NTRK‐rearranged papillary thyroid carcinoma demonstrates frequent subtle nuclear features and indeterminate cytologic diagnoses

Abstract

BACKGROUND:The studies on the cytomorphologic features of NTRK-rearranged papillary thyroid carcinoma (PTC) are limited and some reported characteristics, such as frequent indeterminate diagnoses and presence of fibrotic fragments, are inconsistent in literature. METHODS: NTRK gene rearrangements were detected in thyroidectomy specimens of PTC by either fluorescence in situ hybridization or next-generation sequencing. All the cytologic slides of NTRK-rearranged PTC were reviewed to evaluate the cytomorphologic features. The preoperative cytologic diagnoses of NTRK-rearranged PTC were compared with those of NTRK/BRAF wild-type and BRAF V600E -positive PTC. RESULTS: Fourteen PTC cases were identified to harbor NTRK gene rearrangements. Most of them showed a mixed architectural pattern of cell fragments (n = 13, 92.9%) and microfollicles (n = 9, 64.3%) with relatively rare papillary structures (n = 4, 28.6%). Nuclear grooving was frequently present (n = 11, 78.6%) but was mostly subtle and limited. Seven cases (50.0%) showed rounded nuclei without discernible nuclear elongation, and only 3 (21.4%) cases presented with nuclear pseudoinclusions. Among these cases, 7 (50.0%) were diagnosed as The Bethesda System for Reporting Thyroid Cytopathology (TBS) category III, 2 (14.3%) were diagnosed as TBS IV, and 5 (35.7%) were diagnosed as TBS V. The rate of TBS III-IV diagnoses for NTRK-rearranged PTCs was significantly higher (64.3%) than that for the 25 consecutive NTRK/BRAF wild-type PTCs (20.0%, P = .013) and the 70 consecutive BRAF V600E -positive PTCs (7.1%, P < .001) as selected. CONCLUSIONS: NTRK-rearranged PTC demonstrated intermediate nuclear features, such as subtle nuclear grooving, infrequent nuclear elongation, and rare pseudoinclusions, resulting in a significantly higher rate of TBS III-IV diagnoses compared to PTC with other molecular alterations. Cancer Cytopathol 2022;130:136-143.

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

“…Rearrangements of genes encoding tyrosine-kinase receptors lead to ligand-independent dimerization, thus, being oncogenic drivers in many types of cancer, including TC. Actionable kinase gene rearrangements are found in genes coding for anaplastic lymphoma kinase gene ( ALK ), RET , MET , neurotrophic tyrosine receptor kinase ( NTRK ), fibroblast growth factor receptor ( FGFR ), or ROS proto-oncogene 1 receptor ( ROS1 ) [ 143 , 144 , 145 ].…”