title: NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States.
abstract: 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 (BRAF(V) (600E)) (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 BRAF(V) (600E) 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); BRAF(V) (600E) 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 BRAF(V) (600E) 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.
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Manju L
authors.initials: ML
authors.lastname: Prasad
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Monika
authors.initials: M
authors.lastname: Vyas
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Horne
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Renu K
authors.initials: RK
authors.lastname: Virk
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Morotti
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Anatomic Pathology, Bellaria Hospital, University of Bologna School of Medicine, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Marina N
authors.initials: MN
authors.lastname: Nikiforova
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Christison-Lagay
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Robert
authors.initials: R
authors.lastname: Udelsman
authors.affiliation: Department of Surgery, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Dinauer
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D000293:Adolescent; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002291:Carcinoma, Papillary; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D009511:New England; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics*; D020812:Receptor, trkC / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D050783:Proto-Oncogene Proteins c-ets; D051096:Proto-Oncogene Proteins c-ret; D020917:Receptor, trkA; D020812:Receptor, trkC; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C000715470:MAS1 protein, human; C073597:TPR protein, human; C099282:RET protein, human; C482119:BRAF protein, human
keywords: neurotrophic tyrosine kinase; papillary thyroid carcinoma; pediatric cancer; receptor type 3/ets variant 6 (NTRK3/ETV6) fusion oncogene; thyroid neoplasms