Optimal screening method for targetable gene rearrangements in papillary thyroid carcinoma with wild-type BRAF

The continued advancement of targeted therapies for actionable gene rearrangements has increased the demand for cost-effective screening methods for detecting these gene rearrangements in papillary thyroid carcinoma (PTC). Herein, ribonucleic acid (RNA) sequencing was performed on 106 patients with PTC having wild-type BRAF . The patients were divided into two groups: Group 1 (n = 58) included patients selected by an endocrine pathologist based on characteristic pathological features, including multinodular invasive growth, prominent intratumoral stromal fibrosis, mixed-growth patterns with varying degrees of nuclear atypia, pale eosinophilic to clear cytoplasm, and/or multiple lymph node (LN) metastasis. These patients were prescreened and then subjected to pan-tyrosine receptor kinase (TRK) immunohistochemistry (IHC) staining and RNA sequencing. In Group 2, RNA sequencing was conducted on samples from 48 randomly selected patients. Gene rearrangements were identified in 66 patients (62.3%), with a significantly higher proportion in Group 1 (77.6%) than in Group 2 (43.8%) ( p  < 0.001). NTRK was the most common gene rearrangement, which was detected in 31 patients (29.2%). The second most common gene rearrangement was RET (18.9%), followed by ALK (9.4%), and then BRAF (2.8%). Patients with gene rearrangements were significantly younger and had smaller primary tumors, although they demonstrated greater extrathyroidal extension and LN metastasis than those without rearrangements. Pan-TRK IHC revealed a sensitivity of 52% and a specificity of 94% for the prediction of NTRK gene rearrangements. This study demonstrates that pathological screening combined with pan-TRK IHC is a cost-effective method for examining targetable gene rearrangements in patients with PTC having wild-type BRAF.