Molecular Testing of Thyroid Nodules

Over the past few decades, the molecular landscape of thyroid carcinoma has largely been deciphered. In the fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors of the thyroid gland, thyroid tumors have been subclassified into several new categories based not only on the cell of origin (follicular and C cells) and pathologic features, but also on molecular classification and biological behavior. Benign and low-risk neoplasms are mainly defined by a RAS-like molecular signature, characterized by cell differentiation close to that of the normal thyroid cell. Conversely, malignant neoplasms are mainly defined by a BRAFV600E-like molecular profile with low differentiation of thyroid cancer cells and strong activation of the MAPK signaling pathway. Dedifferentiation in high-grade and anaplastic thyroid cancers involves additional mutations affecting TP53, TERT promoter, SWI/SNF complexes, mismatch repair, and WNT/β-catenin pathways. Comprehensive molecular profiling of thyroid tumors has enhanced the development of ancillary molecular tests that can either reduce the need for diagnostic surgery in cytologically indeterminate thyroid nodules or enable targeted therapeutic options in advanced thyroid cancers. Herein, a comprehensive review of the genomic landscape of thyroid tumors and the available ancillary molecular tests for thyroid lesions along with their clinical utility will be discussed.