title: Thyroid follicular adenomas may display features of follicular carcinoma and follicular variant of papillary carcinoma.
abstract: Thyroid follicular adenomas (FA) are encapsulated tumors lacking vascular, capsular or lymphatic invasion and the typical nuclear features of papillary carcinoma (PC). However, some FA demonstrate nuclear atypia reminiscent of either follicular carcinomas (FC) or follicular variant of papillary carcinomas (FVPC), suggesting they may represent precursors of malignant transformation. We hypothesized that an objective evaluation of nuclear chromatin patterns could be used to define atypical follicular tumors (AFT) that are likely to be premalignant. To test this hypothesis, we used a computer-aided image analysis system to define the chromatin pattern of nuclei from thyroid tumors. To validate the system, we analyzed 3000 nuclei from 10 FA, 10 FC, and 10 FVPC samples and accurately distinguished between these classes of tumors. Then, we analyzed nine AFT and, in parallel, we analyzed the tumors for activating mutations of N2-RAS and over-expression of RET. The predominant chromatin pattern of AFT was of FA type in two cases, FC type in two cases, and PC type in three cases. One case contained similar numbers of FC and PC nuclei and one was comprised of a mixture of the three nuclear types. Neither RAS mutation nor RET overexpression were detected in FA. N2-RAS mutations were found in 33% of AFT, 20% of FC and 20% of FVPC without correlation with chromatin pattern. Over-expression of RET was detected in 45% of AFT, 20% of FC and 50% of FVPC and was correlated with PC nuclei. These results show that AFT are a heterogeneous group of tumors, containing genuine benign tumors and tumors that share morphological and molecular features with follicular and papillary carcinomas that might be precursors of both types of thyroid carcinomas.
authors.affiliation: INSERM U 555, Faculty of Medicine, Mediterranean University, Marseilles, France. v_vasko@hotmail.com
authors.forename: Vasily V
authors.initials: VV
authors.lastname: Vasko
authors.forename: Jean
authors.initials: J
authors.lastname: Gaudart
authors.forename: Claude
authors.initials: C
authors.lastname: Allasia
authors.forename: Victoria
authors.initials: V
authors.lastname: Savchenko
authors.forename: Julie
authors.initials: J
authors.lastname: Di Cristofaro
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Catherine
authors.initials: C
authors.lastname: De Micco
mesh_terms: D000236:Adenoma / Q000473:pathology*; D002291:Carcinoma, Papillary / Q000473:pathology*; D018265:Carcinoma, Papillary, Follicular / Q000473:pathology*; D002467:Cell Nucleus / Q000473:pathology; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D016208:Databases, Factual; D005091:Exons / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013964:Thyroid Neoplasms / Q000473:pathology*
chemical_list: D015513:Oncogene Proteins; D004247:DNA; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases