Contemporary Thyroid Nodule

Evaluation and Management

Panudda Srichomkwun
Associate professor Vitaya Sridama
Endocrine and Metabolism Unit
Faculty of Medicine, Chulalongkorn University
Thyroid nodule
• Prevalence:
• Palpable thyroid nodule is 5% in women and 1% in men
• Thyroid nodule detected by ultrasound up to 19 – 67 % 7-15%
Benign Malignant
Adenomatous nodule (colloid nodule and hyperplastic nodule) Carcinomas of thyroid follicular-cell origin

Follicular adenoma • Papillary carcinoma, follicular carcinoma, Hürthle-cell

carcinoma, anaplastic carcinoma
Hürthle-cell adenoma
Carcinoma of C-cell origin
Simple or hemorrhagic cyst
• Medullary carcinoma
Thyroiditis
Other: primary thyroid lymphoma, sarcoma, teratoma,
Thyroglossal duct cyst
cancer metastatic to the thyroid (especially kidney, breast,
lung, melanoma)
Clinical Findings Related to Risk of
Carcinoma in a Thyroid Nodule
• History of childhood head or neck therapeutic irradiation, total body irradiation,
or exposure to ionizing radiation from fallout (e.g., Chernobyl)
• Family history of thyroid cancer or of a syndrome associated with thyroid cancer
(e.g., familial adenomatous polyposis, Cowden syndrome, multiple endocrine
neoplastic [MEN] 2)
• Age <20 or >65 years
• Men > women (in terms of proportion of nodules that are a carcinoma)
• History of other cancers, especially kidney, breast, lung, and melanoma
Clinical Findings Related to Risk of
Carcinoma in a Thyroid Nodule
• Vocal cord paralysis
• Abnormal lateral cervical adenopathy
• Firm nodule fixed to surrounding tissue
• Positron emission tomography-positive thyroid nodules
• Focal uptake → higher risk of malignancy
• Diffuse uptake → Hashimoto’s thyroiditis

Risk of carcinoma of a thyroid nodule is independent of

nodule number, size, mode of detection
 TSH level

TSH suppressed TSH normal or high

Thyroid scan Thyroid ultrasound

Risk
• Identification of the sonographic stratification
characteristics of the thyroid nodule
• Detection of additional nonpalpable nodules
for which FNA may be indicated
• Determination of accuracy of FNA by palpation

Size > 2 cm
Fine needle aspiration
Hyperfunctioning Hypofunctioning
(hot) nodule (cold) nodule
Suspicious sonographic characteristics of
thyroid nodules
Sensitivity Specificity
Extrathyroidal
Hypoechogenicity compared to 81% 53% extension
surrounding thyroid
parenchyma
Marked hypoechogenicity 41% 94%
compared to stap muscles
Microcalcification 44% 89%
Irregular, microlobulated 55% 80%
margins
Solid consistency 86% 48%
Taller than wide shape on 48% 92%
transverse view

Tumor location: Isthmus > upper > middle> lower Werner & Ingbar’s the Thyroid 11th edition
Thyroid. 2020 Mar;30(3):401-407
Ultrasound Imaging Classification of Thyroid nodule
Avoiding overdiagnosis of low-risk cancers
• FNA is not recommended
for all nodules < 1 cm
• Highest accuracy • Modify cut off by patients’
• Largest reduction of biopsy number risk factors and presence of
• Lowest false negative rate lymph node
J Clin Endocrinol Metab 2019;104:95-102.

Limitation
• Inter-observer discrepancies
• Insufficient sensitivity for
the diagnosis of follicular
cancers and follicular variant
of papillary cancers

