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Familial Medullary Thyroid Carcinoma: Clinical Variability and Low Aggressiveness Associated with RET Mutation at Codon 804

Départment de Biologie Clinique and Service de Médecine Nucléaire, Institut Gustave Roussy (F.L., E.B., B.C., J.-M.B., M.S.), 94805 Villejuif, France; Dipartimento di Medicina Sperimentale e Clinica G. Salvatore, Università di Catanzaro (E.C., F.A., S.F.), 88100 Catanzaro, Italy; Istituto CSS-Mendel (C.C., B.D.), 00161 Rome, Italy; Service de Médecine Nucléaire, Centre François Baclesse (S.B.), 14076 Caen, France; Division of Medical Oncology, Ospedale San Luigi (D.G.), 95123 Catania, Italy; and Dipartimento di Scienze Cliniche, Università di Roma La Sapienza (S.F.), 00161 Rome, Italy

Address all correspondence and requests for reprints to: Sebastiano Filetti, M.D., Dipartimento Scienze Cliniche, Clinica Medica 2, Policlinico Umberto I Viale del Policlinico, 155, 00161 Rome, Italy. E-mail: . filetti{at}tin.it

Abstract

Sixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease.

Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype.

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