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Thyroid Nodules

Thyroid nodules are a common clinical finding and may occur in more than half of healthy adults due to a variety of causes, including thyroid cancer, although most nodules present low risk of malignancy. The primary challenge of laboratory testing of thyroid nodules in adults is to rule out malignancy. After an initial evaluation for thyroid dysfunction, fine needle aspiration (FNA) is used to obtain tissue from suspicious thyroid nodules for diagnosis and to determine the need for surgery.

Quick Answers for Clinicians

How have technologies such as sensitive ultrasound and guided fine needle aspiration changed the evaluation of thyroid nodules?

The development of sensitive thyroid ultrasound and ultrasound-guided fine needle aspiration (FNA) have caused a dramatic increase in the diagnosis of thyroid cancer, primarily of small papillary neoplasms. However, the mortality rate due to thyroid cancer has not changed, suggesting that these technologies have resulted in overdiagnosis (and, by extension, overtreatment) of subclinical thyroid cancers. To assist clinicians in determining whether a nodule warrants follow-up or can be monitored without intervention, professional organizations, including the American Thyroid Association (ATA), National Comprehensive Cancer Network (NCCN), and American Association of Clinical Endocrinologists (AACE), have created recommendations for when FNA should be performed. See Fine Needle Aspiration for more information.

When is fine needle aspiration of thyroid nodules recommended?

Fine needle aspiration (FNA) should be performed if nodules are suspicious for malignancy and a finding of malignancy would impact clinical decision-making. Recommendations for specific module characteristics (specifically, ultrasound features and size) that should prompt suspicion for malignancy vary. Guideline-issuing organizations generally agree that FNA should be performed on nodules larger than 1 cm in diameter that are solid, hypoechoic, include microcalcifications, have extrathyroidal extensions or irregular borders, or are taller than they are wide. Otherwise, recommendations vary as to which nodule characteristics should prompt FNA. See the Fine Needle Aspiration section and links to society guidelines.

How does the laboratory evaluation of thyroid nodules differ in pregnant versus nonpregnant patients?

The initial evaluation of thyroid nodules is the same in pregnant and nonpregnant patients, although pregnancy-specific reference intervals should be used for thyroid function tests (see the ARUP Consult Thyroid Disease in Pregnancy topic for more information). Fine needle aspiration (FNA) is recommended in both pregnant and nonpregnant patients, and cytologic criteria do not differ during pregnancy. Thyroid nodules may enlarge during pregnancy, but this is not indicative of malignancy. In women with decreased thyroid-stimulating hormone (TSH) levels, it is reasonable to defer FNA until after pregnancy and lactation, after which a radionuclide scan can be performed to determine whether the nodule is hypersecreting and therefore unlikely to be malignant. The use of any radioactive agent in the diagnosis of thyroid cancer is contraindicated during pregnancy and lactation.

Indications for Testing

Thyroid nodule testing is appropriate in individuals with known, suspected, or incidentally discovered thyroid nodules.

Laboratory Testing

Initial Evaluation

Thyroid Function and Antibody Tests

Thyroid-stimulating hormone (TSH) is the recommended first test of thyroid function in patients with thyroid nodules. The American Association of Clinical Endocrinologists (AACE) recommends a workup for thyrotoxicosis if TSH is decreased or hypothyroidism if TSH is increased. The American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) recommend radionuclide scanning (radioiodine imaging) if TSH is decreased to determine whether the nodule is hyperfunctioning. Hyperfunctioning (hot) nodules are rarely malignant and therefore do not require cytologic assessment; instead, proceed with testing for thyrotoxicosis. Ultrasonography is recommended (if not already performed) for all nodules to evaluate the probability of malignancy and to determine whether fine needle aspiration is indicated.

Serum thyroglobulin (Tg) testing is not recommended in the diagnosis of thyroid nodules due to a lack of specificity. For more information on the initial evaluation of thyroid disease, see the ARUP Consult Initial Evaluation of Thyroid Disease topic. For more information on antibody testing, see the ARUP Consult Autoimmune Thyroiditis topic.

Other Tests

Serum calcium and parathyroid hormone tests are recommended if a parathyroid adenoma is suspected (based on incidental radiographic findings or clinical symptoms of hypercalcemia, bone loss, or chronic kidney disease).

