title: Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics.
abstract: Distant metastases (DM) are a rare occurrence in well-differentiated thyroid carcinoma. The aim of this study was to analyze the clinical, pathologic, and molecular features of primary thyroid carcinoma with low-risk histology that develop DM.
  
  
  
  A detailed clinicopathologic review and targeted next-generation sequencing were performed on a cohort of well-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion, or significant lymph node metastases but exhibiting DM.
  
  
  
  Primary well-differentiated thyroid carcinoma with low-risk histologic features and DM was a rare occurrence, accounting for only 3% of metastatic non-anaplastic thyroid carcinoma. All 15 cases meeting the inclusion criteria harbored DM at presentation. The majority (11/15) of these tumors were follicular variant of papillary thyroid carcinoma (PTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated Hürthle cell carcinoma (n = 2), encapsulated follicular carcinoma (n = 1), and an encapsulated papillary carcinoma classical variant (n = 1). Of the 12 encapsulated carcinomas, 10 had capsular invasion only and no vascular invasion. Ninety-two percent of the tumors exhibited extensive intra-tumoral fibrosis. Among the eight tumors that were subjected to next-generation sequencing analysis, a RAS mutation was the main driver (5/8), and TERT promoter mutation was highly prevalent (6/8). In four cases, TERT promoter mutations were associated with RAS or BRAF mutations. BRAF-mutated classical variant of papillary carcinoma also presented with DM but was less common (1/8). In 11/15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3/4 incidental cases that were genotyped, TERT promoter mutations were found.
  
  
  
  When DM occur in primary thyroid carcinoma with low-risk histology, they are almost always found at presentation. The majority are encapsulated follicular variant of PTC with capsular invasion only. TERT promoter mutations occur at a higher rate than that seen in PTC in general and may help explain the aggressive behavior of these histologically deceptive primary carcinomas.
authors.affiliation: 1 Department of Pathology, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.affiliation: 2 Department of Medicine, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: R Michael
authors.initials: RM
authors.lastname: Tuttle
authors.affiliation: 2 Department of Medicine, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Mona M
authors.initials: MM
authors.lastname: Sabra
authors.affiliation: 3 Department of Surgery, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.affiliation: 1 Department of Pathology, Memorial Sloan-Kettering Cancer Center , New York, New York.
authors.forename: Ronald
authors.initials: R
authors.lastname: Ghossein
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000556:secondary*; D000368:Aged; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics / Q000556:secondary*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019098:Telomerase / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase
keywords: Hürthle cell carcinoma; RAS; TERT; distant metastasis; follicular variant; papillary thyroid carcinoma