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Clinical Practice Guidelines

Clinical utility of molecular tests for thyroid nodules and cancer is supported by the practice guidelines from major professional organizations in the field.

The American Thyroid Association (ATA) Guidelines

The current ATA Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer1 contain specific recommendations addressing the diagnostic use of molecular testing for thyroid nodules with Bethesda III-IV cytology (Recommendations 15 and 16) and for informing the extent of surgery (Recommendations 17, 19, 20).

  • Recommendation 15 states that for nodules with AUS/FLUS cytology, investigation such as repeat FNA or molecular testing may be used to supplement malignancy risk assessment (Weak recommendation, Moderate-quality evidence).
  • Recommendation 16 states that for the management of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cytology nodules, molecular testing may be used to supplement malignancy risk assessment data (Weak recommendation, Moderate-quality evidence).
  • Recommendation 17 states that mutational testing for BRAF or the mutation marker panel (BRAF, RAS, RET/PTC, PAX8/PPARγ, etc.) may be considered in nodules with suspicious for malignancy cytology (Bethesda V) if such data would be expected to alter surgical decision-making (Weak recommendation, Moderate-quality evidence).
  • Recommendation 19 states that when surgery is considered for patients with a cytologically indeterminate nodule, recommendation for thyroid lobectomy may be modified based on clinical or sonographic characteristics and/or molecular testing (Strong recommendation, Moderate-quality evidence).
  • Recommendation 20 states that total thyroidectomy may be preferred in patients with indeterminate nodules which are positive for known mutations specific for carcinoma (Strong recommendation, Moderate-quality evidence).

The National Comprehensive Cancer Network (NCCN) Guidelines

The National Comprehensive Cancer Network NCCN guidelines Version 2.2020 provide recommendations for use of molecular testing in indeterminate cytology nodules to select observation over surgery and for selecting the extent of surgery2.

  • The NCCN guidelines recommend consideration of molecular diagnostics for nodules with a cytologic diagnosis of AUS/FLUS (Bethesda III) and Follicular or Hurthle cell neoplasms (Bethesda IV), when there are no high clinical and/or radiographic factors suspicious of malignancy.
  • If molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of malignancy comparable to the risk of malignancy seen in a benign FNA cytology (approximately 5% or less), consider nodule surveillance.
  • If molecular testing suggests papillary thyroid carcinoma, especially in the case of BRAF V600E mutation, apply the same management as for papillary carcinoma.
  • For anaplastic thyroid carcinoma, molecular testing for actionable mutations is recommended.

American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults

The 2020 American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults3 contain specific recommendations regarding molecular testing to inform surgical decision making.

  • Molecular testing is recommended as a diagnostic adjunct for cytologically indeterminate thyroid nodules when the need for thyroidectomy is unclear after consideration of clinical, imaging, and cytologic features (Recommendation 11).
  • The guidelines include information on the impact of molecular testing results on decisions regarding the extent of initial surgery, with adverse molecular testing results (such as BRAF V600E and TERT mutations) favoring total thyroidectomy and indolent molecular testing results (such as BRAF K601E) favoring partial thyroidectomy (Table 11).

American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi

The 2016 joint recommendations from these medical associations contain a recommendation for use of mutational markers (all part of ThyroSeq® GC) for cytologically indeterminate nodules. 4

  • Consider the detection of BRAF and RET/PTC and, possibly, PAX8/PPARG and RAS, mutations if such detection is available (best evidence level 2, grade B).

UptoDate Evaluation and Management of Thyroid Nodules with Indeterminate Cytology

UptoDate provides recommendations for evaluation and management of thyroid nodules with indeterminate cytology, including regarding management based on results of molecular testing.5

  • If molecular testing is available, further nodule management then depends on the results of molecular testing.
  • For nodules with a “benign molecular pattern” or negative result on molecular testing, observation is suggested. Other data, clinical characteristics, and patient preference should also be taken into account when deciding between observation or lobectomy.
  • For nodules with a “suspicious molecular pattern” or positive result on molecular testing, diagnostic lobectomy or total thyroidectomy is indicated in most patients.
  • The choice of lobectomy versus total thyroidectomy may depend on the specific mutation detected as well as other clinical factors and patient preference.


1.Haugen BR, et al. Thyroid. 2016. 2.National Comprehensive Cancer Network (NCCN) Carcinoma Guidelines. 3.Patel KN, et al. Ann Surg. 2020. 4.Gharib H, et al. Endocr Pract. 2016. 5.Ross DS, et al. UptoDate. 2020.