Molecular findings in thyroid tumors: Practical diagnostic, prognostic, and therapeutic insights

Over the last decade, there has been substantial growth in our understanding of the molecular drivers for thyroid tumors with the advent of next generation sequencing. Importantly, these drivers correlate with histopathologic features and clinical behavior. Briefly, RAS/RAS-like alterations result in modest activation of the MAPK pathway and produce follicular-patterned neoplasms, including follicular adenomas and follicular carcinomas, as well as non-invasive follicular thyroid neoplasm with papillary-like nuclear features and follicular subtype of papillary thyroid carcinoma (PTC). In contrast, BRAF V600E and related alterations result in robust activation of the MAPK pathway and display a papillary architecture with well-developed PTC nuclear features, including classic PTC and its non-follicular subtypes. Interestingly, a subset of thyroid carcinomas activates the MAPK pathway to an intermediate degree, resulting in mRNA expression patterns overlapping between the BRAF V600E-like and RAS-like categories, including tumors with fusions involving NTRK1-3, ALK, and FGFR2, which often display PTC features. In contrast, oncocytic tumors exhibit mitochondrial mutations and chromosomal copy number changes. Finally, a small subset of non-oncocytic tumors exhibits non-MAPK mechanisms of neoplasia, including transcriptional dysregulation, epigenetic alterations, or rare structural variants. In each molecular category, secondary alterations can occur; most notably TERT promoter and TP53 mutations occur with increasing frequency in high-grade differentiated, poorly differentiated, and anaplastic thyroid carcinomas. This article will review the diagnostic, prognostic, and therapeutic significance of molecular alterations across the spectrum of follicular cell derived thyroid tumors and discuss strategies for investigating unusual molecular alterations encountered in clinical practice.