Although the routine measurement of serum calcitonin is neither recommended nor discouraged, calcitonin measurements are recommended in patients with thyroid nodules with suspicious ultrasound findings or indeterminate cytologic findings (see Fine Needle Aspiration); a family history or clinical suspicion of medullary thyroid carcinoma (MTC); or a family history or clinical suspicion of multiple endocrine neoplasia type 2 (MEN2). For more information on calcitonin testing, see the ARUP Consult Thyroid Cancer topic.

Ultrasound is a primary means of investigating thyroid nodules. Ultrasound features are frequently used to determine the need for FNA.

Fine Needle Aspiration

FNA biopsy is the procedure of choice to evaluate suspicious thyroid nodules and should be performed with ultrasound guidance. FNA enables the minimally invasive targeting of a specific nodule as well as the retrieval of a relatively pure population of cells. Cytomorphologic analysis of FNA specimens enables most of the diagnosis and classification of thyroid cancers, but specimens are often sparse, which can make diagnosis challenging.

Calcitonin, Tg, and parathyroid hormone concentrations should be obtained using the FNA washout (ie, a saline needle rinse specimen collected in conjunction with the cytology specimen) from thyroid nodules when clinically appropriate (eg, when MTC is suspected). FNA and measurement of Tg in the washout may also be useful if lymph nodes are suspected to have metastases; a low Tg concentration suggests the absence of thyroid cancer metastasis.

Recommendations vary for which nodules should be biopsied with FNA. For more information on features that should prompt FNA biopsy, see:

Appropriate follow-up is based on the results of cytologic analysis of FNA specimens.

Recommended Follow-Up Based on Cytologic Analysis of FNA Specimens (According to the Bethesda System for Reporting Thyroid Cytopathology)
Result	Recommended Next Steps
Nondiagnostic or unsatisfactory biopsy	Repeat ultrasound-guided FNA Solid nodules: if repeatedly nondiagnostic, consider ultrasound-guided core-needle biopsy or surgery Cystic or predominantly cystic nodules: if repeatedly nondiagnostic and without suspicious features, follow up with clinical evaluation and ultrasound
Benign	Consider repeat clinical evaluation, ultrasound examination, and TSH measurement in approximately 1 yr; if unchanged after 1 yr, repeat ultrasound approximately 1 yr thereafter If repeatedly benign, asymptomatic, and without suspicious features, discontinue routine follow-up Repeat FNA if suspicious clinical or ultrasound features, symptoms, or >50% increase in nodule volume Consider surgery if pressure or structural symptoms occur or if suspicious ultrasound findings appear
Atypia of undetermined significance/follicular lesion of undetermined significance	Consider elastography Low-risk indeterminate lesions: repeat FNA and review with experienced cytopathologist; consider core-needle biopsy Consider molecular testing: if benign, monitor nodule; if not informative, consider surgery for definitive diagnosis; if suggestive of malignancy, consider surgery for definitive diagnosis and treatment High-risk indeterminate lesions: surgery and close clinical follow-up is generally recommended
Follicular neoplasm or suspicious for follicular neoplasm	Consider molecular testing: if benign, monitor nodule; if not informative or suggestive of malignancy, consider surgery for definitive diagnosis/treatment If high suspicion of malignancy, consider surgery for definitive diagnosis/treatment
Suspicious for malignancy	Repeat FNA if needed Surgery for definitive diagnosis/treatment is recommended
Malignant	Differentiated thyroid carcinoma: surgery is recommended Anaplastic thyroid carcinoma, metastatic lesions, thyroid lymphoma: review previous results, perform ultrasound examination, perform FNA biopsy of concomitant suspicious nodules and lymph nodes; if ultrasound is suspicious, confirm metastatic nature of lymph node with measurement of Tg or calcitonin in FNA washout; surgery generally recommended
Sources: AACE, 2016; ATA, 2016; NCCN, 2019; Cibas, 2017

Histology and Molecular Markers

Histologic examination of thyroid tissue samples is used to establish or confirm the diagnosis of thyroid cancer, classify the cancer, stratify risk, and guide management after thyroid surgery. Molecular markers are also useful to establish a diagnosis of malignancy if cytology samples obtained via FNA are indeterminate. For more information on histology and molecular markers, see the ARUP Consult Thyroid Cancer topic.