Medullary Thyroid Carcinoma (MTC)

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Medullary thyroid cancer (MTC) is a rare malignant neoplasm originating from parafollicular C cells of the thyroid gland and accounts for 1%-2% of thyroid malignancies.1 MTC is associated with genetic mutations of the rearranged during transfection (RET) gene, which code for a receptor tyrosine kinase (RTK) that vary depending on whether they occur sporadically (75% of cases) or are inherited, as seen in multiple endocrine neoplasia (MEN) type 2A and 2B.2 Familial MTC (FMTC) is a subgroup of MEN 2A with a very low incidence of pheochromocytomas and hyperparathyroidism.3 

In short, RTK regulates cellular proliferation, differentiation, migration, and apoptosis through the phosphorylation of amino acid residues in several proteins involved in intracellular signaling pathways.4 Faulty and antiapoptotic cell signaling favor oncogenesis and is the underlying mechanism that results in malignant transformation in MEN 2 subtypes and is also present to varying degrees in sporadic MTC.5 

Role of RET Proto-Oncogene

The RET proto-oncogene is located on the long arm of chromosome 10 (10q11.2) and codes for a RTK that promotes cell growth, differentiation, and survival through intracellular signaling pathways. RET mRNA exists in 3 variations due to alternative splicing and code for RET9, RET43, and RET51, which are proteins involved in various processes that regulate intracellular trafficking and development. Ligands that stimulate the RTK receptor are glial cell-line derived neurotrophic factor (GDNF), neurturin, artemin and persephin. These ligands interact with the RTK and its coreceptors resulting in receptor dimerization and autophosphorylation of specific tyrosine residues on the intracellular domain of the receptor. The TKR regulates intracellular activities such as proliferation, survival and migration through the mitogen-activated protein kinase (MAPK) and the phosphoinositide 3-kinase pathways (PI3K).6 

Inherited MTC 

MEN Type 2 is a group of autosomal dominant disorders with an estimated prevalence of 1 per 30,000 in the general population. MEN2A is the most common of the MEN2 subtypes (70% to 80%) and is characterized by mutations in RET proto-oncogenes which result in MTC, pheochromocytomas, and hyperparathyroidism.5 The clinical course of MTC in patients with MEN 2A is variable, and the disease progression is associated with codon-specific mutations. Around 90% of MEN2A patients present point mutations of RET, which code for a RTK expressed in cells derived from neural crest, such as thyroid parafollicular C cells, parathyroid cells, and chromaffin cells of the adrenal medulla – explaining the triad of (1) MTC, (2) pheochromocytoma, and (3) hyperparathyroidism. Patients with MEN2A present with genetic mutations, usually a Cys634Arg alteration in exon 11, that affect cysteine-rich residues on the RTK receptor, resulting in ligand-independent constitutive activation of the receptor through the formation of disulfide bonds. In other words, dimerization and auto-phosphorylation of intracellular tyrosine residues occurs in the absence of RTK ligands, and results in overactivation of signaling pathways.

MEN 2B accounts for approximately 5% of MEN type 2, and approximately 90% develop aggressive MTC that usually manifests in childhood. In 95% of cases, it is attributed to a specific Met918Thr mutation in exon 16, resulting in a structural change of the intracellular domain of the RTK protein.  This allows the protein to autophosphorylate without the need for dimerization, also resulting in overactivation of intracellular signaling pathways. The remaining cases are associated with an A883F mutation and a double mutation V804M/Y806C at codon 804.5,6  

FMTC was once classified as a separate entity but is now recognized as a subtype of MEN2A. Unlike MEN 2A and 2B syndromes, the germline mutations associated with FMTC are dispersed throughout the gene. These mutations may affect different properties of the RTK, but, ultimately, the end result is uncontrolled activation of the MAPK and the PI3K pathways that results in uncontrolled growth and alterations in cell differentiation.6 It is unknown why pheochromocytomas and hyperparathyroidism is infrequent in this subtype.7

Sporadic MTC

Most cases (75%) of MTC are sporadic and present later in life. Sporadic cases may occur in the absence of RET mutations, which themselves are only found in 44% of sporadic MTCs. When RET mutations are identified in supposed sporadic cases, they are somatic and not germline. The presence of germline mutations, which can be revealed through genetic testing, should be ruled out before defining the case as sporadic. The most common RET mutations in sporadic MTC are Met918Thr and Cys634 point mutations. When the RET gene is involved, the pathogenic process of neoplasia is similar to hereditary cases. 

Activating mutations in RAS are present in about 30% of all human cancers. Mainly H‑RAS and K‑RAS have been reported in varying percentages in RET-negative MTC samples.6 Similar to RET, the RAS proto-oncogene codes for proteins that are also involved in cellular growth, differentiation and proliferation though GTPase activity. The most common somatic mutations present in the oncogenic variants of RAS alleles is the maintenance of RAS in the activated states, resulting in downstream, uncontrolled, upregulation of intracellular signaling pathways.8 

References

1. Wells SA, Asa SL, Dralle H, et al. Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid Off J Am Thyroid Assoc. 2015;25(6):567-610. doi:10.1089/thy.2014.0335

2. Moline J, Eng C. Multiple endocrine neoplasia type 2: an overview. Genet Med Off J Am Coll Med Genet. 2011;13(9):755-764. doi:10.1097/GIM.0b013e318216cc6d

3. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86(12):5658-5671. doi:10.1210/jcem.86.12.8070

4. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhibitors: multi-targeted or single-targeted? World J Clin Oncol. 2011;2(2):80-93. doi:10.5306/wjco.v2.i2.80

5. Ferreira CV, Siqueira DR, Ceolin L, Maia AL. Advanced medullary thyroid cancer: pathophysiology and management. Cancer Manag Res. 2013;5:57-66. doi:10.2147/CMAR.S33105

6. Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma. Nat Rev Endocrinol. 2016 Apr;12(4):192-202. doi: 10.1038/nrendo.2016.11.

7. Mulligan LM, Ponder BA. Genetic basis of endocrine disease: multiple endocrine neoplasia type 2. J Clin Endocrinol Metab. 1995;80(7):1989-1995. doi:10.1210/jcem.80.7.7608246

8. Moura MM, Cavaco BM, Leite V. RAS proto-oncogene in medullary thyroid carcinoma. Endocr Relat Cancer. 2015;22(5):R235-R252. doi:10.1530/ERC-15-0070

Reviewed by Harshi Dhingra, MD, on 7/15/2021.

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