Medullary Carcinoma of the Thyroid and the MEN Syndromes

Douglas B. Evans, MD
Department of Surgical Oncology The University of Texas M. D. Anderson Canc
Last Modified: November 1, 2001

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Medullary thyroid carcinoma (MTC) originates in the thyroid C cells which produce both calcitonin and carcinoembryonic antigen. MTC occurs either as a sporadic event or secondary to a germline mutation with an autosomal dominant pattern of inheritance. MTC will develop in 90% of gene carriers during life and once metastatic, approximately 20% of patients will die of disease. Familial MTC may occur as part of multiple endocrine neoplasia type 2A (MEN 2A; MTC, pheochromocytoma, and parathyroid hyperplasia) or MEN 2B (MTC, pheochromocytoma, mucosal and alimentary neuromas, and marfanoid habitus) or without other endocrinopathies (familial non-MEN MTC; FMTC). Until recently, patients who were known members of a familial MTC kindred were screened by measurement of serum levels of pentagastrin-stimulated calcitonin.

Single point mutations within the RET proto-oncogene on chromosome 10 have been found responsible for all forms of familial MTC. The RET proto-oncogene encodes a receptor tyrosine kinase that is expressed in derivatives of neural-crest cells and therefore, expressed in neural-crest-derived tumors such as MTC. The use of DNA testing in at-risk family members allows early thyroidectomy prior to the development of invasive MTC. Despite the tremendous advances made in the molecular biology of MTC, the opportunity to improve the outcome for the majority of patients who present with sporadic disease still lies in the performance of a safe and comprehensive initial surgical procedure. Total thyroidectomy is recommended in all patients with biopsy-proven or suspected MTC. Patients with familial MTC have bilateral, multifocal disease, and patients with presumed sporadic disease have a 20% to 30% incidence of multifocal disease and may also represent the index case of familial MTC. MTC is characterized by early spread to regional lymph nodes. It is likely that the majority of patients with invasive MTC have metastasis to regional lymph nodes at the time of diagnosis. This is supported by the frequent finding of persistent elevations in calcitonin levels following primary tumor resection (thyroidectomy) and the high rates of cervical recurrence (in regional lymph nodes) reported in retrospective studies. These data have provided the rationale for surgeons to perform a more extensive lymphadenectomy at the time of initial thyroidectomy and to consider reoperative cervical lymphadenectomy in patients with persistent elevation in calcitonin level following thyroidectomy. The extent of primary surgery performed at our institution can be categorized as follows:

A. Patients with MEN 2A or FMTC
Patients with a positive RET mutational analysis, a normal basal calcitonin level, and a normal cervical sonogram undergo total thyroidectomy without lymphadenectomy. Surgery is performed at the age of 5 years in children belonging to MEN 2A or FMTC families and known to carry a mutation of the RET proto-oncogene. In patients with an elevated basal calcitonin level or with a thyroid nodule visualized by sonography or present on physical examination, we perform total thyroidectomy with central compartment lymphadenectomy and bilateral modified neck dissection.

B. Patients with MEN 2B
Thyroidectomy should be performed as early as possible in children born with the clinical manifestations of MEN 2B, such as mucosal neuroma syndrome. Analysis for a RET mutation at codon 918 should be performed in all children born to parents with MEN 2B and in all children with ambiguous clinical features suggestive of MEN 2B. Because invasive MTC has been found at birth in children with MEN 2B, thyroidectomy should not be delayed.

C. Patients with presumed sporadic MTC
The majority of patients with MTC (75%) have the sporadic form of this disease. We advocate an aggressive approach to this disease based upon published data demonstrating improved local-regional disease control and suggesting improved survival in patients treated with compartment-oriented lymphadenectomy at the time of total thyroidectomy. Therefore, in patients with a palpable thyroid nodule diagnosed as MTC by fine-needle aspiration cytology, we perform total thyroidectomy with in-continuity clearance of the central neck and standard modified radical neck dissection on the side of the lesion. The inferior parathyroid glands are routinely resected with the paratracheal lymphatic tissue. The operative specimen should be carefully examined for parathyroid glands; when found, they should be confirmed as parathyroid tissue with frozen-section analysis and autografted into either the sternocleidomastoid muscle or the nondominant forearm. In any patient with palpable cervical lymphadenopathy, a bilateral modified radical neck dissection is performed at the time of total thyroidectomy. The goal of this aggressive surgical approach is to maximize local regional tumor control and survival while minimizing the need for reoperation. Adjuvant external-beam radiation therapy should be considered in patients at high risk for local-regional tumor recurrence following maximal surgical therapy. Although prospectively acquired data are lacking, postoperative external-beam radiation therapy should be considered in patients with positive surgical margins of excision, extranodal soft tissue extension, and extensive mediastinal tumor extension.


References

  1. Evans DB, Burgess MA, Goepfert H, Gagel RF. Medullary thyroid cancer. In Bardin CW (ed). "Current Therapy in Endocrinology and Metabolism, Sixth Edition." St. Louis: Mosby-Year Book, Inc, 1997;127-132.
  2. Evans DB, Fleming JB, Lee JE, Cote G, Gagel RF. The surgical treatment of medullary thyroid carcinoma. Sem Surg Oncol 1999;16:50-63.
  3. Fleming JB, Lee JE, Bouvet M, et al. Operative strategy for the treatment of medullary thyroid carcinoma. In press: Ann Surg.
  4. Wohllk N, Cote G, Evans DB, et al. Application of genetic screening information to the management of medullary thyroid carcinoma and multiple endocrine neoplasia type 2. Endocrinol Metab Clin North Am 1996;25:1-25.


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