BMJ 2020;368:l6670
ATA Sonographic Risk Stratification of Thyroid Nodule

Sonographic Ultrasound Features Estimated Risk of FNA cut off Surveillance

pattern Malignancy (%)
Benign Pure cystic nodules without solid contents <1 No FNA Not required
Very low suspicion Spongiform or partially cystic nodule <3 FNA >2 cm Not required but if
without ultrasound features in suspicion desired, repeat at > 24
patterns mo
Low suspicion Hyper- isoechoic nodule or partially cystic 5–10 FNA >1.5 cm. Repeat ultrasound at
nodule with eccentric solid areas without 12-24 mo
high-risk features
Intermediate Hypoechoic solid nodule with smooth 10–20 FNA >1 cm Repeat ultrasound at
suspicion margins without high-risk features 12-24 mo
High suspicion Solid hypoechoic or solid hypoechoic >70–90 FNA >1 cm Repeat ultrasound and
component of partially cystic nodule with > FNA at 12 mo
1 of the following features: irregular
margin, microcalcifications, taller than wide
shape, rim calcification with extrusive soft
tissue component, and evidence of 18% non classifiable by ATA criteria
extrathyroidal extension
Thyroid. 2016 Jan 1; 26(1): 1–133
ACR-TIRADS Thyroid Nodule Sonographic Characterization and Scoring
Point Composition Echogenicity Shape Margin Echogenic foci
0 Cystic Anechoic Wider than tall Smooth None
Spongiform ill-defined Comet tails
1 Mixed cystic solid Hyper/isoechoic Macrocalcifications
2 Mostly solid or Hypoechoic Lobulated/irregular Peripheral/rim
completely solid
3 Very hypoechoic Taller than wide Extrathyroidal extension Microcalcification

Individual Sonographic Features and Associated Points ACR TIRADs classification

Point Description Malignancy FNA threshold Surveillance Repeat ultrasound
risk (%)
0 TR1: benign <2 No FNA None None
2 TR2: not suspicious <2 No FNA None None
3 TR3: mildly suspicious 5 FNA > 2.5 cm Follow if > 1.5 cm 1,3 and 5 y
4-6 TR4: moderately 5-20 FNA > 1.5 cm Follow if > 1 cm 1,2,3 and 5 y
suspicious
>7 TR5: highly suspicious > 20 FNA > 1 cm Follow if > 0.5 cm Annually for 5 y
https://tiradscalculator.com/ JACR. 14 (5): 587-595.
Fine Needle Aspiration (FNA)
• Cost effective, safe procedure
• Complication rare: pain, small hematoma Ultrasound guided FNA
• Non palpable or difficult to palpate nodule
• Previous non diagnostic cytology
• Target specific areas: particularly
important in partially cystic nodules

Aspiration technique

Capillary technique
The 2017 Bethesda System for Reporting Thyroid Cytopathology:
implied risk of malignancy and recommended clinical management

Diagnostic category Risk of malignancy by the Bethesda system Management

(Bethesda) If NIFTP is not CA If NIFTP is CA
I. Nondiagnostic or 5-10 5-10 Repeat FNA with ultrasound
unsatisfactory guidance
II. Benign 0–3 0–3 Follow up
III. Atypia of undetermined 6–18 10-30 • Molecular testing
significance or follicular
• Repeat FNA
lesion of undetermined
significance (AUS/FLUS) • Lobectomy
Indeterminate nodule
IV. Follicular neoplasm or 10–40 25–40 Surgery
suspicious for a follicular
neoplasm (FN/SFN)
V. Suspicious for malignancy 45-60 50-75 Surgery
(SUSP)
VI. Malignant 94–96 97-99 Surgery
NIFTP: Non-invasive follicular thyroid neoplasm with papillary like nuclear features
 Follicular variant papillary
thyroid carcinoma (FVPTC)

Encapsulated FVPTC Infiltrative FVPTC

Invasive encapsulated FVPTC Noninvasive encapsulated FVPTC Incidence of NIFTP among PTCs 6%
Thyroid . 2021 Oct;31(10):1502-1513

Noninvasive follicular thyroid neoplasm with • NIFTP are not benign

papillary like nuclear feature (NIFTP) • Lobectomy is required for
NIFTP diagnosis

Exclusion criteria:
• Invasion
• Papillae>1%
• Psammoma bodies
• >30%Solid/Trabecular/Insular
Inclusion criteria:
growth
• Encapsulation
• Increased mitoses
• Follicular growth
• Tumor necrosis
• Nuclear features of PTC
JAMA Oncol. 2016;2:1023-1029
 The 2017 Bethesda System for Reporting Thyroid Cytopathology:
implied risk of malignancy and recommended clinical management

