title: Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension.
abstract: BACKGROUND
  The impact of varying degrees of extrathyroid extension (ETE), especially microscopic ETE (METE), on survival in thyroid carcinomas (TC) has not been well established. Our objective was to analyze ETE at the molecular and histologic levels and assess the effect of its extent on outcome.
  
  
  METHODS
  All cases of TC with ETE but without nodal metastases at presentation (NMP) were identified over a 20-year period and grouped into gross and METE. Twelve papillary thyroid carcinomas (PTCs) without ETE and NMP were also analyzed. Cases with paraffin tissues were subjected to mass spectrometry genotyping encompassing the most significant oncogenes in TC: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, and AKT1, and other related genes were surveyed.
  
  
  RESULTS
  Eighty-one (10%) of 829 patients in the database had ETE and no NMP. There was a much higher frequency of poorly differentiated and anaplastic carcinomas (12/29, 41%) in patients with gross ETE than in those with METE (3/52, 6%) (p < 0.01). There was a higher disease-specific survival (DSS) in patients with METE than in those with gross ETE (p < 0.0001). Except for an anaplastic case, no recurrences were detected in 45 patients with METE, including 23 PTC patients followed up for a median of 10 years without radioactive iodine therapy. Within patients with gross invasion into trachea/esophagus, tumors with high mitotic activity and/or tumor necrosis correlated with worse DSS (p < 0.05). Fifty-six cases with ETE were genotyped as follows: BRAFV600E, 39 (70%); BRAFV600E-AKT1, 1 (1.8%); NRAS, 1 (1.8%); KRAS, 1 (1.8%); RET/PTC, 3 (5%); wild type, 11 (19.6%). Within PTCs, BRAF positivity rate increased the risk of ETE (p = 0.01). If PTC follicular variants are excluded, BRAF positivity does not correlate with ETE status within classical/tall cell PTC.
  
  
  CONCLUSIONS
  (i) PTCs with METE without NMP have an extremely low recurrence rate in contrast to tumors with gross ETE. (ii) High mitotic activity and/or tumor necrosis confers worse DSS even in patients stratified for gross ETE in trachea/esophagus. (iii) BRAF positivity correlates with the presence of ETE in PTC, but this relationship is lost within classical/tall cell PTC if follicular variants are excluded from the analysis.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rivera
authors.forename: Julio
authors.initials: J
authors.lastname: Ricarte-Filho
authors.forename: Robert Michael
authors.initials: RM
authors.lastname: Tuttle
authors.forename: Ian
authors.initials: I
authors.lastname: Ganly
authors.forename: Ashok
authors.initials: A
authors.lastname: Shaha
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Knauf
authors.forename: James
authors.initials: J
authors.lastname: Fagin
authors.forename: Ronald
authors.initials: R
authors.lastname: Ghossein
mesh_terms: D002277:Carcinoma / Q000235:genetics; D002291:Carcinoma, Papillary / Q000473:pathology; D004947:Esophagus / Q000473:pathology; D006801:Humans; D009336:Necrosis; D009364:Neoplasm Recurrence, Local / Q000473:pathology*; D048493:Proto-Oncogene Proteins B-raf; D013964:Thyroid Neoplasms / Q000473:pathology*; D014132:Trachea / Q000473:pathology; D016896:Treatment Outcome
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf