Kinase Fusion-Related Thyroid Carcinomas: Towards Predictive Models for Advanced Actionable Diagnostics

Abstract

The past decade has brought significant advances in our understanding of the molecular mechanisms of thyroid carcinogenesis. Among thyroid carcinomas, the most successful class of targeted therapeutics appears to be selective kinase inhibitors. Actionable kinase fusions arise in around 10-15% of cases of thyroid cancer, a significant subset. A cohort of molecular testing platforms, both commercial and laboratory-derived, has been introduced into clinical practice to identify patients with targetable tumors, requiring pathologists to develop an integrative approach that utilizes traditional diagnostic cytopathology and histopathology, immunohistochemistry, and cutting-edge molecular assays for optimal diagnostic, prognostic, and therapeutic efficiency. Furthermore, there has been increasing scrutiny of the clinical behavior of kinase fusion-driven thyroid carcinoma (KFTC), still regarded as papillary thyroid carcinomas, and in characterizing molecular predictors of kinase inhibitor resistance with an aim to establish standardized, evidence-based treatment regimens. This review presents an overview of the current literature on the clinicopathologic and molecular features of KFTC as well as the latest investigational progress and encountered challenges for this unique subset of thyroid neoplasias.

Keywords: Inhibitor; Kinase fusion; NTRK; RET; Resistance; Thyroid cancer.

Fig. 1

Oncogenic signaling pathways in thyroid carcinogenesis. The mitogen-activated protein kinase (MAPK) and PI3K pathways play a central role in thyroid oncogenesis and harbor the most common targetable molecular drivers. Targeted inhibitors listed in gray and in parentheses have yet to receive FDA approval

Fig. 2

Oncogenic mechanisms of kinase fusions. Most tyrosine kinase fusions contain partner-derived dimerization domains that enable ligand-independent activation (A). BRAF fusions, however, may or may not have partner-derived dimerization domains and thought to be activated by loss of autoinhibition (B)

Fig. 3

Histologic features of KFTC include multinodularity (A), lymphovascular spread (not shown) and prominent intratumoral fibrosis (A) that have been noted in several series. RET fusions are well-known to be associated with the diffuse sclerosing PTC (B) characterized by chronic lymphocytic inflammation (white arrow) and squamous metaplasia (black arrow) in addition to stromal fibrosis/sclerosis. NTRK rearranged tumors may show intriguing glomeruloid architectural formations (C, arrow). Primary secretory carcinomas are histologically reminiscent of its salivary counterpart with microcystic architecture (D) and eosinophilic secretions (arrows). The nuclei are vesicular with conspicuous nucleoli

Fig. 4

Common molecular platforms for clinical fusion testing. See text for details

Fig. 5

Mechanisms of acquired resistance to kinase inhibitor therapy. On-target resistance is mediated by acquired mutations at various locations in the kinase domain (A). Alternative pathway activation, such as another receptor tyrosine kinase that drives downstream MAPK and PI3K signaling, bypasses the inhibition of RET in this example