Diagnostic category Risk of malignancy by the Bethesda system Management

(Bethesda) If NIFTP is not CA If NIFTP is CA
I. Nondiagnostic or 5-10 5-10 Repeat FNA with ultrasound
unsatisfactory guidance
II II. Benign 0–3 0–3 Follow up
III. Atypia of undetermined 6–18 10-30 • Molecular testing
significance or follicular
• Repeat FNA
lesion of undetermined
III significance (AUS/FLUS) • Lobectomy

IV. Follicular neoplasm or 10–40 25–40 Surgery Extent of resection

suspicious for a follicular • Compressive symptoms
• The presence of
IV neoplasm (FN/SFN)
contralateral nodule
V. Suspicious for malignancy 45-60 50-75 Surgery
• Thyroid functional status
(SUSP) • Comorbidities
VI. Malignant 94–96 97-99 Surgery • Family history
VI NIFTP: Non-invasive follicular thyroid neoplasm with papillary like nuclear features • Surgical risk
• Patient preferences

TNAPP is web-based (https://aace-thyroid.deontics.com)
Clinical 1 - these factors are more supportive
Clinical
characteristics of limiting FNA or surgery
Clinical 2 - these factors are more supportive
of intervention with FNA or surgery
Exclusion
• Patients with known thyroid cancer
• Elevated calcitonin level
• First degree relatives of patients with MTC
or MEN 2 syndromes
• Patients with suspicious neck
lymphadenopathy
• Positive PET or sestamibi imaging
• Hard/fixed nodule
• USG: extrathyroidal extension

Ultrasound AACE US risk category: US1-3

Features ACR TIRADS: TR 1-5

FNA Follow up & frequency of FU Discharge

Cytology Bethesda system: calculate malignancy risk

Features

Repeat FNA Molecular testing Surgery Surveillance Discharge

Endocr Pract. 2021 Jul;27(7):649-660

Case 1 : 40-year-old woman
• Palpable thyroid nodule, clinical euthyroid
• No clinical risk factor for thyroid cancer
• PE: left thyroid nodule 2.5 cm, no lymphadenopathy
FNA, serum TSH, Ultrasound thyroid Bethesda 2: benign

Management
• Thyroid hormone suppressive therapy
• Minimal invasive technique
• Follow up, repeat FNA

ACR TIRAD 4
Thyroid hormone suppressive therapy
for thyroid nodules
• Suppression of TSH secretion in normal subjects by the administration of thyroid
hormone results in thyroid atrophy (goal TSH <0.1 mU/L)
• Only 17 - 25 % of patients will have a decrease in nodule size (more than 50
percent) in iodine-sufficient regions Iodine status
• Risk: atrial fibrillation, reduced bone density

ATA 2015 guideline does not

recommend suppression therapy
of benign thyroid nodules in iodine
sufficient populations

Eur J Endocrinol. 2021;185(1):R13-R21

Minimally Invasive Techniques for Treatment of
Symptomatic, Benign Thyroid Nodules

J Clin Endocrinol Metab, 2020, 105(9):2869–2883

Repeat FNA
Benign cytologic result
At first aspiration
At least twice
At first aspiration +
positive US results
At first aspiration +
negative US results
At first aspiration +
negative US results
+ increased size at F/U
Radiology. 2010 Jan;254(1):292-300
Likelihood of Nodule
Being benign (%) If second cytology is benign, ultrasound
98.1 assessment of this nodule is no longer necessary
100 High risk ultrasound features
79.6 • Repeat ultrasound and FNA at 12 mo
Intermediate and low risk ultrasound features
99.4
• Repeat ultrasound at 12 -24 mo.
• Consider FNA if tumor growth (20% increase in
98.6
2 nodule dimensions with minimal increase 2
mm or >50% change in volume)
Very low risk ultrasound features
• Not required but if desired, repeat ultrasound
at > 24 mo
2015 American Thyroid Association Management Guidelines for Adult
Patients with Thyroid Nodules and Differentiated Thyroid Cancer
The Natural History of Benign Thyroid Nodules
• Benign and small sonographically nonsuspicious asymptomatic thyroid nodules (total 992 patients)
• 5 of 992 patients (0.3%) were thyroid carcinoma
2 patients→ PTC

