BlueCross BlueShield of Tennessee Medical Policy Manual

Molecular Markers in Fine Needle Aspirates of the Thyroid


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:





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

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

Angell, T., Frates, M., Medici, M., Liu, X., Kwong, N., Cibas, E., et al. (2015). Afirma benign thyroid nodules show similar growth to cytologically benign nodules during follow up. The Journal of Clinical Endocrinology & Metabolism. Retrieved March 8, 2016 from

BlueCross BlueShield Association. Evidence Positioning System. (6:2018). Molecular markers in fine needle aspirates of the thyroid (2.04.78). Retrieved January 18, 2019 from (74 articles and/or guidelines reviewed)

Brauner, E., Holmes, B., Krane, J., Nishino, M., Zurakowski, D., Hennessey, J., et al. (2015). Performance of the Afirma gene expression classifier in Hürthle cell thyroid nodules differs from other indeterminate thyroid nodules. Thyroid, 25 (7), 789-796. (Level 4 evidence)

Han, P., Hyun-seok, K., Soonweng, C., Fazeli, R., Najafian, A., Khawaja, H., et al. (2016). Association of BRAF V600E mutation and microRNA expression with central lymph node metastases in papillary thyroid cancer: a prospective study from four endocrine surgery centers. Thyroid, 26 (4), 532-542. (Level 4 evidence)

Labourier, E., Shifrin, A., Busseniers, A., Lupo, M., Manganelli, M., Andruss, B., et al. (2015). Molecular testing for miRNA, mRNA, and DNA on fine-needle aspiration improves the preoperative diagnosis of thyroid nodules with indeterminate cytology. Journal of Clinical Endocrinology and Metabolism, 100 (7), 2473-2750. (Level 3 evidence)

Lin, J.D., Fu, S.S., Chen, J.Y., Lee, C.H., Chau, W.K., Cheng, C.W., et al. (2016). Clinical manifestations and gene expression in patients with conventional papillary thyroid carcinoma carrying the BRAF (V600E) mutation and BRAF pseudogene. Thyroid, 26 (5), 691-704. Abstract retrieved January 23, 2018 from PubMed database.

Najafian, A., Noureldine, S., Azar, R., Atallah, C., Trinh, G., Schneider, E.B., et al. (2017). RAS mutations, and RET/PTC and PAX8/PPAR-gamma chromosomal rearrangements are also prevalent in benign thyroid lesions: implications thereof and a systematic review. Abstract retrieved January 23, 2018 from PubMed database.

National Comprehensive Cancer Network. (2018, December). NCCN clinical practice guidelines in oncology (NCCN Guidelines®). Thyroid carcinoma (V.3.2018). Retrieved January 18, 2019 from the National Comprehensive Cancer Network.

Noureldine, S., Olson, M., Agrawal, N., Prescott, J., Zeiger, M., & Tufano, R. (2015). Effect of gene expression classifier molecular testing on the surgical decision-making process for patients with thyroid nodules. Journal of American Medical Association Otolaryngology-Head & Neck Surgery, 141 (12), 1082-1088.  Abstract retrieved March 8, 2016 from PubMed database.

Palmetto Government Benefit Adminstrators. (2018). Afirma assay by Veracyte coding and billing guidelines (M00015, V2). Retrieved January 23, 2018 from

Sacks, W.L., Bose, S., Zumsteg, Z.S., Wong, R., Shiao, S.L., Braumstein, G.C., et al. (2016). Impact of Afirma gene expression classifier on cytopathology diagnosis and rate of thyroidectomy. Cancer, 124 (10), 722-728. Abstract retrieved December 12, 2016 from PubMed database.

Santhanam, P., Khthir, R., Gress, T., Elkadry, A., Olajide, O., Yaqub, A., & Driscoll, H. (2016). Gene expression classifier for the diagnosis of indeterminate thyroid nodules: a meta-analysis. Medical Oncology, 33 (2), 14. Abstract retrieved January 23, 2018 from PubMed database.

Singer, J., Hanna, J., Visaria, J., Gu, T., McCoy, M., & Kloos, R. (2016). Impact of a gene expression classifier on the long-term management of patients with cytologically indeterminate thyroid nodules. Current Medical Research and Opinion, 32 (7), 1225-1232. (Level 4 evidence)

Sipos, J., Blevins, T., Shea, H., Duick, D., Lakhian, S., Michael, B., et al. (2016). Long-term non-operative rate of thyroid nodules with benign results on the afirma gene expression classifier. Endocrine Practice, 22 (6), 666-672. Abstract retrieved December 12, 2016 from PubMed database.

Valderrabano, P., Khazai, L., Leon, M., Thompson, Z., Ma, Z., Chung, C. (2017). Evaluation of ThyroSeq v2 performance in thyroid nodules with indeterminant cytology. Endocrine Related Cancer, 24 (3), 127-136. Abstract retrieved June 21, 2017 from PubMed database.

Witt, R. (2015). Outcome of thyroid gene expression classifier testing in clinical practice. Laryngoscope, 126 (2), 524-527. (Level 4 evidence)

Wong, K.S., Angell, T.E., Strickland, K.C., Alexander, E.K., Cibas, E.S., Krane, J.F. & Barletta, J.A. (2016). Noninvasive follicular variant of papillary thyroid carcinoma and the Afirma gene expression classifier. Thyroid, 26 (7), 911-915. Abstract retrieved December 12, 2016 from PubMed database.

Wu, J.X., Young, S., Hung, M.L., Li, N., Yang, S.E., Cheung, D.S., et al. (2016). Clinical factors influencing the performance of gene expression classifier testing in indeterminate thyroid nodules. Thyroid, 26 (7), 916-922. Abstract retrieved December 12, 2016 from PubMed database.

Yang, S, Sullivan, P., Zhang, J., Govind, R., Levin, M., Rao, J., & Moatamed, A. (2016). Has Afirma gene expression classifier testing refined the indeterminate thyroid category in cytology? Cancer Cytopathology, 124 (2), 100-109. (Level 4 evidence)

Yip, L., Nikiforova, M., Yoo, J., McCoy, K., Stang, M., Armstrong, M., et al. (2015). Tumor genotype determines phenotype and disease-related outcomes in thyroid cancer: a study of 1510 patients. Annals of Surgery, 262 (3), 519-525. Abstract retrieved March 8, 2016 from PubMed database.




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