A associação da idade com a hiperplasia de células C para carcinoma medular de tireóide está relacionada a várias mutações na linhagem germinativa do proto-oncogene RET que poderia ser utilizado para identificar o tempo adequado para cirurgia profilática.
Neste estudo europeu multicêntrico, publicado recentemente no The New England Journal of Medicine, realizado entre julho de 1993 e fevereiro de 2001, os autores selecionaram pacientes que tinham um ponto de mutação no RET na linhagem germinativa. Os pacientes tinham idade menor ou igual a 20 anos, eram assintomáticos e tinham sido submetidos à tireoidectomia após a confirmação da mutação no RET. Os critérios de exclusão foram carcinomas medulares de tireóide com mais de 10 mm na maior porção e metástases à distância.
No total, 207 pacientes de 145 famílias foram identificados. Houve uma significante associação entre a idade e a progressão da hiperplasia de células C para carcinoma medular de tireóide e, finalmente, metástases linfonodais nos pacientes cujas mutações no RET foram agrupadas de acordo com os códons afetados dos domínios extracelulares e intracelulares e naqueles com o genótipo do códon 634. Não foram observadas metástases linfonodais nos pacientes com idade menor que 14 anos. A penetrância associada à idade esteve inalterada pelo tipo de substituição de aminoácido codificado pelas diversas mutações no códon 634. As diferenças específicas do códon na idade de apresentação da neoplasia e as taxas familiares de envolvimento concomitante da adrenal e da paratireóide sugerem que o risco de progressão esteve baseado no potencial de transformação individual da mutação RET.
Os autores concluíram que estes dados fornecem consensos iniciais para o tempo de tireoidectomia profilática nos portadores assintomáticos de mutações do gene RET.
Early Malignant Progression of Hereditary Medullary Thyroid Cancer - The New England Journal of Medicine
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| Volume 349:1517-1525 |
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October 16, 2003 |
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Early Malignant Progression of Hereditary Medullary Thyroid Cancer
Andreas Machens, M.D., Patricia Niccoli-Sire, M.D., Josef Hoegel, Ph.D., Karin Frank-Raue, M.D., Theo J. van Vroonhoven, M.D., Hans-Dietrich Roeher, M.D., Robert A. Wahl, M.D., Peter Lamesch, M.D., Friedhelm Raue, M.D., Bernard Conte-Devolx, M.D., Henning Dralle, M.D., for the European Multiple Endocrine Neoplasia (EUROMEN) Study Group
ABSTRACT
Background An age-related progression from C-cell hyperplasia to medullary thyroid carcinoma is associated with various germ-line mutations in the rearranged during transfection (RET) proto-oncogene that could be used to identify the optimal time for prophylactic surgery.
Methods In this European multicenter study conducted from July 1993 to February 2001, we enrolled patients who had a RET point mutation in the germ line, were 20 years of age or younger, were asymptomatic, and had undergone total thyroidectomy after confirmation of the RET mutation. Exclusion criteria were medullary thyroid carcinomas of more than 10 mm in greatest dimension and distant metastasis.
Results Altogether, 207 patients from 145 families were identified. There was a significant age-related progression from C-cell hyperplasia to medullary thyroid carcinoma and, ultimately, nodal metastasis in patients whose RET mutations were grouped according to the extracellular- and intracellular-domain codons affected and in those with the codon 634 genotype. No lymph-node metastases were noted in patients younger than 14 years of age. The age-related penetrance was unaffected by the type of amino acid substitution encoded by the various codon 634 mutations. The codon-specific differences in the age at presentation of cancer and the familial rates of concomitant adrenal and parathyroid involvement suggest that the risk of progression was based on the transforming potential of the individual RET mutation.
Conclusions These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations.
Source Information
From the Klinik für Allgemein-, Viszeral-, und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany (A.M., H.D.); the Centre Hospitalier Régional et Universitaire de Marseille, Service d'Endocrinologie et Maladies Métaboliques, Marseilles, France (P.N.-S., B.C.-D.); the Abteilung Biometrie und Medizinische Dokumentation, Universität Ulm, Ulm, Germany (J.H.); the Endokrinologische Gemeinschaftspraxis, Heidelberg, Germany (K.F.-R., F.R.); the Department of Surgery, University Hospital Utrecht, Utrecht, the Netherlands (T.J.V.); the Klinik für Allgemeine und Unfallchirurgie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany (H.-D.R.); the Chirurgische Klinik, Bürgerhospital Frankfurt am Main, Frankfurt am Main, Germany (R.A.W.); and the Chirurgische Klinik und Poliklinik für Abdominal-, Transplantations-, und Gefäßchirurgie, Universität Leipzig, Leipzig, Germany (P.L.).
Address reprint requests to Dr. Machens at the Klinik für Allgemein-, Viszeral-, und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, D-06097 Halle (Saale), Germany, or at gensurg@medzin.uni-halle.de.
