Both leading molecular thyroid tests may reduce the need for diagnostic surgery
Authors: Mike Fillon
Journal: CA A Cancer Journal for Clinicians (2021)

A new study compared the performance characteristics of an RNA test and a DNA-RNA test for predicting the malignancy risks of the approximately 20% of thyroid nodules that display indeterminate fine-needle aspiration (FNA) cytology results. The researchers found that each test allowed nearly half of patients with indeterminate nodules to opt for observation to avoid diagnostic surgery and the possibility of lifelong thyroid hormone supplementation following surgery and to alleviate stress. The study was published in JAMA Oncology (2021;7:70-77. doi:10.1001/jamaoncol.2020.5935). Study author Masha J. Livhits, MD, an endocrine surgeon and assistant professor of surgery at the David Geffen School of Medicine at the University of California Los Angeles, says that the study breaks new ground because it is the first and only direct comparison of the 2 leading commercially available molecular test technologies that clinicians use to help to determine whether cytologically indeterminate thyroid nodules should be observed or undergo hemithyroidectomy. Livhits explained, “Prior studies are limited by evaluating only one test (not both), and it is difficult to compare the performance of tests across studies as that performance is dependent on the prevalence of malignancy in a given population.” Patients in this randomized clinical trial came from the UCLA Health system and underwent thyroid FNA biopsies between August 1, 2017, and November 30, 2019. Only patients with at least 1 cytologically indeterminate nodule according to categories III and IV of the Bethesda System for Reporting Thyroid Cytopathology were included. The FNA biopsies were performed by radiologists, endocrinologists, and endocrine surgeons at 9 clinical sites. These specimens were analyzed by experienced head and neck cytopathologists and also sent for molecular testing if their cytopathology was indeterminate. Of 427 indeterminate nodules from 397 patients, 55 (from 51 patients) were excluded according to criteria such as a concurrent malignant cytology finding from another thyroid nodule from the same patient or physician preference for one of the molecular tests rather than inclusion in a randomized study. The 372 included nodules (from 346 patients) were block-randomized by month to undergo testing with either the RNA test or the DNA-RNA test. Molecular test results (classified as benign or suspicious for malignancy) were compared with the corresponding surgical specimen diagnoses from expert thyroid pathologists, although nodules with benign molecular test results were assumed to be truly benign even if they were not resected if they had stable follow-up surveillance ultrasounds. Nodules with noninvasive follicular thyroid neoplasm with papillary-like features were grouped with cancer “because it represents a premalignant entity that should be managed surgically,” wrote the researchers. The study’s primary outcomes were the sensitivity, specificity, positive predictive value, and negative predictive value for each of the molecular tests. Of the 372 cytologically indeterminate nodules that were included for analysis, 54% (n = 201) were randomized to undergo the RNA test, and 46.0% (n = 171) were randomized for the DNA-RNA test. The patients’ median age was 55 years, and 76.9% were female (n = 266). The RNA test demonstrated benign results in 107 nodules (53.2%) and suspicious results in 73 nodules (36.3%). There were 19 samples (9.5%) judged to be inadequate for analysis and 2 samples (1.0%) that were suspicious for parathyroid (rather than thyroid) tissue. Of the 107 benign nodules tested with the RNA test, 12 (11.2%) were surgically resected. Of the 73 nodules with suspicious RNA test results, 58 (79.5%) were resected. The DNA-RNA test demonstrated negative results in 103 nodules (60.2%) and positive results in 60 nodules (35.1%). There were 7 samples (4.1%) that were insufficient for molecular analysis and 1 sample (0.6%) that was suspicious for being a sample of parathyroid tissue. Of the nodules with negative results from the DNA-RNA test, 11 (10.7%) were surgically resected. Of the nodules with positive results from the DNA-RNA test, 49 (81.7%) were resected. In analyses including comparisons with either surgical or clinical surveillance results, the RNA test and the DNA-RNA test had similar results (with P values ranging from .32 to >.99) for sensitivity (100.0% and 96.9%, respectively), specificity (79.6% and 84.8%, respectively), positive predictive value (53.5% and 63.3%, respectively), and negative predictive value (100.0% and 99.0%, respectively). All 4 performance characteristics were also statistically similar in comparisons with surgical results only. Use of either test allowed 49% of patients with indeterminate thyroid nodules to avoid diagnostic surgery. “While the 2 most commonly used molecular tests for thyroid nodules are the RNA-based Afirma test [Veracyte, Inc., San Francisco, California] and the DNA- and RNA-based ThyroSeq v3 test [University of Pittsburgh Medical Center and Sonic Healthcare USA], it is not clear which test is better,” says William C. Faquin, MD, PhD, professor of pathology at Harvard Medical School and director of head and neck pathology at Massachusetts Eye and Ear Infirmary in the Divisions of Head and Neck Pathology and Cytopathology at Massachusetts General Hospital in Boston. “The importance of this study is that it provides a clear-cut comparison using a parallel randomized clinical trial to assess the performance of both of these molecular testing options. Both the Afirma and ThyroSeq v3 tests performed equally well in this role. The current study in JAMA Oncology is very helpful in synthesizing a lot of the data, which can be confusing, and providing a clear message about the strong performances of both tests.” Dr. Livhits says that the key takeaway message is that molecular analysis with either test can help patients to avoid unnecessary diagnostic surgery. “Our results indicate that the two tests have similar diagnostic performance, with very high sensitivity and moderate specificity,” she says. “Therefore, the choice of which test to use may be based on other factors, such as the cost of the test and the turnaround time. This is important given the increasing detection of thyroid nodules and the need to avoid overtreatment. ThyroSeq v3 provides data on specific mutations, which were reported in our study, that may impact the prognosis of nodules ultimately found to be malignant and may guide the extent of treatment or provide therapeutic targets in the rare advanced, metastatic cases.” For clinicians seeking more guidance on this topic, Dr. Faquin recommends the American Thyroid Association Guidelines (thyroid.org/professionals/ata-professional-guidelines/). “They address in detail the application of molecular testing in the cytologic evaluation of thyroid nodules. The topic is also covered very well in several review articles in the cytology and endocrinology literature.” Photo credit: Cancer Cytopathol. 2011;120:73-86. doi:10.1002/cncy.20178