Introduction: Use of molecular biomarkers and profiling panels in the management of thyroid nodules has shown efficacy in guiding treatment decisions and reducing unnecessary surgeries, particularly in cases with indeterminate cytology.
Methods: A task force was convened by the Surgical Affairs Committee of the American Thyroid Association (ATA) to determine clinical scenarios for which surgeons may find molecular profiling to be advantageous in the management of thyroid nodules.
Results: The Task Force suggested that molecular testing may be of little benefit in the following scenarios:
Scenarios in which molecular profiling would be useful are shown in Table 1. The Table shows the estimated likelihood of malignancy in thyroid nodules with Bethesda cytology categories III, IV, and V using ancillary molecular profiling tests, and shows the Tasks Force’s management recommendations based on the test findings.
The task force noted that the performance of the diagnostic tests, including the positive and negative predictive value, is influenced by the prevalence of cancer in each cytologic category at an individual institution, as this prevalence can vary widely by medical center. They added that the gene expression classifier (GEC) test will perform better in Bethesda categories with lower cancer frequency, such as atypia of uncertain significance (AUS), follicular lesion of undetermined significance (FLUS) or follicular neoplasm (FN). The 7-gene molecular panel will perform better in settings and categories of higher cancer frequency.
Conclusion: Molecular profiling of thyroid cytology specimens may help guide treatment decisions regarding nodules with indeterminate cytology specimens. The results of molecular profiling tests should be used in combination with clinical and sonographic risk factors for malignancy and with an understanding of the prevalence of malignancy for the Bethesda cytologic categories at an individual institution.
Ferris RL, Baloch ZW, Bernet V, et al. American Thyroid Association Statement on Surgical Application of Molecular Profiling for Thyroid Nodules: current impact on perioperative decision-making. Thyroid. 2015 May 18. [Epub ahead of print]
Commentary by Priyathama Vellanki MD
Dr. Priyathama Vellanki is an Assistant Professor, Division of Endocrinology, Metabolism and Lipids at Emory University School of Medicine in Atlanta, GA.
Thyroid nodules with intermediate cytology results continue to be a diagnostic dilemma for the clinician. According to the Bethesda system, indeterminate categories include:
• Atypia of uncertain significance (AUS)1
• Follicular neoplasm of uncertain significance (FLUS)1
• Follicular neoplasm (FN)1
• Suspicious for malignancy (SMC)1
These categories have varying malignancy risks: AUS/FLUS has a malignancy risk of 5-15%, FN has a malignancy risk of 15-30% and SMC has a malignancy risk of 60-75%.1
Due to the higher risk of malignancy, the 2009 American Thyroid Association (ATA) guidelines suggest molecular markers may be used to help guide management.2 In the case of FN or SMC, the guidelines suggest a diagnostic lobectomy. For AUS/FLUS, in general, fine-needle aspiration (FNA) is repeated and usually yields the diagnosis. When repeat cytology results are indeterminate, a diagnostic thyroid lobectomy is recommended. After surgery, approximately 30% of indeterminate nodules characterized as AUS/FLUS and FN may be malignant.3 This means the majority of indeterminate nodules characterized as AUS/FLUS and/or FN do not need surgery. In this setting molecular testing may help to stratify the malignancy risk in order to guide clinical management.
Molecular testing for indeterminate thyroid nodules is based on research demonstrating mutations in specific genes; gene rearrangements are found in malignant thyroid nodules. Most mutations are found in BRAF, RET/PTC rearrangements and RAS. Based on this, three methodologies for molecular testing currently exist and are commercially available.
1. Gene-based where a panel of genes is tested for mutations
2. Gene expression profile of specific implicated genes and uses RNA
3. Next-generation DNA sequencing
These tests have been validated at different centers since the ATA's 2009 guidelines covering the management of thyroid nodules.
Understanding sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) is key in the application of these tests.4 Sensitivity and specificity are relevant to the test itself while PPV and NPV are dependent on the prevalence of malignancy in a given population.
Sensitivity is the probability of the test to be positive in people that have the disease. Therefore, if a highly sensitive test is negative, it rules out disease. Specificity is the probability of the test to be negative when there is no disease. Therefore, if a highly specific test is positive, it rules in disease. Sensitivity and specificity are inherent to the quality of the test. However, with molecular testing, the interest to the clinician is the PPV and NPV. PPV is the probability of the patient having disease if the test is positive. NPV is the probability of the patient not having disease if the test is negative. Furthermore, PPV and NPV are dependent on the prevalence of the disease in a particular population or, in this case, the probable prevalence of thyroid cancer and the pretest probability of the indeterminate cytology result to be malignant.
Therefore, in AUS/FLUS and FN—where the probability of cancer is lower—if a highly sensitive test with a high NPV is negative, then the probability of thyroid cancer is low. However, if the cytology is categorized as suspicious for malignancy and a highly sensitive test is positive and has a high PPV, then the likelihood of cancer is high and may warrant total thyroidectomy.
None of the molecular tests have a 100% PPV or NPV. In addition, the prevalence of thyroid cancer in the different Bethesda indeterminate categories may vary by medical center. Therefore, prior to choosing a molecular test for a patient, it is important to know the prevalence of thyroid cancer in an indeterminate nodule at the particular medical center where the patient is treated. While it is not possible to incorporate the prevalence of thyroid cancer at each institution, the 2015 ATA guidelines for molecular testing offer guidance for use of molecular markers and address the utility of the different molecular tests in the Bethesda indeterminate categories. The ATA also summarizes the course of action based on the indeterminate category and the result of the molecular testing.
1. Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. Nov 2009;19(11):1159-1165.
2. Cooper DS, Doherty GM, Haugen BR, Kloos RT, et al. American Thyroid Association Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. Nov 2009;19(11):1167-1214.
3. Wang CC, Friedman L, Kennedy GC, et al. A large multicenter correlation study of thyroid nodule cytopathology and histopathology. Thyroid. Mar 2011;21(3):243-251.
4. Parikh R, Mathai A, Parikh S, Chandra Sekhar G, Thomas R. Understanding and using sensitivity, specificity and predictive values. Indian J Ophthalmol. Jan-Feb 2008;56(1):45-50.