title: Molecular alterations in partially-encapsulated or well-circumscribed follicular variant of papillary thyroid carcinoma.
abstract: BACKGROUND
  Studies have described an encapsulated and an infiltrative form of the follicular variant of papillary thyroid carcinoma (FVPTC). Encapsulated FVPTCs have been reported to have virtually no recurrence risk or metastatic potential and to harbor RAS mutations but not BRAF mutations. In contrast, infiltrative tumors have significant metastatic potential, a risk of recurrence, and a BRAF mutation frequency of approximately 25%. In our experience, a substantial number of FVPTCs are neither fully encapsulated nor infiltrative, but instead are partially encapsulated (PE) or well circumscribed (WC). We have previously reported that PE/WC FVPTCs behave in an indolent fashion similar to encapsulated tumors. The purpose of the current study was to evaluate the molecular alterations in PE/WC FVPTC.
  
  
  METHODS
  We identified 28 PE/WC FVPTCs resected consecutively at our institution. Targeted mutation analysis of 41 genes including members of the RAS and RAF families was performed on DNA extracted from formalin-fixed, paraffin-embedded blocks using single-base extension chemistry and mass spectrometry.
  
  
  RESULTS
  Lymph node metastases were absent in all cases with sampled lymph nodes, and no patients developed tumor recurrences (median follow-up time, 72.8 months). Overall, 13 cases (46%) harbored RAS mutations, including seven (25%) with NRAS mutations (p.Gln61Arg) and six (21%) with HRAS mutations (five had p.Gln61Arg and one had a p.Gln61Lys substitution). No PE/WC FVPTCs had BRAF mutations.
  
  
  CONCLUSIONS
  The results of this study confirm our previous finding that PE/WC FVPTCs pursue an indolent clinical course. Additionally, we found that PE/WC tumors have a similar molecular profile to that of encapsulated FVPTCs with frequent RAS mutations (46%) and no BRAF mutations. These molecular results provide further evidence that PE/WC and encapsulated FVPTCs are biologically similar and should be distinguished from more aggressive infiltrative FVPTCs.
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Brooke E
authors.initials: BE
authors.lastname: Howitt
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Jia
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Sholl
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001900:Boston; D018265:Carcinoma, Papillary, Follicular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D047368:Tumor Burden; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D019908:Proto-Oncogene Proteins c-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins