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Management of medullary thyroid carcinoma and MEN2 syndromes in childhood

Nature Reviews Endocrinology volume 7, pages 596–607 (2011)Cite this article

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Abstract

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90–95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype–phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise.

Key Points

  • Medullary thyroid carcinoma (MTC) during childhood is rare and almost always results from a dominantly inherited or de novo activating mutation in the RET proto-oncogene

  • C-cell hyperplasia is the initial stage of tumorigenesis that leads to the development of microscopic noninvasive MTC and ultimately to locoregional and distant metastases due to frankly invasive carcinoma

  • Multiple endocrine neoplasia (MEN) type 2A, which accounts for 90–95% of childhood MEN2 cases, is most frequently caused by mutations in RET exons 10 (codons 609, 611, 618 and 620) and 11 (codon 634)

  • MEN2B is almost always due to the Met918Thr mutation (exon 16) in the RET proto-oncogene and is associated with the most aggressive clinical presentation of MTC during childhood

  • MTC is primarily a surgical disease; the best hope of cure is for an experienced thyroid surgeon to remove the thyroid in at-risk patients before metastasis occurs

  • Strong genotype–phenotype correlations facilitate guidelines for treating children with MEN2; current approaches for determining the optimal timing for thyroidectomy incorporate ultrasonography and calcitonin data in addition to the genotype

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Figure 1: The RET receptor and commonly mutated codons and associated phenotypes in the MEN2 syndromes, including the recent ATA risk stratification.8
Figure 2: The development and progression of MTC in childhood.
Figure 3: Earliest age at detection and onset of metastatic disease in hereditary MTC.
Figure 4: Oral manifestations of multiple endocrine neoplasia type 2B syndrome.
Figure 5: Multistep process for MEN2 genetic testing.

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Acknowledgements

The authors acknowledge all of the children and families with MEN2 who have taught them so much about this disease. The authors thank Michelle D. Williams and Douglas B. Evans for contributing to Figure 2, and also acknowledge Lucy Faith's support of their surgical endocrinology education and research programs. Written consent for publication was obtained from a patient and a responsible relative of a patient for the inclusion of Figure 4. C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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  1. The Department of Endocrine Neoplasia and Hormonal Disorders, PO Box 301402, Unit 1461, Houston, 77230-1402, TX, USA

    Steven G. Waguespack, Camilo Jimenez & Gilbert J. Cote

  2. The Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, PO Box 301402, Unit 1461, Houston, 77230-1402, TX, USA

    Thereasa A. Rich & Nancy D. Perrier

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  1. Steven G. Waguespack
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S. G. Waguespack wrote the article, and all authors researched the data for the article, provided substantial contributions to discussion of the content and reviewed/edited the manuscript before submission.

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Correspondence to Steven G. Waguespack.

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Waguespack, S., Rich, T., Perrier, N. et al. Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7, 596–607 (2011). https://doi.org/10.1038/nrendo.2011.139

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