Results of early thyroidectomy for medullary thyroid carcinoma in children with multiple endocrine neoplasia type 2

Children with multiple endocrine neoplasia type 2 (MEN2) often develop medullary carcinoma of the thyroid (MCT) or its precursor, C-cell hyperplasia. Survival results are improved if malignancy is diagnosed early from the results of plasma immunoreactive calcitonin (iCT) measurement. The effect of early detection and thyroidectomy in children with MEN2 syndrome was determined by reviewing the experience between 1975 and 1985. Seventeen children with MEN2 who were 12 years old or younger underwent a total thyroidectomy for MCT or C-cell hyperplasia. iCT was measured in all patients preoperatively and postoperatively. Of the 17 children, 14 (82%) had MEN2a and 3 (18%) had MEN2b. There were 14 (82%) female and three (18%) male patients; their mean age was 6.97 years (range 1.5 to 12 years). In all patients, the diagnosis of MCT was made from initial elevated levels of iCT after stimulation with pentagastrin. Three patients had clinical evidence of disease preoperatively. All patients underwent a total thyroidectomy and lymph nodes were removed from the central zone; a neck dissection was performed in the three with clinically obvious disease. MCT with C-cell hyperplasia was found in 11 children and C-cell hyperplasia alone in six. Of the 11 with carcinoma, eight had bilateral disease and three unilateral. Six children had bilateral C-cell hyperplasia. All 17 children were alive and feeling well at the time of this report; however, three had evidence of metastatic disease according to iCT measurements. None of the children had recurrent nerve injuries; one had evidence of hypoparathyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presymptomatic screening for medullary thyroid carcinoma in patients with multiple endocrine neoplasia type 2A

Presymptomatic screening of medullary thyroid carcinoma in MEN IIA families enables the early diagnosis of this tumor with its significant morbidity. Biochemical screening consists of basal and stimulated serum calcitonin evaluation. Genetic screening is based on DNA analysis using linked DNA markers. Thyroidectomy at an occult tumor stage may be curative. Calcitonin measurement was carried out in 58 apparently unaffected family members at risk and 11 MEN IIA patients. Calcitonin elevation was detected in nine individuals. All nine underwent thyroidectomy. Histologic examination confirmed medullary thyroid carcinoma in eight patients and in one case C cell hyperplasia. Postoperatively, eight patients (89%) are clinically and biochemically tumor-free (mean follow-up 30 months). DNA screening results in one affected family are presented. DNA analysis allowed recognition of one apparently unaffected individual at risk as a MEN IIA gene carrier. One family member at risk was found not to carry the gene and may be excluded from further screening.

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Resumen El tamizaje presintomático del carcinoma medular de la glándula tiroides en familias con síndrome NEM 2A hace posible el diagnóstico precoz de este tumor, el cual en forma característica se asocia con significativa morbilidad. El tamizaje bioquímico consiste en la determinación de los niveles calcitonina sérica basal y estimulada. El tamizaje genético se basa en el análisis de ADN utilizando marcadores ligados al ADN. La tiroidectomía que se realiza cuando el tumor es todavía clínicamente oculto puede ser curativa. La determinación de calcitonina fue realizada en 58 familiares aparentemente no afectados pero de reconocido riesgo y en 11 pacientes con síndrome NEN 2A; se detectó calcitonina elevada en 9 individuos, y todos los nueve fueron sometidos a tiroidectomía. El examen histológico confirmó carcinoma medular en 8 e hiperplasia de células C en 1. Postoperatoriamente 8 pacientes (89%) se hallan clínica y bioquimicamente libres de tumor (promedio del seguimiento, 30 meses). Se presentan los resultados del tamizaje de ADN en una familia afectada. El análisis de ADN permitió el reconocimiento de un individuo aparentemente no afectado pero de riesgo como portador del gen NEM 2A. Un familiar con riesgo fue marcado como no portador del gen y puede ser excluído de tamizajes ulteriores.

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Résumé Le dépistage du cancer médullaire de la thyroïde avant l'apparition des symptômes dans les familles MEN 2A facilite le diagnostic de cette maladie accompagnée d'une morbidité non négligeable. Le dépistage biochimique consiste en une évaluation de la calcitonine basale et stimulée. Le dépistage génétique comporte une analyse de l'ADN qui utilise des marqueurs spécifiques des liaisons d'ADN. La thyroïdectomie a des chances d'être curative au stade de tumeur occulte. La calcitonine a pu ètre mesurée chez 58 membres d'une famille atteinte mais sans symptômes et chez 11 patients MEN 2A. La calcitonine était élevée chez 9. Tous ces patients ont eu une thyroïdectomie et un cancer médullaire a été retrouvé chez 8 et une hyperplasie des cellules C chez le neuvième. Postopérativement, 8 patients (89%) sont sans tumeur clinique et biologique (suivi moyen: 30 mois). Les résultats du dépistage par l'ADN chez une famille atteinte sont présentés et a permis d'identifier un seul membre apparemment non symptomatique qui était à risque de porter le gêne MEN 2A. On a déterminé également qu'un membre n'était pas porteur du gêne; il peut être exclu de tout examen de dépistage ultérieur.

     

Evaluation of a family at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome.

A multidisciplinary group was formed to advise on strategy and to co-ordinate the management of a family at risk for the multiple endocrine neoplasia type 2A (MEN 2A) syndrome. A proposed strategy is outlined in which DNA analysis and provocative calcitonin testing is central.     

Provocative testing for occult medullary carcinoma of the thyroid: findings in seven children with multiple endocrine neoplasia type IIa

A rise in the serum calcitonin (CT) following provocative testing has facilitated making the diagnosis of occult medullary carcinoma of the thyroid (MCT) or C cell hyperplasia (CCH) in asymptomatic children of kindred with multiple endocrine neoplasia (MEN) type IIa. Findings were reviewed for seven children varying in age from 3 to 16 years screened at our institution between 1976 and 1986. Three had elevated basal calcitonin (S-CT). Six had significant elevation of calcitonin (delta-CT) after stimulation. Total thyroidectomy was performed in all seven. Five had MCT with bilobar involvement in three. CCH was present in all five. Two patients had no gross, microscopic, or immunohistochemical evidence of MCT or CCH. One of three had an elevated S-CT. The other had a significant delta-CT. All patients have normal postoperative S-CT and delta-CT. Our experience indicates the importance of beginning stimulation tests of affected kindred at less than 3 years of age. It appears, however, that neither elevated S-CT or positive delta-CT are perfect predictors of parafollicular cell pathology. Solitary parathyroid enlargement, second thyroid malignancy, and branchial pouch anomalies may occur with MEN IIa. One patient with MCT had a focus of papillary carcinoma. One patient with primary hyperparathyroidism had a solitary enlarged parathyroid adenoma. Additional findings were the presence of nodules of ectopic thymus in close association with the thyroid gland in three patients.     

Evaluation of children with multiple endocrine neoplasia type IIb following thyroidectomy

Medullary thyroid carcinoma (MTC) develops in all patients with multiple endocrine neoplasia type IIb (MEN IIb), a rare syndrome that either occurs sporadically or is inherited in an autosomal dominant pattern. The MTC in patients with MEN IIb has been reported to be biologically aggressive with onset at a young age and rapid progression as evidenced by widespread metastases and death, frequently in the teenage years. Seven children, aged 2 to 11 years (mean, 7 years), from three kindreds with MEN IIb were evaluated for evidence of tumor recurrence 3 to 10 years following thyroidectomy. In one child, age 11, a thyroid mass was palpable preoperatively. However, in the remaining six children (aged 2 to 10 years), the diagnosis of MTC was established by an increased concentration of plasma calcitonin (CT), either basally or following pentagastrin (Pg) stimulation. All patients underwent total thyroidectomy with removal of central lymph nodes from the neck. At the time of surgery, six children were found to have bilateral macroscopic MTC, five without and one with cervical metastases. One child (age 2 years) had C-cell hyperplasia, a premalignant precursor of MTC. Currently, five of the seven children are without evidence of recurrent disease clinically and have normal plasma CT levels (less than 0.3 ng/mL) following calcium (Ca) and Pg stimulation 3, 3, 10, 10, and 10 years after thyroidectomy. Two of the seven children have biochemical evidence of residual MTC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylactic thyroidectomy in pediatric carriers of multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma: mutation in C620 is associated with Hirschsprung's disease

Purpose

Prophylactic total thyroidectomy is now recommended after having confirmed RET mutations in children of parents with multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. We reviewed our experience to determine the incidence of medullary thyroid carcinoma with respect to age at surgery, the location of the mutation, and its association with Hirschsprung's disease (HD).

Methods

A retrospective review from 1996 to 2005 revealed 20 children with genetic screening for multiple endocrine neoplasia type 2A or familial medullary thyroid carcinoma who underwent a prophylactic total thyroidectomy with parathyroid gland preservation.

Results

The median age of the 20 patients (9 boys and 11 girls) included in this study was 8.2 years (range, 3.7-16.9 years) at the time of their surgery. Final pathology revealed normal thyroid tissue (n = 3; median age, 5.9 years), C-cell hyperplasia (n = 13; median age, 10 years), or medullary thyroid carcinoma (n = 4; median age, 8 years). Four children, all with mutations in C620, had a previous diagnosis of HD. At a median follow-up of 3.7 years (range, 1 month to 8.4 years), all patients were well and cancer free.

Conclusions

There is no correlation between histologic findings and median age at surgery. Hirschsprung's disease was found in 50% of the patients with the RET mutation in C620. In children of C620 parents, symptoms of HD should be actively sought, and if such are found, rectal biopsies should be performed even if mutation results are not yet available. Based on the age of the earliest cancer and the safety of total thyroidectomy, children should promptly undergo surgery after genetic screening and before their fifth year of life.     

The early diagnosis of medullary carcinoma of the thyroid gland in patients with multiple endocrine neoplasia type II.

Pentagastrin is a potent stimulator of thyrocalcitonin secretion from "C" cells. Since medulllary carcinoma of the thyroid gland (MCT) is a tumor composed of "C" cells, pentagastrin was used to screen a large kindred with multiple endocrine neoplasia type II (MCT, pheochromocytoma (s), and parathyroid hyperplasia). Four children with no thyroid abnormalities evident on physical examination, with negative thyroid scans, and with normal levels of plasma thyrocalcitonin both before and after calcium infusion, were found to have elevated peripheral levels of this hormone following pentagastrin injection. All four children were found to have very small foci of MCT, in both thyroid lobes at the time of total thyroidectomy. Pentagastrin stimulation used conjointly with selective catheterization of the inferior thyroid vein provided even greater diagnostic accuracy in detecting elevations in thyrocalcitonin secretion. This test has great diagnostic utility, especially in screening patients with multiple endocrine neoplasia type II.     

Iodine 123 metaiodobenzylguanidine radio-guided navigation surgery for recurrent medullary thyroid carcinoma in a girl with multiple endocrine neoplasia type 2B

Multiple endocrine neoplasia type 2B (MEN 2B) is an inherited cancerous syndrome characterized by medullary thyroid carcinoma (MTC), adrenal pheochromocytoma, marfanoid habitus, and enteric ganglioneuromatosis. In this syndrome, a high frequency of persistent elevation of the serum calcitonin level, a sensitive marker for MTC, after total thyroidectomy has been reported, and the prognosis of such patients depends upon complete resection of recurrent MTC by repeated surgery. The authors performed iodine 123 metaiodobenzylguanidine (¹²³I-MIBG) radio-guided navigation surgery for recurrent MTC in a 14-year-old girl with MEN 2B. She had undergone 4 neck operations, including total thyroidectomy at the age of 7 years. An intravenous injection of 100 MBq ¹²³I-MIBG was followed by the fifth surgery. At surgery, the cervical and upper mediastinal areas were filled with adhesional scar tissue, in which a γ-scintillation probe conducted hot spots of isotope uptake by cancerous cells. Histopathology of resected specimens showed scattered nests of MTC cells corresponding to γ-scintillation counts. Intraoperative ¹²³I-MIBG scanning is of substantial benefit for children with MEN 2B undergoing surgery for recurrent MTC.     

A case of multiple endocrine neoplasia type 2A (MEN2A) with a mutation in the RET gene]

A 44-year-old woman complained of headache and palpitation. Magnetic resonance imaging showed bilateral adrenal tumors 10 x 9 cm in size on the left side and 8 x 4 cm in size on the right side. CT scan revealed a 0.7 x 0.7 cm mass in the thyroid. Hormonal examinations showed high values of urinary cathecholamines and serum calcitonin. DNA sequence analysis of peripheral white blood cells revealed that codon 634 in exon 11 of the RET gene was mutated from TGC (Cys) to TAC (Tyr). From these findings, a diagnosis was made of MEN2A with bilateral adrenal pheochromocytomas and medullary thyroid carcinoma. Bilateral adrenalectomy and thyroidectomy were performed. The same mutation of the RET gene was detected in all her 3 children, in two of whom, early stage medullary thyroid carcinoma was detected and thyroidectomy was performed. DNA analysis of the RET gene was useful for the diagnosis of carriers of MEN2A and the early detection of medullary thyroid carcinoma.     

Medullary thyroid carcinoma and pheochromocytoma accompanied with nodular hyperplasia in multiple endocrine neoplasia type 2

Three patients with familial multiple endocrine neoplasia type 2 underwent total adrenalectomy and subsequently near-total or total thyroidectomy. The overt pheochromocytomas were present bilaterally in two patients and unilaterally in another patient. In addition, multiple nodules measuring a few mm in diameter were demonstrated in all adrenal medullas examined. All patients exhibited bilateral medullary thyroid carcinomas which varied in size from a few minute nodules accompanied by the microscopic C-cell hyperplasia to distinct large tumors. The thyroid C-cell hyperplasia appeared to be confined to the upper and middle thirds of the lateral lobe, and micronodules of the C-cell hyperplasia enlarged to coalesce, forming one large carcinoma mass. On the other hand, nodular hyperplasia of the chromaffin cells was distributed diffusely throughout the adrenal medulla and each nodule appeared to develop individually into a large pheochromocytoma. These findings suggested that, at least in the family members at a high risk for multiple endocrine neoplasia type 2, the development of both medullary thyroid carcinoma and pheochromocytoma was always preceded by a multicentric nodular hyperplasia. On the basis of the pathogenesis of these tumors, the most rational surgical approach was presented.     

Medullary thyroid carcinoma and pheochromocytoma accompanied with nodular hyperplasia in multiple endocrine neoplasia type 2

Three patients with familial multiple endocrine neoplasia type 2 underwent total adrenalectomy and subsequently near-total or total thyroidectomy. The overt pheochromocytomas were present bilaterally in two patients and unilaterally in another patient. In addition, multiple nodules measuring a few mm in diameter were demonstrated in all adrenal medullas examined. All patients exhibited bilateral medullary thyroid carcinomas which varied in size from a few minute nodules accompanied by the microscopic C-cell hyperplasia to distinct large tumors. The thyroid C-cell hyperplasia appeared to be confined to the upper and middle thirds of the lateral lobe, and micronodules of the C-cell hyperplasia enlarged to coalesce, forming one large carcinoma mass. On the other hand, nodular hyperplasia of the chromaffin cells was distributed diffusely throughout the adrenal medulla and each nodule appeared to develop individually into a large pheochromocytoma. These findings suggested that, at least in the family members at a high risk for multiple endocrine neoplasia type 2, the development of both medullary thyroid carcinoma and pheochromocytoma was always preceded by a multicentric nodular hyperplasia. On the basis of the pathogenesis of these tumors, the most rational surgical approach was presented. Presented at the 14th Annual Congress of the Japan Society for Cancer Therapy, Sendai, September 30, 1976.     

Multiple endocrine neoplasia type 2A (MEN 2A) syndrome in a South African family. Biochemistry and molecular genetics.

Multiple endocrine neoplasia type 2A (MEN 2A), an uncommon heritable disease, was investigated in an Afrikaner kindred. Serum calcitonin levels after combined pentagastrin and calcium chloride stimulation were measured to determine thyroid involvement, as were urinary metadrenalin levels to determine adrenal gland involvement. MEN 2A genotype status was determined using the DNA probe MCK2 (D10S15). The index patient, who showed both thyroid and adrenal gland involvement, died of phaeochromocytoma complications. Thirty-four of his 114 family members, in 4 generations, were investigated. Nine had positive histological and calcitonin tests and were predicted to be MEN 2A genotypes by DNA analysis. One asymptomatic individual had a positive calcitonin test after being predicted to be a MEN 2A genotype with the probe MCK2. In 3 DNA-positive cases calcitonin stimulation tests were negative. Preclinical detection of the heritable form of MEN 2A will be facilitated by utilising the DNA probe MCK2 to determine carrier status in this large South African family. It is also the first South African family in which biochemical and molecular genetic techniques were used to facilitate diagnosis.     

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

BACKGROUND: Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. METHODS: A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. RESULTS: Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. CONCLUSION: The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.