the Diagnosis and Management of Thyroid Nodules

Section 1: Initial evaluation of thyroid nodules:

·       Initial evaluation should include age, personal and family history of MEA, Previous head or neck irradiation, physical evaluation, thyroid function testing, and neck US, (Strong recommendation, moderate certainty evidence ⁽⁷⁾).

Section 2: Thyroid ultrasound:

·       Neck US, including the thyroid gland and the central and lateral cervical compartments, should be performed in all patients suspected with nodular thyroid disease, (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

·       It is recommended for the US report to describe nodule(s) size, location, US features, and expected risk of malignancy using EU-TIRADS, (Strong recommendation, moderate certainty evidence ⁽⁸⁾), (table 3).

·       Doppler imaging, elasto-sonography, and CEUS may be recommended as ancillary techniques (Conditional recommendation, very low certainty evidence ⁽⁸⁾).

·       CEUS may be recommended for defining the size and boundaries of the ablated area after minimally invasive procedures, (Conditional recommendation, low certainty evidence ⁽⁸⁾).

Section 3: Non-ultrasound imaging modalities:

·       Thyroid scintigraphy is recommended when serum TSH is subnormal to diagnose functioning nodules and/or multinodularity, avoid FNA and determine eligibility for RAI as an alternative to surgery, (Strong recommendation, moderate certainty evidence ⁽³⁾).

·       The use of CT and/or MRI in the study of thyroid nodules should be limited to the assessment of local extension or retrosternal growth of nodular goiter, (Strong recommendation, low certainty evidence ⁽³⁾).

Section 4: Thyroid biopsy:

·       FNA may be recommended after clinical assessment, laboratory evaluation, and US risk stratification, in a shared decision with the patient, (Good practice statement).

·       FNA is advised in:

o   EU-TIRADS 3: >20 mm, (Conditional recommendation, very low certainty evidence ⁽⁸⁾).

·       FNA is recommended in:

o   EU-TIRADS 4: >15 mm.

o   EU-TIRADS 5: >10 mm, (Strong recommendation, very low certainty evidence ⁽⁸⁾).

·       In high suspicion pattern, we recommend FNA if ≥10 mm, (Strong recommendation, moderate certainty evidence ⁽³⁾), (Table 4).

·       In intermediate suspicion pattern, we recommend FNA if ≥10 mm, (Strong recommendation, low certainty evidence ⁽³⁾), (Table 4).

·       In low suspicion pattern, we advise FNA if ≥15 mm, (Conditional recommendation, low certainty evidence ⁽³⁾), (Table 4).

·       In very low suspicion pattern, we advise FNA if ≥20 mm (or ultrasound observation), (Conditional recommendation, moderate certainty evidence ⁽³⁾), (Table 4).

·       In benign pattern, we recommend against FNA, (Strong recommendation, moderate certainty evidence ⁽³⁾), (Table 4).

·       We recommend FNA regardless of lesion size when patients have a history of neck irradiation, a family history of medullary thyroid cancer or MEN2, extracapsular growth, metastatic cervical lymph nodes or Coexistent suspicious clinical findings (e.g., dysphonia), (Strong recommendation, moderate certainty evidence ⁽⁷⁾).

·       Repeat FNA is recommended in case of a first non-diagnostic sample, (except in case of a solitary cyst), a Bethesda class III cytology, discrepancy between US risk score (i.e. high risk) and cytological findings (i.e. benign cytology), and significant nodule growth (an increase ≥20% in at least two nodule diameters with a minimum increase of 2 mm at the time of re-evaluation) of thyroid nodule(s), (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

·       FNA is recommended in suspicious lymph nodes, with thyroglobulin or calcitonin washout dependent on phenotype, (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

•       Core-needle biopsy is not recommended as a first-line tool to assess thyroid nodules after US but could be considered a second line procedure for specific conditions e.g. repeat Bethesda class III cytology and suspicion of poorly differentiated thyroid cancer, thyroid lymphoma, thyroid metastases), (Strong recommendation, low certainty evidence ⁽⁸⁾).

Section 5: Cytopathology-based management, (Based on Bethesda Categories), (Table 5):

·       We recommend correlation of the cytological diagnosis with clinical, ultrasound and laboratory results, (Good practice statement).

·       For Bethesda I (non-diagnostic), repeat FNA is advised. If repeat FNA is still non-diagnostic, consider CNB. If still non-diagnostic, consider surgery (Conditional recommendation, very low level of evidence, ^8).

·       For Bethesda II, (Benign), we are against further immediate diagnostic studies or treatment, (Strong recommendation, high certainty evidence ⁽³⁾).

·       For Bethesda III, (Atypia of Undetermined Significance, (AUS)) we recommend repeating FNA and with repeat Bethesda III, consider molecular testing if available or offer surgery, (Conditional recommendation, high certainty evidence ⁽⁸⁾).

·        For Bethesda IV, (Follicular Neoplasm), we advise molecular testing or diagnostic lobectomy, (Conditional recommendation, low certainty evidence ⁽⁸⁾).

·       For Bethesda V, (Suspicious for malignancy), we recommend molecular testing, lobectomy, or near-total thyroidectomy, (molecular testing may help to decide whether to perform a total thyroidectomy or a thyroid lobectomy), (Strong recommendation, low certainty evidence ⁽³⁾).

·       For Bethesda VI, (Malignant), we recommend lobectomy or near-total thyroidectomy, (Strong recommendation, moderate certainty evidence ⁽³⁾).

·       We recommend multidisciplinary workup in case of advanced cancer, (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

Section 7: Molecular diagnostics of indeterminate thyroid nodule cytology:

·       Molecular testing is recommended in cytologically indeterminate nodules, if available, or offer surgery (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

Section 8: Non-surgical approaches of thyroid nodules:

·       Thyroid hormone treatment is not recommended in euthyroid individuals with nodular thyroid disease, (Strong recommendation, moderate certainty evidence ⁽⁸⁾).

·       Iodine and/or selenium supplementation is not recommended unless individuals are deficient in these micronutrients, (Strong recommendation, low certainty evidence ⁽⁸⁾).

·       RAI is recommended as an alternative to surgery and MIT in hyper-functioning solitary thyroid nodules, (Strong recommendation, moderate certainty evidence (8)).

·       RAI may be recommended as an alternative to surgery in benign normo-functioning multinodular goiter, (Conditional recommendation, low certainty evidence (8)).

·       EA is recommended for pure, or dominantly cystic, thyroid lesions, (Strong recommendation, moderate certainty evidence (8)).

·       TA is recommended for the treatment of solid benign thyroid nodules that cause local symptoms as an alternative to surgery and for cystic lesions that relapse after EA, (Strong recommendation, low certainty evidence (8)).

·       Benign cytological diagnosis is recommended before MIT. Except for EU-TIRADS 2 nodules, (Strong recommendation, low certainty evidence (8)).

·       After MIT, we recommend follow-up with clinical, biochemical and US assessments after 6 and 12 months and re-evaluating the patient after 3–5 years, (Strong recommendation, low certainty evidence (8)).

Section 9: Surgical approaches of thyroid nodules:

·       Surgery is recommended in the following scenarios: Symptomatic nodular thyroid disease, nodules that have been classified as benign at cytology and/or US and become symptomatic over time, calcitonin levels higher than the established cut-offs, responsive calcitonin after stimulation test in RET-mutated gene carriers, nodules with indeterminate cytology (Bethesda class III and IV) that are not suitable for active surveillance and nodules with a Bethesda class V and VI cytology, (Strong recommendation, moderate certainty evidence (8)).