Studies evaluating one commercially available “rule out” molecular test have shown that about half of the cytologically indeterminate nodules were genomically benign. A large, prospective and double blind, multicenter study involving 49 academic and community sites demonstrated that this test has high sensitivity and NPV. 

When it reclassified an indeterminate cytopathology sample as benign, the sample had less than 6% likelihood of being malignant (>94% NPV)8 — a result comparable to a benign cytopathology diagnosis.9,10

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Clinical experiences from multiple academic and community practices suggest that molecular reclassification of indeterminate nodules as benign, coupled with clinical judgment, could enable patients to be followed and observed, sparing them the stress, health risk and expense associated with unnecessary diagnostic surgery.11

Additional molecular testing can also help optimize care for patients whose thyroid nodules are identified as suspicious or malignant, whether by cytopathology alone or in cases where the “rule out” molecular test was unable to rule out cancer (e.g., molecularly suspicious).

Indeed, a recent cost-effectiveness study concluded that the most cost-effective strategy in the United States was routine “rule out” molecular testing, followed by selective “rule in” molecular testing.12

For example, cytopathology does not definitively identify about 50% of medullary thyroid cancer cases,13 which typically require more extensive surgery.

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As a result, many patients require follow-up surgery once the presence of medullary thyroid cancer becomes known postoperatively. Molecular tests for medullary thyroid cancer and other genetically identifiable conditions (e.g., the presence of the BRAF V600E mutation) can help guide surgical strategy for these patients.

Physician decision-making for patients with cytologically indeterminate nodules has changed dramatically since the ATA last published guidelines in 2009. Physicians managing these patients have a responsibility to remain current on this topic.

The new ATA guidelines should help physicians by clearly differentiating the roles of molecular tests, and by suggesting diagnostic tests that have an appropriate body of evidence validating their routine clinical use, while withholding recommendations for tests that do not yet have such supporting evidence.

Richard T. Kloos, MD, is Senior Medical Director at Veracyte, Inc. Previously, Dr. Kloos was professor in the divisions of endocrinology and metabolism and nuclear medicine at The Ohio State University (OSU) and attending physician at the OSU Comprehensive Cancer Center. He has also served as Secretary and Chief Operating Officer for the American Thyroid Association.


  1. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167-1214.
  2. Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, et al. A Large Multicenter Correlation Study of Thyroid Nodule Cytopathology and Histopathology. Thyroid. 2011;21:243-251.
  3. Lewis CM, Chang K-P, Pitman M, Faquin WC, Randolph GW. Thyroid Fine-Needle Aspiration Biopsy: Variability in Reporting. Thyroid. 2009;19(7):717-723.
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  6. Olson MT, Boonyaarunnate T, Han PA, et al. A tertiary center’s experience with second review of 3885 thyroid cytopathology specimens. J Clin Endocrinol Metab. 2013;98:1450-1457.
  7. Beaudenon-Huibregtse S, Alexander EK, Guttler RB, et al. Centralized Molecular Testing for Oncogenic Gene Mutations Complements the Local Cytopathologic Diagnosis of Thyroid Nodules. Thyroid. 2014;10:1479-1487.
  8. Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative Diagnosis of Benign Thyroid Nodules with Indeterminate Cytology. N Engl J Med. 2012;367:705-715.
  9. Wang CC, Friedman L, Kennedy GC, Wang H, Kebebew E, Steward DL, et al. A Large Multicenter Correlation Study of Thyroid Nodule Cytopathology and Histopathology. Thyroid. 2011;21:243-251.
  10. Lewis CM, Chang K-P, Pitman M, et al. Thyroid Fine-Needle Aspiration Biopsy: Variability in Reporting. Thyroid. 2009;19(7):717-723.
  11. Steward D and Kloos R. Clinical Diagnostic Gene Expression Thyroid Testing. Otolaryngol Clin North Am. 2014;47(4):573-593.
  12. Lee L, How J, Tabah RJ, Mitmaker EJ. Cost-Effectiveness of Molecular Testing for Thyroid Nodules with Atypia of Undetermined Significance Cytology. J Clin Endocrinol Metab. 2014;99(8):2674-2682.
  13. Trimboli P, Treglia G, Guidobaldi L, et. al. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clin Endocrinol. 2015;82(2):280-285.

This article originally appeared on Endocrinology Advisor