Abstract
Molecular testing offers more objective information in the diagnosis and personalized decision making for thyroid nodules. In Korea, as the BRAF V600E mutation is detected in 70–80% of thyroid cancer specimens, its testing in fine-needle aspiration (FNA) cytology specimens alone has been used for the differential diagnosis of thyroid nodules until now. Thus, we aimed to develop a mutation panel to detect not only BRAF V600E, but also other common genetic alterations in thyroid cancer and to evaluate the diagnostic accuracy of the mutation panel for thyroid nodules in Korea. For this prospective study, FNA specimens of 430 nodules were obtained from patients who underwent thyroid surgery for thyroid nodules. A molecular test was devised using real-time PCR to detect common genetic alterations in thyroid cancer, including BRAF, N-, H-, and K-RAS mutations and rearrangements of RET/PTC and PAX8/PPARr. Positive results for the mutation panel were confirmed by sequencing. Among the 430 FNA specimens, genetic alterations were detected in 293 cases (68%). BRAF V600E (240 of 347 cases, 69%) was the most prevalent mutation in thyroid cancer. The RAS mutation was most prevalently detected for indeterminate cytology. Among the 293 mutation-positive cases, 287 (98%) were diagnosed as cancer. The combination of molecular testing and cytology improved sensitivity from 72% (cytology alone) to 89% (combination), with a specificity of 93%. We verified the excellent diagnostic performance of the mutation panel applicable for clinical practice in Korea. A plan has been devised to validate its performance using independent FNA specimens.
Highlights
Thyroid nodules are the most prevalent endocrine disorders and are detected in approximately 50% of the adult population using high-resolution ultrasonography [1,2]
Fine-needle aspiration (FNA) cytology (FNAC) is the standard initial diagnostic approach and, using FNAC, most thyroid nodules are categorized as benign (Bethesda class II, 60–70% of cases), whereas approximately 5% are diagnosed as malignant (Bethesda class VI) [3,4]
Since the first report of using BRAF V600E mutation analysis for FNA specimens by Kimura et al [5], a “7-gene panel” consisting of BRAF V600E, RAS, RET/papillary thyroid carcinoma (PTC), and PAX8/PPARγ mutations has been developed to overcome the low sensitivity of the testing for BRAF V600E single mutation and to increase the predictive value for malignancy, especially for indeterminate cytology from FNAC [6]
Summary
Thyroid nodules are the most prevalent endocrine disorders and are detected in approximately 50% of the adult population using high-resolution ultrasonography [1,2]. The majority of thyroid nodules are classified as either benign or malignant, still approximately 20–30% of the cases are classified as indeterminate (Bethesda classes III, IV and V) using FNAC [3,4]. Since the first report of using BRAF V600E mutation analysis for FNA specimens by Kimura et al [5], a “7-gene panel” consisting of BRAF V600E, RAS, RET/PTC, and PAX8/PPARγ mutations has been developed to overcome the low sensitivity of the testing for BRAF V600E single mutation and to increase the predictive value for malignancy, especially for indeterminate cytology from FNAC [6]. Mutation analysis of somatic mutations and gene fusions are considered as “rule-in” tests with their high specificity and positive predictive values. These tests have been used to predict thyroid cancer and to reduce the need for exploratory thyroid surgery
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