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Clinicopathologic features of kinase fusion-related thyroid carcinomas: an integrative analysis with molecular

Ying-Hsia Chu1, Lori J Wirth2, Alexander A Farahani1

  • 1Departments of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc
|August 2, 2020
PubMed

Insights

Kinase fusion-positive thyroid carcinomas (KFTC) show diverse molecular profiles and aggressive behavior. Identifying these gene rearrangements is crucial for targeted therapy in radioiodine-refractory cases.

Area of Science:

  • Oncology
  • Molecular Pathology
  • Genetics

Background:

  • Actionable kinase gene rearrangements are key in thyroid carcinoma therapy.
  • Challenges remain in histopathologic recognition, genotype-tumor behavior correlation, and resistance to kinase inhibitors (KI).
  • Kinase fusion-positive thyroid carcinomas (KFTC) represent a distinct molecular subtype.

Purpose of the Study:

  • To characterize the clinicopathologic and molecular features of 62 KFTC.
  • To identify common kinase fusions and associated genetic alterations.
  • To evaluate the efficacy of kinase inhibitor therapy in radioiodine-refractory KFTC.

Main Methods:

  • Retrospective review of clinical records, post-operative histology, and molecular profiles of 62 KFTC.
  • Identification of kinase fusions using molecular profiling.
  • Analysis of treatment outcomes for patients receiving kinase inhibitor therapy.

Main Results:

  • KFTC, including papillary, poorly differentiated, undifferentiated, and secretory carcinomas, frequently exhibit multinodular growth and prominent fibrosis.
  • Commonly identified kinase fusions include STRN-ALK, EML4-ALK, various BRAF, MET, NTRK, RET, and ROS1 fusions.
  • Ten patients received kinase inhibitor therapy, with 6 showing durable responses; however, 57% experienced persistent/recurrent disease, 38% distant metastasis, and 6% cancer-related death within 6 months follow-up.

Conclusions:

  • KFTC are molecularly diverse with overlapping features and a propensity for aggressive clinical behavior.
  • Characteristic histology with multinodular growth and fibrosis, especially with lymphovascular invasion, warrants molecular testing for gene rearrangements.
  • Findings support molecular therapy for radioiodine-refractory thyroid carcinomas and highlight the need for comprehensive molecular profiling.

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