Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

Hansen, Hanne Sand; Tørring, Helle; Godballe, Christian; Jäger, Anne Charlotte; Nielsen, Finn Cilius

doi:10.1002/1097-0142(20000815)89:4<863::aid-cncr19>3.3.co;2-q

Cited by 9 publications

(11 citation statements)

References 6 publications

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“…This is important for the decisions regarding timing of premorbid diagnoses and treatment/prophylactic procedure in RET gene carriers, as age is an independent predictor of aggressive disease at thyroidectomy: MTC is more aggressive and might develop earlier in codons 618 and 620. This supports the clinical impression that patients with RET mutations in codons 609 and 611 are older at presentation [Calva et al, 2009; Hansen et al, 2000; Mian et al, 2009; Siggelkow et al, 2001], and have more indolent tumors than patients with RET mutations at 618 and 620 [Machens et al, 2009], but there are notable exceptions as shown in our systematic study. It is important to point out that also a patient with codons 609 mutation can present with MTC by age 4.…”

Section: Discussionsupporting

confidence: 89%

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Frank‐Raue¹,

et al. 2010

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Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

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Section: Discussionsupporting

confidence: 89%

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Frank‐Raue¹,

et al. 2010

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“…These results were confirmed by the clinical observation that MTC occurs earliest in patients with c634 mutation, whereas patients with c611 and c804 mutations display slow progression to MTC. 30,46,53,63 Because multivariate analysis in a subset of 74 patients failed to show impact of specific mutations on outcome, we compared distribution of N, CCH, MTC, and MMTC for different codons at TT (Table 2). We found that c634 patients have significantly higher combined rates of MTC ϩ MMTC compared with c618 and c620 (P Ͻ .001).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the c620 mutations bear low risk for postoperative morbidity and delayed TT in analogy to recommendations for c611 mutations might be appropriate. 53,66 However, more clinical data on all relevant codons and the possible influence of different point mutations in the same codon are needed to define definitive codon-specific guidelines in the future. Until then, ETT in combination with preoperative calcitonin screening is a save approach and can assure maximal cure rate in all kindred of MEN-2A families.…”

Section: Discussionmentioning

confidence: 99%

Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis

et al. 2003

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ABSTRACT. Objectives. The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter.Methods. Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0 -20 years) and histologic degree of C-cell disease (normal ‫؍‬ N, C-cell hyperplasia ‫؍‬ CCH, medullary thyroid carcinoma ‫؍‬ MTC, metastatic MTC ‫؍‬ MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6 -20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed.Results. In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0 -15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codonrelated histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation. 4 Usually, the first tumor occurring during life is medullary thyroid carcinoma (MTC), 5 a neoplasm of parafollicular C-cell origin. Malignant transformation of C-cells is multifocal in both thyroid lobes and characterized by different histologic stages: Diffuse C-cell hyperplasia (carcinoma in situ), uni-and multifocal MTC with or without local (lymph nodes), or distant metastasis (liver, bone). 6 The malignant transformation of the C-cells begins very early in life: in MEN-2B patients, MTC can occur in infancy, whereas MTC is less aggressive in MEN 2A. 7-10 Nevertheless, in children of MEN-2A families thyroidectomized at 1 to 6 years of age, histologic analyses revealed all stages of C-cell disease, even metastatic MTC. [7][8][9][10][11][12] The only potentially curative treatment for medullary thyroid carcinoma is surgical removal of all thyroid tissue, 13-15 a goal that is not regularly achieved in patients with clinically manifest MTC. 16 The molecular bases of MEN-2A and MEN-2B are missense mutations in the RET protooncogene, a transmembrane tyrosine kinase receptor located on chromosome 10q11.2. In MEN 2A, the most frequent germ line mutations involve the extracellular domain of rearranged during transfection (RET...

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“…Existe consenso quanto à indicação de tireoidectomia profilática nos indivíduos carreadores (7,(53)(54)(55). No entanto, a extensão e o momento ideal do procedimento cirúrgico ainda são aspectos controversos.…”

Section: Aspectos Terapêuticos Cirurgiaunclassified

“…Os estudos sugerem que indivíduos carreadores de mutações nos códons 634 e 618, consideradas mais agressivas e diagnosticadas mais precocemente, devem ser tireoidectomizados entre 5 e 7 anos (7,51-55). Para mutações de risco intermediário (códons 611, 620 e 790), o procedimento é indicado antes dos 14 anos, enquanto para as de baixo risco (códons 768 e 804), antes dos 20 anos de idade (7,(51)(52)(53)(54)(55). Na NEM 2B, o procedimento deve ser indicado o mais precocemente possível, sendo recomendado antes dos 6 meses de vida (7,(51)(52)(53)(54)(55).…”

Section: Aspectos Terapêuticos Cirurgiaunclassified

Neoplasia endócrina múltipla tipo 2

Maia

Gross

Puñales

2005

Arq Bras Endocrinol Metab

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The term multiple endocrine neoplasia (MEN) was introduced by Steiner et al. in 1968 to describe disorders that include a combination of endocrine tumors. The Wermer syndrome was designed as MEN 1 and the Sipple syndrome as MEN 2. Sizemore et al. (1974) completed that the MEN 2 category included 2 subgroups: patients with medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid disease and a normal appearance (MEN 2A) and other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B). MTC is usually the first tumor diagnosed. The diagnosis of MTC has several implications: disease extent should be evaluated, pheochromocytoma and hyperparathyroidism should be screened and whether the MTC is sporadic or hereditary should be determined by a direct analysis of the RET proto-oncogene. Here, the pathological characteristics, genetic abnormalities, and clinical features of MEN 2 are discussed. The diagnostic and therapeutic approaches used to patients with clinical disease and carriers identified through familiar screening are also described. Progresses related especially to genetic screening and earlier intervention have permitted an improvement in the long-term outcome. However, treatment for disseminated disease is still ineffective.

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Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome?

Cited by 9 publications

References 6 publications

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10

Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis

Neoplasia endócrina múltipla tipo 2

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