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Epidemiology

Thyroid cancer is the most common malignancy of the endocrine system and accounts for approximately 2% of all cancer diagnoses.¹ Thyroid cancer in general has been increasing in incidence over the past 3 decades and is 3 times more common in women than in men, according to the European Network of Cancer Registries in 2012.² Medullary thyroid cancer (MTC) is the 3^rd most common type of thyroid malignancy behind papillary and follicular thyroid cancer and represents 1% to 2% of all thyroid cancers in the US. This percentage was higher in previous years (as high as 9% in the 1970’s) however, an increase in papillary and follicular thyroid cancer relative to MTC over the past few decades has correlated to a decrease in this number. The incidence of MTC has remained stable during past 30 years.²

Sporadic MTC

Most cases of MTC are sporadic, however, a quarter of cases occur as part of Multiple Endocrine Neoplasia Type 2 (MEN 2) syndrome.³ Sporadic MTC cancer accounts for 75% of cases and has a male-to-female ratio of 1:1.3. Mean age of onset is in the 5^th decade of life.¹ Point mutations to RET are the most common type of defect in sporadic MTC and may also include small deletions and/or insertions. The Met918Thr mutation is the most prevalent RET somatic point mutation, followed by alterations affecting codon Cys634.⁴

Inherited MTC

MEN2 syndrome is inherited in an autosomal dominant pattern with almost 100% penetrance for MTC and is associated with germline mutations to the RET proto-oncogene. It has an estimated prevalence of 1 in 30,000 in the general population. Unlike sporadic cases, MEN 2 familial form does not show any predilection for sex. MTC associated with MEN 2 represents 25% of all cases. MEN is categorized into two distinct subtypes: MEN 2A and MEN2B.¹

MEN2A

MEN2A is the most common subtype, accounting for 95% of MEN 2 patients. Patients with MEN 2A typically develop MTC around the third decade of life. MEN2A is further subdivided into four main groups: (1) Classical MEN2A which includes MTC with pheochromocytoma or hyperparathyroidism or both; (2) MEN2A with Hirschsprung’s disease; (3) MEN2A with cutaneous lichen amyloidosis; and (4) Familial MTC (FMTC).¹ In families with MEN2A, the most common RET mutations (90%) are missense mutations involving codons located in the extracellular region: 609, 611, 618, and 620 (exon 10), and 634 (exon 11).⁴

Familial MTC is considered a subtype of MEN2A syndrome. Both conditions are associated with RET proto-oncogenic mutations, however, for unexplained reasons, patients with FMTC do not develop hyperparathyroidism or pheochromocytomas as seen in MEN2A. Unlike MEN2A and 2B syndromes, the germline mutations associated with FMTC are dispersed throughout the RET gene.⁴

MEN2B

MEN2B affects 5 percent of patients with MEN 2, which is characterized by the development of more aggressive forms of MTC at an early age (usually in the first decade of life).¹ About 75% of cases are sporadic. These patients have no family history of neuroendocrine tumors and are due to de novo mutations, usually to RET. The remaining 25% of cases occur in families with previous or current manifestations of MEN2B which include Marfanoid habitus, ganglioneuromas, pheochromocytoma and MTC. In MEN2B, 95% of patients have a specific M918T RET mutation affecting exon 16. Other less commonly documented mutations are A883F (2% to 3%) and a double-mutation V804M/Y806C at codons 804 and 806. Rare germline double-point mutations in codons 804 and 904 have also been reported.⁴

References:

1. Raue F, Frank-Raue K. Epidemiology and clinical presentation of medullary thyroid carcinoma. Recent Results Cancer Res Fortschritte Krebsforsch Progres Dans Rech Sur Cancer. 2015;204:61-90. doi:10.1007/978-3-319-22542-5_3

2. Filetti S, Durante C, Hartl D, et al. Thyroid cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(12):1856-1883. doi:10.1093/annonc/mdz400

3. 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

4. A comprehensive overview of the role of the RET proto-oncogene in thyroid carcinoma | Romei, Cristina; Ciampi, Raffaele; Elisei, Rossella | download. Accessed June 29, 2021. https://booksc.org/book/50076132/264ce9

Article reviewed by Debjyoti Talukdar, MD, on July 1, 2021.

Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.

Medullary Thyroid Carcinoma (MTC)