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      Factors Predicting Outcome of Total Thyroidectomy in Young Patients with Multiple Endocrine Neoplasia Type 2: A Nationwide Long-Term Follow-up Study

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          Multiple endocrine neoplasia type 2 (MEN 2) is caused by a RET mutation in chromosome 10. All MEN 2 patients develop medullary thyroid carcinoma (MTC). The age-related risk of MTC is associated with the type of RET mutation. Our aim was to identify prognostic factors associated with recurrent MTC in MEN 2 patients.


          In a nationwide case–control study, all patients who underwent total thyroidectomy in the Netherlands under the age of 20 years were classified into standard (1), high (2), or very high risk (3) for MTC based on RET-mutation type. Disease-free patients were compared with those with recurrent disease.


          A total of 93 patients were included in the study. Sixty-six percent had MTC on histology, the youngest being 1 year old. Codon 634 was most affected. Sixteen (18%) patients had persistent or recurrent disease, one of whom died. Significantly associated determinants of outcome in univariate analysis were higher age at surgery, no age-appropriate prophylactic surgery according to risk level, elevated preoperative calcitonin levels, affected codon, and the presence of lymph node metastases at surgery. On multivariate analysis only age of surgery was the single independent factor associated with persistent disease.


          Prophylactic thyroidectomy beyond the recommended age is associated with persistent/recurrent disease. In addition, codon 634 mutation is associated with a high risk of recurrence requiring early surgery for all these patients.

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          Most cited references 25

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          Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

          Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.
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            Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

            Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.
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              Early malignant progression of hereditary medullary thyroid cancer.

              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. 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. 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. These data provide initial guidelines for the timing of prophylactic thyroidectomy in asymptomatic carriers of RET gene mutations. Copyright 2003 Massachusetts Medical Society

                Author and article information

                World J Surg
                World Journal of Surgery
                Springer-Verlag (New York )
                9 January 2010
                9 January 2010
                April 2010
                : 34
                : 4
                : 852-860
                [1 ]Department of Surgery, University Medical Center Utrecht, Hpnr. G04.228, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
                [2 ]Pediatric Surgical Center of Amsterdam, Emma Children’s Hospital AMC, Academic Medical Center and VU Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands
                [3 ]Department of Endocrinology, University Medical Center Utrecht, Hpnr. G04.228, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
                [4 ]Department of Endocrinology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
                [5 ]Department of Surgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
                [6 ]Department of Pediatric Surgery, Erasmus Medical Center Rotterdam, P.O. Box 2060, 3000CB Rotterdam, The Netherlands
                [7 ]Department of Surgery, Leiden University Medical Center, P.O. Box 9600, 2300RC Leiden, The Netherlands
                [8 ]Department of Medical Genetics, University Medical Center Utrecht, Hpnr. G04.228, Heidelberglaan 100, 3584CX Utrecht, The Netherlands
                [9 ]Department of Surgery/Pediatric Surgery, Radboud University Nijmegen Medical Center, P.O. Box 9101, 6500HB Nijmegen, The Netherlands
                © The Author(s) 2010
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                © Société Internationale de Chirurgie 2010



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