Impact of Mutational Testing on the Diagnosis and Management of Patients with Cytologically Indeterminate Thyroid Nodules: A Prospective Analysis of 1056 FNA Samples

Context: Thyroid nodules are common in adults, but only a small fraction of them is malignant. Fine-needle aspiration (FNA) cytology provides a definitive diagnosis of benign or malignant disease in many cases, whereas about 25% of nodules are indeterminate, hindering most appropriate management. Objective: The objective of the investigation was to study the clinical utility of molecular testing of thyroid FNA samples with indeterminate cytology. Design: Residual material from 1056 consecutive thyroid FNA samples with indeterminate cytology was used for prospective molecular analysis that included the assessment of cell adequacy by a newly developed PCR assay and testing for a panel of mutations consisted of BRAF V600E, NRAS codon 61, HRAS codon 61, and KRAS codons 12/13 point mutations and RET/PTC1, RET/PTC3, and PAX8/PPAR gamma rearrangements. Results: The collected material was adequate for molecular analysis in 967 samples (92%), which yielded 87 mutations including 19 BRAF, 62 RAS, 1 RET/PTC, and five PAX8/PPAR gamma. Four hundred seventy-nine patients who contributed 513 samples underwent surgery. In specific categories of indeterminate cytology, i.e. atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignant cells, the detection of any mutation conferred the risk of histologic malignancy of 88, 87, and 95%, respectively. The risk of cancer in mutation-negative nodules was 6, 14, and 28%, respectively. Of 6% of cancers in mutation-negative nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology, only 2.3% were invasive and 0.5% had extrathyroidal extension. Conclusion: Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients. (J Clin Endocrinol Metab 96: 3390-3397, 2011)