Early malignant progression of hereditary medullary thyroid cancer.
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.
Machens
Andreas
A
Klinik für Allgemein-, Viszeral-, und Gefässchirurgie, Martin-Luther-Universität Halle-Wittenberg, Halle, Saale, Germany. gensurg@medzin.uni-halle.de
Niccoli-Sire
Patricia
P
Hoegel
Josef
J
Frank-Raue
Karin
K
van Vroonhoven
Theo J
TJ
Roeher
Hans-Dietrich
HD
Wahl
Robert A
RA
Lamesch
Peter
P
Raue
Friedhelm
F
Conte-Devolx
Bernard
B
Dralle
Henning
H
D000293:Adolescent; D000367:Age Factors; D018276:Carcinoma, Medullary / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D002648:Child; D003062:Codon / Q000235:genetics; D018450:Disease Progression; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D006965:Hyperplasia; D008197:Lymph Node Excision; D008297:Male; D009367:Neoplasm Staging; D017354:Point Mutation; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012306:Risk; D011795:Surveys and Questionnaires; D013961:Thyroid Gland / Q000473:pathology / Q000601:surgery; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D013965:Thyroidectomy
D003062:Codon; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases