Malignant progression from C-cell hyperplasia to medullary thyroid carcinoma in 167 carriers of RET germline mutations.
BACKGROUND
Hereditary medullary thyroid carcinoma (MTC) is the most common and potentially life-shortening phenotypic manifestation of RET (rearranged during transfection) germline mutations. If a distinct time lag between the successive stages of malignant progression were identifiable, the information could be used to individualize prophylactic surgery. The study objective was to investigate the impact of RET genotype on disease progression from C-cell hyperplasia (CCH) to MTC.


METHODS
An institutional series of 167 (67 index, 100 nonindex) consecutive carriers of RET gene point mutations in exons 10, 11, 13, 14, or 16 who underwent total thyroidectomy between November 1994 and November 2002.


RESULTS
Regarding codons 618, 620, 634, 768, 790, and 804, patient age at diagnosis differed significantly depending on the type of pathology encountered (CCH, MTC without and with nodal metastasis). The variability in age, which may reflect the number of necessary somatic mutations, explained the pathological strata in 38% (codon 634) to 77% (codon 768) of patients. Conversely, 62% (codon 634) to 23% (codon 768) of variability in age at different pathological strata may have been determined by the RET genotype.


CONCLUSIONS
The pace of malignant progression of the RET genotype should be taken into account when considering prophylactic thyroidectomy in RET gene carriers.
Machens
Andreas
A
Department of General, Visceral and Vascular Surgery, Martin-Luther-University, Halle-Wittenberg, Halle/Saale, Germany.
Holzhausen
Hans-Jürgen
HJ
Thanh
Phuong Nguyen
PN
Dralle
Henning
H
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D018276:Carcinoma, Medullary / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D003062:Codon; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D006965:Hyperplasia; D008197:Lymph Node Excision; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013961:Thyroid Gland / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000209:etiology*; D013965:Thyroidectomy; D013997:Time Factors
D003062:Codon; D011518:Proto-Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases