Medullary thyroid cancer (MTC) is a rare type of neuroendocrine tumor of the thyroid gland. It arises from the parafollicular or C cells. C cells are derived from the embryonic neural crest cells and make up up to 1% of the thyroid cells and although they can be found anywhere in the thyroid, they are mainly concentrated in the upper poles of the thyroid lobes.1–5 The malignant C cells secrete high levels of calcitonin and carcinoembryonic antigen (CEA), which are both widely used biomarkers for the identification of MTC.1,3
MTC accounts for 2% to 4% of all thyroid cancer cases and it behaves quite differently from other thyroid carcinomas.1 It clinically presents between 40 and 50 years of age with a slight, but statistically significant, increase in diagnosis from 50 to 54 years.1,6
MTC is known to be sporadic in 75% of cases; in 25% of cases it has a hereditary origin, as part of the multiple endocrine neoplasia (MEN) type 2 syndromes (MEN2a and MEN2b), which are autosomal-dominant,7 and as part of familial medullary thyroid cancer (FMTC).4 In MEN2a patients, MTC is associated with pheochromocytoma, parathyroid tumors, cutaneous lichen amyloidosis, and sometimes Hirschsprung’s disease.5,8–10 MEN2b patients are at a higher risk of developing pheochromocytoma; they present marfanoid habitus and normally develop multiple neural ganglioma, more frequent of the digestive tract mucosa.5,11
RET mutations in the neural crest tissue are associated with MTC development so it is not surprising that 40% to 50% of sporadic MTC cases are known to have acquired these mutations.4 RET proto-oncogene encodes a transmembrane receptor of the tyrosine kinase family,7 and specific mutations stimulate the continuous phosphorylation of a particular set of tyrosine residues, activating intracellular signaling pathways that are responsible for cell survival, differentiation, and proliferation.1
While sporadic MTC is usually unilateral, MTC cases associated with multiple MEN syndromes are usually multicentric and bilateral, involving the upper portions of both thyroid lobes.4
MTC can also lead to the appearance of paraneoplastic syndromes, like Cushing syndrome and carcinoid syndrome, which can also produce hormones, such as corticotropin, serotonin, prostaglandins, and melanin.4
The majority of MTC cases begin with the presence of a palpable thyroid nodule. While in familial cases a positive genetic screen prompts for a diagnosis of multiple endocrine neoplasia that could lead to the identification of MTC, other signs and symptoms can be identifiable. MTC can also include palpable lymph node metastases or local compression and flushing and diarrhea, due to the high levels of calcitonin.5 In addition changes in voice, associated with local compression or invasion, dysphagia, cough, and shortness of breath are also present in up to 15% of patients with MTC.12
The true diagnosis of MTC is frequently completed at surgical pathology, after the lobe of the thyroid is resected from the patient.7 Patients usually present with a palpable thyroid nodule that can be solitary or appear in the context of a multinodular goiter.1 Nodules that are suspicious may be evaluated with an ultrasound and ancillary lab tests. The normal diagnostic procedure includes fine-needle aspiration (FNA) of the suspicious nodules on thyroid ultrasonography. If a diagnosis of MTC is suspected, serum calcitonin and CEA measurements, germline RET genetic testing, and the evaluation for distant metastases are considered.7
Histopathologic characterization of MTC often reveals nests of round or ovoid cells with fibrovascular stroma with no follicle development.4 Another highly morphological characteristic of MTC is the presence of conspicuous amyloid deposition consisting of pre-procalcitonin.7
As mentioned above calcitonin is a known biomarker for MTC and the most important one. Calcitonin levels are useful not only for diagnosis, as well for the surgical planning of the patient, the follow-up, and ultimately prognosis.1 In MTC diagnosis, calcitonin shows nearly 100% sensitivity and 95% specificity.13
Surgery is the only primary treatment for MTC, where total thyroidectomy with central lymph node dissection is the procedure of choice.1 Total thyroidectomy significantly increases the efficacy and effectiveness of postoperative calcitonin level monitoring as a marker for relapse.4 If serum CEA levels are within the normal limits and calcitonin levels are not detectable 2-3 months after surgery, then it is considered that the patient is cured and has the best prognosis.4
In patients with mutations that put them at higher risk it is advised a prophylactic thyroidectomy at age 5 or when the mutation is found, in particular if the RET mutation is in codon 609, 611, 618, 630, or 634.4 If mutations are present in codon 883, 918, or compound heterozygotes, prophylactic total thyroidectomy is recommended as early as one year of age.4 In situations where the tumor is unresectable and there is the presence of symptoms, tyrosine-kinase inhibitors (TKI) like vandetanib and cabozantinib may be prescribed.4
1. Ceolin L, Duval MA da S, Benini AF, Ferreira CV, Maia AL. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 2019;26(9):R499-R518. doi:10.1530/ERC-18-0574
2. Gupta MK. Medullary thyroid cancer: an introduction. Curr Oncol. 2019;26(5):294. doi:10.3747/co.26.5743
3. Larouche V, Akirov A, Thomas CM, Krzyzanowska MK, Ezzat S. A primer on the genetics of medullary thyroid cancer. Curr Oncol. 2019;26(6):389-394. doi:10.3747/co.26.5553
4. Master SR, Burns B. Medullary Thyroid Cancer. Louisiana State University HSC: StatPearls Publishing, Treasure Island (FL); 2020.
5. Harvey A, Pasieka JL. Sporadic medullary thyroid cancer. Cancer Treat Res. 2010;153:57-74. doi:10.1007/978-1-4419-0857-5_4
6. Randle RW, Balentine CJ, Leverson GE, et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery. 2017;161(1):137-146. doi:10.1016/j.surg.2016.04.053.
7. Thomas CM, Asa SL, Ezzat S, Sawka AM, Goldstein D. Diagnosis and pathologic characteristics of medullary thyroid carcinoma-review of current guidelines. Curr Oncol. 2019;26(5):338-344. doi:10.3747/co.26.5539
8. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the RET proto-oncogene in Hirschsprung’s disease. Nature. 1994;367(6461):378-380. doi:10.1038/367378a0
9. Gagel RF, Levy ML, Donovan DT, Alford BR, Wheeler T, Tschen JA. Multiple endocrine neoplasia type 2a associated with cutaneous lichen amyloidosis. Ann Intern Med. 1989;111(10):802-806. doi:10.7326/0003-4819-111-10-802
10. Howe JR, Norton JA, Wells SAJ. Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery. 1993;114(6):1070-1077.
11. O’Riordain DS, O’Brien T, Crotty TB, Gharib H, Grant CS, van Heerden JA. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery. 1995;118(6):936-942. doi:10.1016/s0039-6060(05)80097-2.
12. Fialkowski EA, Moley JF. Current approaches to medullary thyroid carcinoma, sporadic and familial. J Surg Oncol. 2006;94(8):737-747. doi:10.1002/jso.20690
13. Bugalho MJM, Santos JR, Sobrinho L. Preoperative diagnosis of medullary thyroid carcinoma: fine needle aspiration cytology as compared with serum calcitonin measurement. J Surg Oncol. 2005;91(1):56-60. doi:https://doi.org/10.1002/jso.20269
Article reviewed by Kyle Habet, MD, on June 23, 2021.