Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type IIA: Implications for therapy

Gill, James R.; Reyes‐Múgica, Miguel; Iyengar, Sudha K.; Kídd, Kenneth K.; Touloukian, Robert J.; Smith, Cynthia; Keller, Marc S.; Genel, Myron

doi:10.1016/s0022-3476(96)70084-7

Cited by 78 publications

(42 citation statements)

References 12 publications

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“…Consensus about the need for thyroidectomy as early as at 1 year of age is well established for MEN 2B, for which the course of disease is worse and metastases are often present at the time of diagnosis (4,20). For MEN 2A gene carriers, most authors have recommended that thyroidectomy be performed as early as 4-6 years of age (8,11,14,21). In our series, the seven MEN 2A gene carriers younger than 6 years of age had bilateral or unilateral MTC.…”

Section: Discussionmentioning

confidence: 79%

Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC)

Niccoli-Sire¹,

Murat

Baudin

et al. 1999

European Journal of Endocrinology

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Background: Once genetic testing accurately identifies MEN 2 gene carriers, affected children are given the opportunity to undergo thyroidectomy at the earliest stages of the C-cell disease. Objective: To define reliable parameters by which to identify the best moment for thyroidectomy in patients who are carriers of the MEN 2 gene. Patients and methods: Seventy-one MEN 2/FMTC gene carriers, collected through the national register of the French Calcitonin Tumours Study Group, were evaluated. All the patients included were younger than 20 years of age and underwent total thyroidectomy. Basal and pentagastrin-stimulated calcitonin were assayed using an immunoradiometric method (sensitivity less than 2 pg/ml). Calcitonin measurement was evaluated on the basis of histopathological findings in surgical thyroid specimens. Results: We found C-cell hyperplasia or medullary thyroid carcinoma in all the 71 gene carriers -even for the youngest patients -and nodal metastases were present in four cases. Calcitonin measurement (basal or pentagastrin-stimulated) detected C-cell disease preoperatively in all patients. Six of the 71 patients were not surgically cured: one had nodal metastases, one had an advanced staged disease and four had an incomplete nodal dissection or had not undergone lymph node surgery. Conclusions: Determination of calcitonin forms an integral part of the management of MEN 2 gene carriers. Thyroidectomy is undisputably indicated when basal calcitonin is abnormal. When basal calcitonin is undetectable, a pentagastrin-stimulated increase in calcitonin to more than 10 pg/ml indicates an early thyroidectomy to cure the patient.

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Section: Discussionmentioning

confidence: 79%

Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC)

Niccoli-Sire¹,

Murat

Baudin

et al. 1999

European Journal of Endocrinology

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“…13,14 Experiences of thyroidectomy in adolescents and children led to constant adjustment of timing of TT during the last 2 decades. 9,11,21,26 Currently, most authors recommend TT at 5 years of age, while several groups propose surgery even at 2 and 3 to 5 years of age. 10,26 -28 To evaluate the evidence of these recommendations, we performed a meta-analysis of all published cases being aware that retrospective analysis has limitations and may not truly describe the clinical course of all MEN-2A patients.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][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][14][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.…”

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confidence: 99%

“…23 Currently, TT is recommended at 5 years of age in disease gene carriers. 11,24,25 Based on the experience with very young children with MTC at the time of surgery, several authors even propose TT at the age of 2 years 10,25,26 or between 3 and 5 years 28 to obtain optimal cure rates. The first aim of this study was to compare therapeutic results of early TT (ETT: 1-5 years) versus late TT (LTT: 6 -20 years) in the pediatric age group in a retrospective manner.…”

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confidence: 99%

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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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“…Microcarcinoma despite normal pentagastrin test has been observed in children 4±9 years old (8,9). Lymph node metastasis may occur very early in the course of the disease and has been observed at the age of 14 years (10) or even earlier (11). Therefore, prophylactic thyroidectomy before the development of microcarcinoma is usually recommended (8±12).…”

Section: Introductionmentioning

confidence: 99%

Presentation of a kindred with familial medullary thyroid carcinoma and Cys611Phe mutation of the RET proto-oncogene demonstrating low grade malignancy

Siggelkow

Melzer²,

Nolte³

et al. 2001

European Journal of Endocrinology

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Objective: Both multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are caused by germline mutations of the RET proto-oncogene. A broad spectrum of malignancy within and between families has been described with no clear genotype±phenotype correlation due to a scarcity of available data of large kindreds. Design: Here we present the only known family with a germline mutation of codon 611 TGC to TTC (exon 10) in the RET proto-oncogene leading to a replacement of cysteine by phenylalanine (Cys611Phe or C611F). Results: Twenty family members of this large kindred are gene carriers (GCs) and seven (5±13 years old) are potential carriers but have yet to be analysed. The clinical course of medullary thyroid carcinoma (MTC) in this family is characterized by a very slow evolution and progression of the tumour with no MTC-related death to date. Of 11 patients (30±69 years old) having undergone thyroidectomy six were classified as pT 1 , four as pT 2 and one as C-cell hyperplasia according to the TNM system of the International Union Against Cancer. Due to cervical and mediastinal lymph node metastasis one patient (44 years old) had to be operated on a second time. The seven non-operated GCs of the fourth and fifth generation (17±26 years old) are yearly monitored with pentagastrin stimulation tests; one non-operated GC (43 years old) has refused any further investigations. Screening for primary hyperparathyroidism and phaeochromocytoma was negative in all cases. Conclusion: We suggest from these experiences that the general advice for thyroidectomy in early childhood should be modified in certain families, depending on genotype.

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Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type IIA: Implications for therapy

Cited by 78 publications

References 12 publications

Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC)

Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC)

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

Presentation of a kindred with familial medullary thyroid carcinoma and Cys611Phe mutation of the RET proto-oncogene demonstrating low grade malignancy

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