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Detection of an Activating Mutation of the Thyrotropin Receptor in a Case of an Autonomously Hyperfunctioning Thyroid Insular Carcinoma¹

Dipartimento di Medicina Sperimentale e Clinica, Cattedra di Endocrinologia, and Facoltà di Farmacia, Cattedra di Farmacologia (D.R.), University of Reggio Calabria, Catanzaro; Istituto di Clinica Medica I (S.T.), Istituto di Medicina Interna e di Malattie Endocrine e del Metabolismo, Cattedra di Endocrinologia (A.B., P.V.), University of Catania, Catania; Servizio di Anatomia Patologica, Ospedale S. Pietro e Gravina (G.G.), Caltagirone; and Cattedra di Endocrinologia, Università Cattolica, Laboratorio di Oncogenesi Molecolare, Istituto Tumori Regina Elena (A.P.), Rome, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Cattedra di Endocrinologia, Dipartimento di Medicina Sperimentale e Clinica, Via T. Campanella, 88100 Catanzaro, Italy. E-mail: filetti{at}mbox.vol.it

Thyroid carcinomas, even when well differentiated, usually appear as hypofunctioning at scintigraphy. We report a case of an aggressive insular thyroid carcinoma presenting as an autonomously functioning thyroid nodule and causing severe thyrotoxicosis. The tumor was metastatic to a cervical lymph node and both lungs.

An activating mutation of the TSH receptor gene in both the primary tumor and the lymph node metastasis was found, due to a base substitution at codon 633 (normal guanine at position 1896 replaced by cytosine CAC for GAC causing aspartic acid substitution by histidine). Other known oncogenes (gsp, ras, PTC/ret, trk, met, and p53) were not involved.

This is the first description of an activating TSH receptor mutation in a thyroid hyperfunctioning carcinoma in which an aggressive malignant phenotype coexisted with activation of the cAMP cascade and differentiated thyroid functions.

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