Nodules grew in 153 patients (15.4%)

• Multinodular
• Nodule diameter > 7.5 mm
• Age at diagnosis < 43 years or less

Increased size of nodule nodules were not

predictive of malignancy
Nodules shrank in 184 patients (18.5%)

New nodules 93 patients (9.3%)

JAMA. 2015;313(9):926-935
Case 2 : 40-year-old woman
• Palpable thyroid nodule, clinical euthyroid • Inexperience doctor
• No clinical risk factor for thyroid cancer • Predominantly cyst nodule
• Macrocalcification
• PE: left thyroid nodule 2.5 cm, no lymphadenopathy
FNA, serum TSH, Ultrasound thyroid Bethesda 1: non diagnostic
Management
• Repeat FNA at 4-6 week, using ultrasound
if not use in first FNA
Repeatedly nondiagnostic nodule
• Ultrasound-guided core-needle biopsy
• Observe: low risk ultrasound features
• Surgery: high risk ultrasound features, growth of nodule ACR TIRAD 4
Case 3 : 40-year-old woman
• Palpable thyroid nodule, clinical euthyroid
• No clinical risk factor for thyroid cancer
• PE: left thyroid nodule 2.5 cm, no lymphadenopathy
FNA, serum TSH, Ultrasound thyroid Bethesda 3: atypia/follicular lesion/of
undetermined significance (AUS/FLUS)
Management
AUS: nuclear atypia or Hürthle cell change
• Molecular testing FLUS : presence of microfollicles (architectural atypia)
• Repeat FNA
• Lobectomy
Indeterminate cytology
 Need
• Pre-test risk of malignancy
Molecular testing (prevalence of malignancy in indeterminate FNA)
• Local mutation rate

Rule in test
• Genetic marker
Rule out test
(mutations and
• Gene expression
rearrangements)
classifier (GEC)
• ThyroSeq V0
• Afirma
• ThyroSeq V2
• Afirma-GSC
• ThyGenX/ThyMIr
• ThyroSeq V3

BRAF mutation

Lancet 2013; 381: 1058–69

Nat Rev Endocrinol 2017;13:415-24
 Need
• Pre-test risk of malignancy
(prevalence of malignancy in indeterminate FNA)
• Local mutation rate

Local BRAF mutation rate

Risk of malignancy per the Bethesda
diagnostic category in Thailand
Bethesda system ROM
I 21.7%
II 14.7%
III 35.9%
IV 44.4% 56%
V 76.7%
VI 92.6%
Journal of Pathology and Translational Medicine 2017; 51: 565-570 Malaysian J Pathol 2017; 39(1) : 95 – 96
AUS/FLUS
• Repeat FNA after a 6-12 weeks interval
Repeated AUS/FLUS cytology
Meta-analysis 27 studies, total 3932 AUS/FLUS nodules
• Diagnostic lobectomy
Repeated FNA cytology
60 ATA sonographic pattern Rate of malignancy%
48% Malignancy rate 4%
50
NPV 96% very low 0
40
26% low/Intermediate 19%
30
high 56%
20
non-ATA 36%
10 4% 4% 5% 2%
0
Thyroid. 2018;28(8):1004-1012

• Thyroid scintigraphy in patient with

subnormal TSH level
• Autonomous → low risk of malignancy
benign malignancy
• 18-FDG PET/CT
European Journal of Endocrinology (2021) 185, 497–506 • No FDG avid → low risk of malignancy
Take Home Message
• The evaluation and management of patients with thyroid nodules
depend on risk of malignancy
• Combine information form clinical risk factors (history, physical
examination), ultrasound thyroid features and thyroid cytology

Avoiding Prompt treatment in

• the overdiagnosis of high-risk tumors
low-risk cancers
• Complication from
overtreatment benign
thyroid nodule