title: Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Accounts for More Than Half of "Carcinomas" Harboring RAS Mutations.
abstract: Molecular testing of thyroid nodules is increasingly being utilized to guide clinical management decisions. RAS mutations are the most frequent mutations detected in the context of an indeterminate fine-needle aspiration (FNA) diagnosis. The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was recently introduced to promote conservative management of tumors previously classified as noninvasive follicular variant of papillary thyroid carcinoma (FVPTC). This change in terminology was based on the indolent clinical behavior of these tumors and their molecular profile, which includes frequent RAS mutations. The aim of this study was to determine the percentage of RAS-mutant "carcinomas" that would now be classified as NIFTPs.
  
  
  
  A search was performed for cases with known activating RAS mutations in a database of 199 thyroid carcinomas that underwent molecular characterization as part of Profile:Oncopanel between July 2013 and July 2015. Cases of FVPTC were re-reviewed to identify tumors that now would be categorized as NIFTP. Preceding FNA diagnoses were recorded, and cases with an indeterminate FNA result (defined as a diagnosis of atypia/follicular lesion of undetermined significance, suspicious for follicular neoplasm, or suspicious for malignancy) were identified.
  
  
  
  A total of 27 RAS-mutant thyroid tumors were identified. Fifteen (56%) cases had an NRAS mutation, nine (33%) had an HRAS mutation, and three (11%) had a KRAS mutation. Twenty-four (89%) cases had a preceding FNA, 19 (79%) of which had an indeterminate FNA diagnosis. The surgical resection specimen demonstrated FVPTC in 20 (74%) cases, classical type PTC in two (7%), solid variant of PTC in one (4%), and follicular thyroid carcinoma in four (15%). Of the 20 FVPTCs, 16 (80%) would now be classified as NIFTP. NIFTPs accounted for 59% of RAS-mutant carcinomas overall and 63% of RAS-mutant carcinomas with a prior indeterminate FNA diagnosis.
  
  
  
  NIFTPs accounted for more than half of RAS-mutant "carcinomas" in this cohort. In cases where clinical and sonographic data support a low-risk phenotype, these results suggest that a lobectomy should be considered as the initial surgical approach for a nodule with an indeterminate FNA diagnosis and a RAS mutation.
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Vera A
authors.initials: VA
authors.lastname: Paulson
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Shivdasani
authors.affiliation: 2 Division of Endocrinology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Trevor E
authors.initials: TE
authors.lastname: Angell
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Edmund S
authors.initials: ES
authors.lastname: Cibas
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Krane
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Neal I
authors.initials: NI
authors.lastname: Lindeman
authors.affiliation: 2 Division of Endocrinology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Alexander
authors.affiliation: 1 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
authors.forename: Justine A
authors.initials: JA
authors.lastname: Barletta
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D000328:Adult; D000368:Aged; D044963:Biopsy, Fine-Needle; D002291:Carcinoma, Papillary / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: NIFTP; RAS; fine-needle aspiration; follicular variant of papillary thyroid carcinoma; molecular testing; thyroid