An introduction to managing medullary thyroid cancer

Abstract

MTC is a rare neuroendocrine thyroid tumour accounting for 3% to 10% of all thyroid malignancies. It can occur in a sporadic and a hereditary clinical setting. Hereditary MTC may either occur alone (familial MTC, FMTC) or as part of multiple endocrine neoplasia (MEN) type 2A, or MEN 2B. These disorders are due to germline mutations in the RET (REarranged during Transfection) gene. In carriers of MEN 2B-associated RET mutations, prophylactic thyroidectomy is indicated before the first year of life. In the case of MEN 2A-associated germline RET mutations with a high-risk profile, total thyroidectomy is warranted before the age of 2 years and certainly before the age of 4 years. At that age the risk of invasive MTC and metastases is acceptably low. Depending on the type of RET mutation, thyroidectomy can take place at an older age in patients with a lower risk profile. In case of elevated basal or stimulated serum calcitonin, preventive surgery including total thyroidectomy and central compartment dissection should be performed regardless of age. When MTC presents as a palpable tumour, total thyroidectomy should be combined with extensive lymph node dissection of levels II-V on both sides and level VI to prevent locoregional recurrences.

Figure 1

[A] Microscopic view of normal thyroid tissue with hyperplastic C-cells (arrows) dispersed between the follicles. C-cell hyperplasia (CCH) was defined as clusters of intrafollicular atypical C-cells (more than 50 per "low-power field" at 100× magnification) that lead to partial or complete obliteration of the follicular space. [B] C-cells are positive for immunohistochemical staining for calcitonin (dark areas). [C] Microscopic view of medullary thyroid cancer (MTC). Malignant C-cells have broken through the basement membrane and invaded the interstitium, which has led to stromal fibrosis (arrows). MTC lesions are composed of solid nests of epithelial cells with poorly defined cell borders. [D] Occasionally there is deposition of intensely eosinophilic material, amyloid, which can be stained with Congo-red (arrow). Amyloid is derived from calcitonin.

Figure 2

Development of medullary thyroid cancer (MTC) from a normal C-cell via C-cell hyperplasia (CCH) to MTC.

Figure 3

Magnetic Resonance Imaging (MRI) of the neck of a 51-year-old woman with a germline V804L RET mutation demonstrating a thyroid nodule (arrow on the right) and cervical lymphadenopathy (arrow on the left).

Figure 4

Copyright 2006, The Endocrine Society. Schematic representation of the RET tyrosine kinase. The extracellular region comprises four cadherin domains and a cysteine rich domain. A single transmembrane region spans the cell membrane, and the two tyrosine kinase domains (TK1 and TK2) are located in the intracellular region. There are three isoforms of RET (RET9, RET43, RET 51) which are indicated. aa, Amino acids. [Adapted from De Groot et al. [35]].

Figure 5

Copyright 2006, The Endocrine Society. Overview of the known germline missense mutations in the RET gene and their associated human diseases. The structure of the RET mRNA and the RET protein are depicted schematically. The mutations responsible for the diverse inherited cancer syndromes and the location of the mutations relative to the exons and the functional domains are shown. The most common mutations that are found in about 95% of MEN 2A and FMTC cases are depicted in bold, and MEN 2B mutations are depicted in italics. CLA, Cutaneous lichen amyloidosis. [Adapted from De Groot et al. [35]].