NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States

BACKGROUND An increase in thyroid cancers, predominantly papillary thyroid carcinoma (PTC), has been recently reported in children. METHODS The histopathology of 28 consecutive PTCs from the northeast United States was reviewed. None of the patients (ages 6-18 years; 20 females, 8 males) had significant exposure to radiation. Nucleic acid from tumors was tested for genetic abnormalities (n = 27). Negative results were reevaluated by targeted next-generation sequencing. RESULTS Seven of 27 PTCs (26%) had neurotrophic tyrosine kinase receptor (NTRK) fusion oncogenes (NTRK type 3/ets variant 6 [NTRK3/ETV6], n =5; NTRK3/unknown, n = 1; and NTRK type 1/translocated promoter region, nuclear basket protein [NTRK1/TPR], n = 1), including 5 tumors that measured >2 cm and 3 that diffusely involved the entire thyroid or lobe. All 7 tumors had lymphatic invasion, and 5 had vascular invasion. Six of 27 PTCs (22%) had ret proto-oncogene (RET) fusions (RET/PTC1, n = 5; RET/PTC3, n = 1); 2 tumors measured >2 cm and diffusely involved the thyroid, and 5 had lymphatic invasion, with vascular invasion in 2. Thirteen PTCs had the B-Raf proto-oncogene, serine/threonine kinase (BRAF) valine-to-glutamic acid mutation at position 600 (BRAFV600E) (13 of 27 tumors; 48%), 11 measured <2 cm, and 6 had lymphatic invasion (46%), with vascular invasion in 3. Fusion oncogene tumors, compared with BRAFV600E PTCs, were associated with large size (mean, 2.2 cm vs 1.5 cm, respectively; P =.05), solid and diffuse variants (11 of 13 vs 0 of 13 tumors, respectively; P <.001), and lymphovascular invasion (12 of 13 vs 6 of 13 tumors, respectively; P =.02); BRAFV600E PTCs were predominantly the classic variant (12 of 13 vs 1 of 13 tumors). Two tumors metastasized to the lung, and both had fusion oncogenes (NTRK1/TPR, n = 1; RET/PTC1, n = 1). CONCLUSIONS Fusion oncogene PTC presents with more extensive disease and aggressive pathology than BRAFV600E PTC in the pediatric population. The high prevalence of the NTRK1/NTRK3 fusion oncogene PTCs in the United States is unusual and needs further investigation. Cancer 2016;122:1097-1107.