Thyroid nodules are a common clinical problem affecting approximately 5-7% of the U.S. adult population. Fine needle aspiration (FNA) of the thyroid is currently the most accurate procedure to distinguish between benign and malignant thyroid lesions, reducing the rate of unnecessary thyroid surgery for individuals with benign nodules. Approximately 60-70% of thyroid nodules are classified cytologically as benign and 4-10% deemed malignant. The remaining 20-30% have equivocal findings, usually due to overlapping cytologic features between benign and malignant nodules. Approximately 80% of these individuals undergo surgical resection. Postoperative evaluation has revealed a malignancy rate ranging from 6–30%, making this a clinical process with very low specificity.

Genetic alterations associated with thyroid cancer can be assessed using genetic variant analysis and gene expression profiling. Examples of available molecular marker assays include:

Afirma® Gene Sequencing Classifier (GSC) evaluates 10,196 genes with 1115 core genes.
Afirma® BRAF and Afirma® MTC – These tests are used after receiving a “malignant” or “suspicious” result from Afirma® Gene Sequencing Classifier. A positive result from Afirma® BRAF or Afirma® MTC would inform preoperative planning such as planning for a hemi- vs a total thyroidectomy or performance of a central neck dissection.
ThyGeNEXT® Thyroid Oncogene Panel (formerly ThyGenX®) and ThyraMIR™ - ThyGeNEXT® is a next generation sequencing panel that assesses the most common genetic alterations across ten genes associated with papillary thyroid carcinoma and follicular carcinoma. A positive result on ThyGeNEXT® would “rule in” individuals for surgical resection. For a ThyGeNEXT® negative result, the reflex testing involves the ThyraMIR™ microRNA expression test to rule out for surgical biopsy given the high negative predictive value of the second test. Individuals with a negative result from ThyraMIR™ would be followed with active surveillance and avoid a surgical biopsy.
ThyroSeq® is a next generation sequencing panel that sequences 112 genes. It has been evaluated in individuals with follicular neoplasm and/or suspicious for follicular neoplasm on FNA as a test to increase both sensitivity and specificity for cancer diagnosis.

POLICY

Testing of molecular markers in fine-needle aspirates of the thyroid is considered medically necessary if medical appropriateness criteria are met. (See Medical Appropriateness below.)
Molecular marker tests used in fine needle aspirates of the thyroid not listed in the medical appropriateness criteria, including but not limited to the use of RosettaGX Reveal and single-gene TERT testing, are considered investigational.

MEDICAL APPROPRIATENESS

Testing of molecular markers in fine needle aspirates of the thyroid is considered medically appropriate if ANY ONE of the following are met:
- Test is performed to determine level of cancer risk when ALL of the following criteria are met:
  - Thyroid nodules are without strong clinical or radiologic findings suggestive of malignancy
  - Use of ANY ONE of the following tests:
    - Afirma® Genomic Sequencing Classifier
    - ThyroSeq®
  - Indeterminate cytology on fine needle aspirate, as indicated by ANY ONE of the following:
    - Atypia of undetermined significance
    - Follicular lesion of undetermined significance
    - Follicular neoplasm
    - Follicular neoplasm suspected
  - Surgical decision making would be affected by test results
- Test is performed to confirm suspected malignancy when ALL of the following criteria are met:
  - Use of ANY ONE of the following tests:
    - ThyroSeq®
    - ThyGeNEXT® with or without ThyraMIR™ microRNA
    - Afirma® BRAF after Afirma® Genomic Sequencing Classifier
    - Afirma® MTC after Afirma® Genomic Sequencing Classifier
  - Indeterminate cytology on fine needle aspirate, as indicated by ANY ONE of the following:
    - Atypia of undetermined significance
    - Follicular lesion of undetermined significance
    - Suspicion of malignancy
  - Test results will guide surgical planning for initial resection

IMPORTANT REMINDERS

Any specific products referenced in this policy are just examples and are intended for illustrative purposes only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. These examples are contained in the parenthetical e.g. statement.
We develop Medical Policies to provide guidance to Members and Providers. This Medical Policy relates only to the services or supplies described in it. The existence of a Medical Policy is not an authorization, certification, explanation of benefits or a contract for the service (or supply) that is referenced in the Medical Policy. For a determination of the benefits that a Member is entitled to receive under his or her health plan, the Member's health plan must be reviewed. If there is a conflict between the medical policy and a health plan or government program (e.g., TennCare), the express terms of the health plan or government program will govern.

SOURCES

American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi. (2016). Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules - 2016 update. Retrieved December 12, 2016 from https://www.aace.com/publications/guidelines.

American Thyroid Association. (2016). 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Retrieved December 9, 2016 from https://www.thyroid.org/professionals/ata-professional-guidelines/.

BlueCross BlueShield Association. Evidence Positioning System. (9:2024). Molecular markers in fine needle aspirates of the thyroid (2.04.78). Retrieved July 8, 2025 from https://www.bcbsaoca.com/eps/. (61 articles and/or guidelines reviewed)

CMS.gov: Centers for Medicare & Medicaid Services. Palmetto GBA. (2025, March). Molecular testing for risk stratification of thyroid nodules (L39646). Retrieved July 8, 2025 from https://www.cms.gov/.

CMS.gov: Centers for Medicare & Medicaid Services. Palmetto GBA. (2021, January). Afirma assay by Veracyte coding and billing guidelines (A53098). Retrieved September 28, 2021 from https://www.cms.gov/.

Lee, E., Terhaar, S., McDaniel, L., Gorelik, D., Gerhard, E., et al. (2022). Diagnostic performance of the second-generation molecular tests in the assessment of indeterminate thyroid nodules: A systematic review and meta-analysis. American Journal of Otolaryngology, 43 (3), 103394. Abstract retrieved April 29, 2024 from PubMed database.

Nasr, C. E., Andrioli, M., Endo, M., Harrell, R. M., Livhits, M. J., et al. (2023). Real-world performance of the afirma genomic sequencing classifier (GSC)-a meta-analysis. The Journal of Clinical Endocrinology and Metabolism, 108 (6), 1526–1532. (Level 1 evidence)

National Comprehensive Cancer Network. (2025, March). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Thyroid carcinoma v.1.2025. Retrieved July 8, 2025 from the National Comprehensive Cancer Network.

Steward, D.L., Carty, S.E., Sippel, R.S., Yang, S.P., Sosa, J.A., Sipos, J.A., et al. (2019). Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology - a prospective blinded multicenter study. JAMA Oncology, 5 (2), 204-212. (Level 1 evidence)

ORIGINAL EFFECTIVE DATE: 10/12/2013

MOST RECENT REVIEW DATE: 8/14/2025

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Policies included in the Medical Policy Manual are not intended to certify coverage availability. They are medical determinations about a particular technology, service, drug, etc. While a policy or technology may be medically necessary, it could be excluded in a member's benefit plan. Please check with the appropriate claims department to determine if the service in question is a covered service under a particular benefit plan. Use of the Medical Policy Manual is not intended to replace independent medical judgment for treatment of individuals. The content on this Web site is not intended to be a substitute for professional medical advice in any way. Always seek the advice of your physician or other qualified health care provider if you have questions regarding a medical condition or treatment.

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