Kinase fusion-related thyroid carcinomas: distinct pathologic entities with evolving diagnostic implications

Activating genomic alterations in protein kinases represent a major driving force in thyroid carcinogenesis. Recently, oncogenic kinase fusions have been a central subject of pharmaceutical development, with a rapidly growing number of inhibitors validated for treating molecularly matched malignancies. Thyroid carcinomas harbor actionable kinase fusions in 10–15% of cases, occupying an increasingly recognized subpopulation of thyroid carcinomas with enhanced attention to molecular profiling. With advances in kinase-based cancer therapy, several challenges have emerged for pathologists. To interrogate an expanding list of targetable genes, the diagnostic paradigm has shifted from conventional single-gene methods toward high-throughput nucleic acid sequencing. Considering the relatively low incidence of most kinase fusions, a selective approach for molecular testing that utilizes histologic and immunohistochemical findings in triaging cases becomes essential for laboratory resource management. Moreover, kinase inhibitor resistance inevitably evolves, requiring a multimodal approach to optimal therapy, despite targeted therapies showing an enhanced, durable response. In this review, we assess the current clinicopathologic understanding and ongoing investigational topics in kinase fusion-related thyroid carcinomas.