title: The increase in thyroid cancer incidence during the last four decades is accompanied by a high frequency of BRAF mutations and a sharp increase in RAS mutations.
abstract: BACKGROUND
  Thyroid cancer incidence rates in the United States and globally have increased steadily over the last 40 years, primarily due to a tripling of the incidence of papillary thyroid carcinoma (PTC).
  
  
  OBJECTIVE
  The purpose of this study was to analyze trends in demographic, clinical, pathologic, and molecular characteristics of PTC from 1974 to 2009.
  
  
  METHODS
  We identified and histologically reviewed 469 consecutive cases of PTC from one US institution from 4 preselected periods (1974 to 1985, 1990 to 1992, 2000, and 2009) and assessed BRAF and RAS point mutations and RET/PTC rearrangements among 341 tumors ≥0.3 cm in size. Changes over time were analyzed using polytomous and binary logistic regression; all analyses were adjusted for age and sex.
  
  
  RESULTS
  During this period, the median age of patients at diagnosis increased from 37 to 53 years (P < .001) and the percentage of microcarcinomas (≤1.0 cm) increased from 33% to 51% (P < .001), whereas extrathyroidal extension and advanced tumor stage decreased from 40% to 21% (P = .005) and from 43% to 28% (P = .036), respectively. Changes in tumor histopathology showed a decrease in classic PTC and an increase in the follicular variant (P < .001). The proportion of tumors with a BRAF mutation was stable (∼46%) but increased from 50% to 77% (P = .008) within classic papillary PTCs. The proportion of tumors with RAS mutations increased from 3% to 25% and within follicular pattern tumors from 18% to 44% (P < .001). The proportion of RET/PTC rearrangements decreased from 11% to 2% (P = .038).
  
  
  CONCLUSIONS
  Similar to US national trends, we found an increasing age at diagnosis and greater detection of smaller-sized intrathyroidal PTCs. However, the overall proportion of BRAF mutations remained stable. Sharply rising percentages of the follicular variant histology and RAS mutations after 2000 suggest new and more recent etiologic factors. The increased incidence is not likely to be due to environmental or therapeutic radiation because the percentage of RET/PTC rearrangements decreased.
authors.affiliation: Department of Pathology (C.K.J., Y.E.N.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; Department of Hospital Pathology (C.K.J.), The Catholic University of Korea, Seoul 137-701, Republic of Korea; and Radiation Epidemiology and Biostatistics Branches (J.H.L., A.V.B., M.P.L., A.J.S.), Division of Cancer Epidemiology and Genetics and Cancer Genetics Branch (S.A.W.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Jung
authors.forename: Mark P
authors.initials: MP
authors.lastname: Little
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lubin
authors.forename: Alina V
authors.initials: AV
authors.lastname: Brenner
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wells
authors.forename: Alice J
authors.initials: AJ
authors.lastname: Sigurdson
authors.forename: Yuri E
authors.initials: YE
authors.lastname: Nikiforov
mesh_terms: D000236:Adenoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002291:Carcinoma, Papillary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D014481:United States / Q000453:epidemiology
chemical_list: D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)