally peer-reviewed.
bectomy or total or near-total thyroidectomy) depends on Conflict of Interest: None declared.
many factors such as diagnosis of disease, symptoms, pres-
Authorship Contributions: Concept – M.T.U., M.U., M.K.; Design
ence of nodules in the contralateral lobe, functional status – M.T.U., M.K., O.C.; Supervision – A.I., M.U., N.A.; Data collection
of the thyroid, comorbidities, family history, surgical risk, and/or processing – M.T.U., O.C., A.O.; Analysis and/or interpreta-
and patient preference.[11] tion – N.A., M.U.; Literature review – M.T.U., M.U., O.C.; Writing –
M.T.U., M.K., A.O.; Critical review – N.A., A.I., M.U.
Radioactive Iodine Therapy
In toxic multinodular or nodular goiter; radioactive iodine References
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