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RET Activation and Clinicopathologic Features in Poorly Differentiated Thyroid Tumors

Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche (M.S., F.P., C.M., A.F.), c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II," 80131 Naples, Italy; Departments of Pathology in the Medical Centers of the Universities of Turin (M.P., M.V.), 10126 Torino, Italy, and Oviedo (A.H.), Oviedo 33006, Spain; Istituto Nazionale dei Tumori (G.C.), Fondazione Senatore Pascale, 80131 Naples, Italy; Centro Nacional de Investigaciones Oncologicas (G.G.R.), Madrid 28220, Spain; Istituto Nazionale dei Tumori (M.L.C.), 20133 Milano, Italy; and Department of Pathology (G.T., C.G., R.L.C.), Yale University School of Medicine, New Haven, Connecticut 06510

Address all correspondence and requests for reprints to: Giovanni Tallini, M.D., Department of Pathology, Yale University School of Medicine, Room EP2-608, Yale New Haven Hospital, 20 York Street, New Haven, Connecticut 06510. E-mail: tallini{at}yale.edu

Poorly differentiated carcinoma of the thyroid gland (PDC) represents an heterogeneous group of epithelial neoplasms with morphologic features and clinical characteristics intermediate between well differentiated and anaplastic (undifferentiated) carcinomas. Unlike well differentiated tumors, PDCs are associated with significant morbidity and mortality. The general prevalence of RET/PTC rearrangement in thyroid PDC and its impact on patient outcome are unknown. To address these issues and to identify prognostically relevant clinicopathologic parameters, we have investigated a series of 62 PDCs. RET/PTC rearrangement, analyzed by RT-PCR and immunohistochemistry using antibodies specific for the tyrosine kinase and juxtamembrane portions of the RET protein, was identified in 8/62 (12.9%) PDCs. RET/PTC was more common in cases with histologic evidence indicating coexistence with or possible evolution from a well differentiated papillary carcinoma (5 of 25 tumors, 20%) but did not correlate with other clinicopathologic parameters. The relatively low prevalence of RET activation in PDCs argues against a major role for RET/PTC in the progression from well to poorly differentiated thyroid tumor phenotypes. Survival analysis demonstrates that poor survival in PDC is associated with old age, male sex, invasion of extrathyroidal soft tissues, coexistence in the same tumor of oncocytic features with insular growth pattern, and distant metastases but not RET activation.

This work was supported in part by grants from the Italian Ministry of University & Research, Rome (60% to M.P.); the Italian Association for Cancer Research (AIRC), Milan (to M.S.); FIS Grant 98/5022 (to G.G.R.); Thyroid Research Advisory Council (TRAC) Grant SYN 0400 08 from Knoll Pharmaceutical Co. (to G.T.).

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; JTX, juxtamembrane; PDC, poorly differentiated thyroid carcinoma; PDC-P, PDC with morphologic features of papillary carcinoma; PDC-NP, absence of papillary carcinoma features; TK, tyrosine kinase; TM, transmembrane.

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