title: The variable phenotype and low-risk nature of RAS-positive thyroid nodules.
abstract: BACKGROUND
  Oncogenic mutations are common in thyroid cancers. While the frequently detected RAS-oncogene mutations have been studied for diagnostic use in cytologically indeterminate thyroid nodules, no investigation has studied such mutations in an unselected population of thyroid nodules. No long-term study of RAS-positive thyroid nodules has been performed.
  
  
  METHODS
  We performed a prospective, blinded cohort study in 362 consecutive patients presenting with clinically relevant (>1 cm) thyroid nodules. Fine needle aspiration cytology and mutational testing were obtained for all nodules. Post-operative histopathology was obtained for malignant or indeterminate nodules, and benign nodules were sonographically followed. Histopathological features were compared between RAS- and BRAF-positive malignancies. RAS-positive benign nodules were analyzed for growth or cellular change from prior aspirations.
  
  
  RESULTS
  Overall, 17 of 362 nodules were RAS-positive. Nine separate nodules were BRAF-positive, of which eight underwent surgery and all proved malignant (100%). Out of the 17 RAS-positive nodules, ten underwent surgery, of which eight proved malignant (47%). All RAS-positive malignancies were low risk - all follicular variants of papillary carcinoma, without extrathyroidal extension, metastases, or lymphovascular invasion. RAS-positivity was associated with malignancy in younger patients (P = 0.028). Of the nine RAS-positive benign nodules, five had long-term prospective sonographic follow-up (mean 8.3 years) showing no growth or signs of malignancy. Four of these nodules also had previous aspirations (mean 5.8 years prior), all with similar benign results.
  
  
  CONCLUSIONS
  While RAS-oncogene mutations increase malignancy risk, these data demonstrate a low-risk phenotype for most RAS-positive cancers. Furthermore, cytologically benign, yet RAS-positive nodules behave in an indolent fashion over years. RAS-positivity alone should therefore not dictate clinical decisions.
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. m.medici@erasmusmc.nl.
authors.forename: Marco
authors.initials: M
authors.lastname: Medici
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. n.kwong@partners.org.
authors.forename: Norra
authors.initials: N
authors.lastname: Kwong
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. tangell@partners.org.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Angell
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. emarqusee@partners.org.
authors.forename: Ellen
authors.initials: E
authors.lastname: Marqusee
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. mikim@partners.org.
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Kim
authors.affiliation: Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. mfrates@partners.org.
authors.forename: Mary C
authors.initials: MC
authors.lastname: Frates
authors.affiliation: Department of Radiology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. cbenson@partners.org.
authors.forename: Carol B
authors.initials: CB
authors.lastname: Benson
authors.affiliation: Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. ecibas@partners.org.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Cibas
authors.affiliation: Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jbarletta@partners.org.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
authors.affiliation: Department of Pathology, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. jkrane@partners.org.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Krane
authors.affiliation: Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. druan@partners.org.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Ruan
authors.affiliation: Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. nlcho@partners.org.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
authors.affiliation: Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. agawande@partners.org.
authors.forename: Atul A
authors.initials: AA
authors.lastname: Gawande
authors.affiliation: Department of Surgery, The Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. fmoore@partners.org.
authors.forename: Francis D
authors.initials: FD
authors.lastname: Moore
authors.affiliation: Thyroid Section, Division of Endocrinology, Hypertension and Diabetes, The Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, PBB-B4 Room 417, Boston, MA, 02115, USA. ekalexander@partners.org.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Alexander
mesh_terms: D044963:Biopsy, Fine-Needle / Q000379:methods; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020558:GTP Phosphohydrolases; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D013223:Statistics as Topic; D013961:Thyroid Gland / Q000000981:diagnostic imaging / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology; D016606:Thyroid Nodule / Q000235:genetics / Q000473:pathology; D014463:Ultrasonography; D018631:ras Proteins
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins