Multiple endocrine neoplasia type 2A: A 25-year review

doi:10.1016/S0022-3468(99)90236-1

Journal of Pediatric Surgery

Volume 34, Issue 1, January 1999, Pages 92-97

https://doi.org/10.1016/S0022-3468(99)90236-1 Get rights and content

Abstract

Background/Purpose: Before 1970, treatment decisions for the thyroid lesions in patients with multiple endocrine neoplasia (MEN) were based on physical findings. For the next 20 years, biological markers assumed a preeminent role, and at present, DNA testing is being used to define the need for therapeutic intervention. This report presents a 25-year review of 22 children with MEN-2A, with a mean follow-up of 12.5 years.

Methods: All 22 children underwent a total thyroidectomy, and four (18%) were rendered permanently hypoparathyroid. Since 1976, however, only one patient (6.7%) has lost parathyroid function. Despite the fact that biological screening studies routinely were performed once a year in the majority of our patients and surgery was recommended for any elevation in the serum calcitonin (CT) levels, medullary carcinoma of the thyroid (MTC) developed in 17 children (77%) and only five had C cell hyperplasia (CCH). Thirteen of the 17 had macroscopic tumor described by the pathologist, evidence of recurrent disease (MTC-REC) has developed in four children (24%).

Results: There was considerable overlap in both the basal and stimulated CT levels among the five children with CCH, the 13 with localized MTC (MTC-NED), and the four who later had recurrent MTC. The basal calcitonin levels were between 25 and 110 (mean, 58) in the CCH patients, 30 to 1,130 (mean, 184) in the MTC-NED group, and 108 to 201 (mean, 140) in those with recurrent MTC. The corresponding stimulated calcitonin levels were 45 to 417 (mean, 179) in CCH, 111 to 9,510 (mean, 1,407) in MTC-NED, and 449 to 5,093 (mean, 3,383) in MTC-REC.

Conclusions: (1) Basal and pentagastrin-stimulated CT levels did not reliably discriminate between CCH and MTC and should not be used to define the timing of thyroid surgery in children with MEN-2A. (2) Surgical therapy should be undertaken early in childhood on the basis of molecular genetic testing. (3) Postoperative complications are infrequent in the modern era.

References (11)

N Wohllk et al.
Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2
Endocrinol Metabolism Clin North Am
(1996)
JR Gill et al.
Early presentation of metastatic medullary carcinoma in multiple endocrine neoplasia, type 11A: Implications for therapy
J Pediatr
(1996)
RA Decker et al.
Progress in genetic screening of multiple endocrine neoplasia type 2A: Is calcitonin testing obsolete?
Surgery
(1995)
JB Hazard et al.
Medullary (solid) carcinoma of the thyroid—A clinicopathologic entity
J Clin Endocrinol
(1959)
JH Sipple
The association of pheochromocytoma with carcinoma of the thyroid gland
Am J Med
(1961)

There are more references available in the full text version of this article.

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Thyroid Disorders in Childhood and Adolescence
2008, Pediatric Endocrinology
Chapter 9 Thyroid neoplasms in children and adolescents
2006, Advances in Molecular and Cellular Endocrinology
Citation Excerpt :
The ideal age at which prophylactic total thyroidectomy should be performed in children with RET germline mutations is controversial. Some clinicians recommend surgery in mutation carriers of MEN 2B in the first year of life and for those with gene mutation for MEN 2A at 5 years of age [82,83]. Heptulla et al. [44] recommend prophylactic total thyroidectomy during the first decade of life in patients with FMTC and RET mutations.
This chapter discusses the thyroid neoplasms in children and adolescents. Occurrence of thyroid carcinomas in the pediatric age group is rare. Well-differentiated thyroid carcinoma (WDTC), papillary, and follicular carcinomas comprised only 1.3% of all the newly diagnosed childhood carcinomas in the United States reported from 1973 to 1987, as determined from data collected by the National Cancer Institute of the National Institutes of Health. Survival rates for patients with many pediatric malignancies have improved, but therapeutic radiation and chemotherapy have been implicated in the development of secondary thyroid carcinomas in some patients. Genetic factors are considered as etiologic factors in reports of thyroid carcinomas in familial syndromes such as Pendred syndrome, Gardner syndrome, Cowden syndrome, and Familial polyposis. Medullary thyroid carcinoma (MTC) is also discussed. It originates in calcitonin-producing cells (C-cells) of the thyroid. C-cells are of neuroectodermal origin and do not accumulate iodine.
Diagnosis and management of medullary thyroid carcinoma
2004, Clinics in Laboratory Medicine
Acceptable age for prophylactic surgery in children with multiple endocrine neoplasia type 2a
2003, European Journal of Surgical Oncology
Aims: Germline mutated RET proto-oncogene, causing multiple endocrine neoplasia (MEN)-2a syndrome is the indication for prophylactic total thyroidectomy. Literature regarding the risk and the extent of early surgical intervention is scarce and the optimum age for surgery is still controversial. To optimize management in these young children we evaluate our experience and results.
Patients and methods: From 1990 to 2001 preventive total thyroidectomy was performed in 13 MEN-2a gene carriers (4 boys and 9 girls; median age 7 (4–14) years). Preoperative assessment, surgical procedure, pathological examination, postoperative complications and treatment results were studied.
Results:Surgery existed of a total thyroidectomy alone (n=3) in children with normal basal calcitonin and in combination with tracheo-esophageal exploration (n=6) or central compartment dissection (n=4) in case of abnormal calcitonin levels. Eight children presented with medullary thyroid cancer (MTC), three (median: 5 (4–12) years) with microscopic MTC and five (median 6 (4–14) years) with frank invasive MTC. Four of these five patients were younger than 6 years. Except for long-lasting hypoparathyroidism in one patient there were no complications. At a median follow-up of 6.5 years all patients are disease free.
Conclusion: MTC in RET mutated MEN-2a gene carriers in childhood are found at the age of 4 years. Therefore, DNA testing should be done preferably before that age. Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal.
Early onset of medullary thyroid carcinoma in a kindred with multiple endocrine neoplasia type IIA associated with cutaneous lichen amyloidosis
2002, Endocrine Practice
Citation Excerpt :
Early intervention offers the best possibility of cure, inasmuch as MTC, in classic MEN IIA kindreds, has been found as early as age 2 years (18,19) and metastatic lesions have been found at age 5 years (20). Many authorities now recommend prophylactic surgical treatment for mutation carriers at age 5 years or even earlier, although data about the long-term outcome associated with this procedure are still lacking (18-25). To the best of our knowledge, this is the earliest detection of MTC reported thus far in kindreds affected with the MEN IIA-CLA variant.
To describe the molecular characterization of a kindred affected by the rare variant of multiple endocrine neoplasia type IIA (MEN IIA) associated with cutaneous lichen amyloidosis and to discuss the clinical implications in the management of this syndrome.
A kindred with four affected family members was identified, and DNA analysis was performed by sequencing exon 11 of the RET proto-oncogene. Pre-symptomatic genetic screening was offered to all first-degree relatives.
Sequencing analysis of the RET proto-oncogene revealed a Cys634Trp (TGC → TGG) mutation in all clinically affected family members and in an asymptomatic 5-year-old child who, after thyroidectomy, was found to have multicentric medullary thyroid carcinoma and C-cell hyperplasia. A Gly691Ser (GGT → AGT) polymorphism was also detected in this family but did not segregate with the disease.
To our knowledge, this is the earliest detection of medullary thyroid carcinoma reported thus far in a kindred with MEN IIA associated with cutaneous lichen amyloidosis, and this finding suggests that prophylactic thyroidectomy, in kindreds with this variant, should be performed before the age of 5 years. (Endocr Pract. 2002;8:19-22)
Utility of the ret prot-oncogene in the diagnosis of the hereditary medullary thyroid carcinoma. Correlation with the surgical results
2001, Acta Otorrinolaringologica Espanola
Un 25% de los carcinomas medulares de tiroides (CMT) son de carácter hereditario, y en el 95% de los mismos se puede detectar una mutación en el proto-oncogen RET. El objeto de este trabajo es la evaluación del RET como método de despistaje del CMT hereditario. Se estudiaron 43 sujetos con riesgo de padecer un MEN 2A. En 22 pacientes el estudio del RET determinó la sospecha de un CMT, 15 de los cuales fueron intervenidos en nuestro hospital, confirmándose en todos ellos la existencia de un CMT. De acuerdo con nuestra experiencia quirúrgica, el despistaje familiar mediante el uso del RET es 100% sensible y específico, y aporta ventajas metodológicas, económicas y sociales sobre el empleo de la calcitonina
In about 25% of cases medullary thyroid carcinoma (MTC) is hereditary. In this group is possible to detect germline point mutations of the RET proto-oncogene in about 95% of the studied cases. The purpose of the present paper is to confirm the value of the RET in the screening of the hereditary MTC. We studied 43 subjects at risk for a Multiple Endocrine Neoplasia Type 2A Syndrome. RET analysis was positive for MEN 2A in 22 subjects. Fifteen of the 22 have undergone a total thyroidectomy at our facility. Histopathological study of the surgical specimens confirmed the presence of a MTC in all the cases. According with our experience. RET analysis is a 100% sensitive and specific method of hereditary MTC screening, and we think it has obvious advantages over the calcitonin tests in technical, economic and ethic aspects

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^☆: Presented at the 29th Annual Meeting of the American Pediatric Surgical Association, Hilton Head, South Carolina, May 10–13, 1998.

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Multiple endocrine neoplasia type 2A: A 25-year review☆

Abstract

Endocrinol Metabolism Clin North Am

J Pediatr

Surgery

Medullary (solid) carcinoma of the thyroid—A clinicopathologic entity

J Clin Endocrinol

The association of pheochromocytoma with carcinoma of the thyroid gland

Am J Med