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

Abstract

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. 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 BRAFV600E -positive PTC. 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 BRAFV600E -positive PTCs (7.1%, P < .001) as selected. 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.