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PAX8-PPAR Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma

Institute of Molecular Pathology and Immunology of the University of Porto (P.C., A.P.R., R.J.S., J.M., V.T., M.C.-d.-O., E.F., P.S., M.S.-S.), 4200-465 Porto, Portugal; Department of Pathology (J.M., E.F., P.S., M.S.-S.), Medical Faculty of Porto, 4200-319 Porto, Portugal; Centro de Investigação de Patobiologia Molecular (L.R.), Instituto Português de Oncologia Francisco Gentil, 1070 Lisboa, Portugal; Department of Pathology (I.V.d.C.), Medical Faculty, University of São Paulo, 05509-900 São Paulo, Brazil; and Department of Surgery (M.C.-d.-O.), Medical Faculty of Porto, 4200-319 Porto, Portugal

Address all correspondence and requests for reprints to: Prof. M. Sobrinho-Simões, Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr. Roberto Frias s/n4200, 465 Porto, Portugal. E-mail: ssimoes{at}ipatimup.pt.

Context: The clinicopathological characteristics and the molecular features of the follicular variant of papillary thyroid carcinoma (FVPTC) remain controversial.

Objective/Design/Patients: In an attempt to clarify such controversies and to find whether or not FVPTC cases share the molecular features of follicular tumors, we searched for the presence of PAX8-PPAR rearrangements, RAS mutations, and RAP-1, RAF-1, and BRAF mutations in a series of 40 FVPTCs as well as in 27 follicular thyroid carcinomas (FTCs) and 12 follicular thyroid adenomas (FTAs). Fluorescence in situ hybridization and RT-PCR were used to detect the PAX8-PPAR rearrangement and PCR, single strand confirmational polymorphism, and sequencing for searching the mutations.

Results: The frequency of PAX8-PPAR rearrangement was similar in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%). The same holds true regarding the frequency and type of RAS mutations: FVPTC, 25.0%; FTC, 22.2%; and FTA, 33.3%. BRAF mutations were only detected in FVPTC (10%); the BRAF mutations in these cases (K601E and G474R) are different from the typical BRAF^V600E mutation of conventional PTCs. No mutations were detected in RAP-1 and RAF-1. In FVPTCs, the PAX8-PPAR rearrangement was significantly associated with multifocality and vascular invasion, whereas the RAS mutations were significantly associated with the large tumor size. There were three cases of FVPTC, three FTCs and one FTA, harboring both PAX8-PPAR rearrangement and RAS mutations; patients with such tumors were usually very young.

Conclusions: We conclude that a subset of FVPTC shares some of the molecular features of follicular tumors. Further studies are necessary to clarify the putative clinical significance (e.g. association to blood-born metastases) of PAX8-PPAR rearrangement, RAS mutations, and BRAF^K601E in FVPTCs.

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