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Approximately 15-30% of all thyroid nodules evaluated with fine-needle aspiration biopsy (FNAB) are classified as cytologically indeterminate. The stepwise unraveling of the molecular etiology of thyroid nodules has provided the basis for a better understanding of indeterminate samples and an opportunity to decrease diagnostic surgery in this group of patients. Over the last 15 years, several studies have tested different methodologies to detect somatic mutations (by polymerase chain reaction and next-generation sequencing, for example), and to identify differentially expressed genes or microRNA, aiming at developing molecular tests to improve the presurgical diagnosis of cytologically indeterminate nodules. In this review, we will provide an overview of the currently available molecular tests and the impact of mutation testing on the diagnosis of thyroid cancer. We will also review current published data and future perspectives in molecular testing of thyroid nodule FNAB and describe the current Brazilian experience with this diagnostic approach. Based on currently available data, especially for countries outside the US-Europe axis, a rational use of these tests must be made to avoid errors with regard to test indication and interpretation of test outcomes. In addition to clinical, radiological, and cytological features, we still need to determine local malignancy rates and conduct more independent validation and comparative performance studies of these tests before including them into our routine approach to indeterminate FNAB.

Can current molecular tests help in the diagnosis of indeterminate thyroid nodule FNAB?