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The ETV6-NTRK3 translocation characterizes a subset of radiation associated and pediatric papillary thyroid carcinomas (PTCs). We now describe the clinicopathologic features of ETV6-NTRK3 translocated PTC in an adult population without radiation exposure. Twelve cases were identified by next-generation sequencing (ThyroSeq version 2). The mean patient age was 37 years with a female predilection (10:2). Preoperative fine needle aspiration was performed on 6 patients of which 4 were classified as "malignant," whereas 2 were classified as "follicular lesion of undetermined significance." One third (4/12) of patients demonstrated extrathyroidal extension and one half of patients (5/10) demonstrated lymph node metastases. One patient presented with brain metastasis. Tumors typically (8/12) demonstrated an admixture of follicular and papillary patterns and were usually infiltrative and multinodular (6/12 cases). Tumors often showed clear cell or oncocytic foci and demonstrated overt nuclear features of PTC, though characteristically, interspersed bland areas were common, even in metastases. Cytoplasmic vacuolization resembling that of mammary analog secretory carcinoma was also common but focal. TTF-1 was positive and S100 was negative in all tested cases confirming a thyroid phenotype. Unique morphologies included glomeruloid follicles, reverse polarization of nuclei. Survey of the TCGA datasets revealed similar findings. Thus, ETV6-NTRK3 translocated PTC are locoregionally aggressive and can metastasize distantly. They are characterized by mixture of papillary and follicular architecture and may show cytoplasmic vacuolization akin to other ETV6 translocated carcinomas. Although nuclear features are typically overt, interspersed bland regions may cause diagnostic difficulty in metastatic sites, and may explain discordance on fine needle aspiration.

Clinical and Morphologic Features of ETV6-NTRK3 Translocated Papillary Thyroid Carcinoma in an Adult Population Without Radiation Exposure