Journal Article

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

Wirth, Lori J., Sadow, Peter M., Chu, Ying-Hsia, Farahani, Alexander A., Nosé, Vânia, Faquin, William C., Dias-Santagata, Dora

2020

Overview

The discovery of actionable kinase gene rearrangements has revolutionized the therapeutic landscape of thyroid carcinomas. Unsolved challenges include histopathologic recognition of targetable cases, correlation between genotypes and tumor behavior, and evolving resistance mechanisms against kinase inhibitors (KI). We present 62 kinase fusion-positive thyroid carcinomas (KFTC), including 57 papillary thyroid carcinomas (PTC), two poorly differentiated thyroid carcinomas (PDTC), two undifferentiated thyroid carcinomas (ATC), and one primary secretory carcinoma (SC), in 57 adults and 5 adolescents. Clinical records, post-operative histology, and molecular profiles were reviewed. Histologically, all KFTC showed multinodular growth with prominent intratumoral fibrosis. Lymphovascular invasion (95%), extrathyroidal extension, gross and microscopic (63%), and cervical lymph node metastasis (79%) were common. Several kinase fusions were identified: STRN-ALK, EML4-ALK, AGK-BRAF, CUL1-BRAF, MKRN1-BRAF, SND1-BRAF, TTYH3-BRAF, EML4-MET, TFG-MET, IRF2BP2-NTRK1, PPL-NTRK1, SQSTM1-NTRK1, TPR-NTRK1, TPM3-NTRK1, EML4-NTRK3, ETV6-NTRK3, RBPMS-NTRK3, SQSTM1-NTRK3, CCDC6-RET, ERC1-RET, NCOA4-RET, RASAL2-RET, TRIM24-RET, TRIM27-RET, and CCDC30-ROS1. Individual cases also showed copy number variants of EGFR and nucleotide variants and indels in pTERT, TP53, PIK3R1, AKT2, TSC2, FBXW7, JAK2, MEN1, VHL, IDH1, PTCH1, GNA11, GNAQ, SMARCA4, and CDH1. In addition to thyroidectomy and radioactive iodine, ten patients received multi-kinase and/or selective kinase inhibitor therapy, with 6 durable, objective responses and four with progressive disease. Among 47 cases with >6 months of follow-up (median [range]: 41 [6–480] months), persistent/recurrent disease, distant metastasis and thyroid cancer-related death occurred in 57%, 38% and 6%, respectively. In summary, KFTC encompass a spectrum of molecularly diverse tumors with overlapping clinicopathologic features and a tendency for clinical aggressiveness. Characteristic histology with multinodular growth and prominent fibrosis, particularly when there is extensive lymphovascular spread, should trigger molecular testing for gene rearrangements, either in a step-wise manner by prevalence or using a combined panel. Further, our findings provide information on molecular therapy in radioiodine-refractory thyroid carcinomas.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: 13/51 / 14/63 / 45/23 / 45/91 / 631/208/68 / 631/67/1459/1843 / Adolescent / Adult / Aged / AKT2 protein / Antineoplastic Agents - therapeutic use / Biomarkers, Tumor - genetics / Carcinoma - enzymology / Carcinoma - genetics / Carcinoma - secondary / Carcinoma - therapy / Cdc4 protein / Copy number / Databases, Factual / Disease Progression / E-cadherin / Enzyme inhibitors / Epidermal growth factor receptors / Female / Fibrosis / Gene Fusion / Gene Rearrangement / Genetic Predisposition to Disease / Genotypes / Histology / Humans / Iodine / Iodine Radioisotopes - therapeutic use / Janus kinase 2 / Laboratory Medicine / Lymph nodes / Male / Medicine / Medicine & Public Health / Metastases / Metastasis / Middle Aged / Molecular Diagnostic Techniques / Molecular Targeted Therapy / Mutation / Neoplasm Recurrence, Local / p53 Protein / Papillary thyroid carcinoma / Pathology / Phenotype / Protein Kinase Inhibitors - therapeutic use / Protein Kinases - genetics / Radiopharmaceuticals - therapeutic use / Retrospective Studies / Thyroid cancer / Thyroid gland / Thyroid Neoplasms - enzymology / Thyroid Neoplasms - genetics / Thyroid Neoplasms - pathology / Thyroid Neoplasms - therapy / Thyroidectomy / Time Factors / Treatment Outcome / Tumors / VHL protein / Young Adult