Medullary thyroid cancer (MTC) accounts for less than 5% of thyroid cancers. In contrast with papillary and follicular thyroid carcinomas, which arise from thyroid hormone-producing cells, MTC originates from the parafollicular, calcitonin-producing C cells.1
Most MTCs occur in a sporadic form without a family history, whereas 25%–30% of the cases are inherited through germline mutations in the RET proto-oncogene, being part of the multiple endocrine neoplasia type 2 (MEN2) syndrome. Sporadic MTC typically demonstrates a relatively slow growth rate and occurs between the 4th and 6th decade of life.2 Due to its silent progression up to 70% of cases may present with local cervical metastasis at the time of diagnosis, and 10% may present with distant metastases in the liver, lung, bone, and brain.3
When hereditary, MTC can be associated with other endocrine tumors, such as pheochromocytoma (PHEO) and parathyroid adenoma/hyperplasia, causing hyperparathyroidism (HPTH).1
In addition to producing calcitonin, MTC cells can produce several other neuropeptides, including corticotropin, serotonin, vasoactive intestinal peptide, and prostaglandins, leading to paraneoplastic syndromes such as carcinoid syndrome and Cushing’s syndrome.4–8
The most common symptoms of carcinoid syndrome are flushing, diarrhea, abdominal cramping, right heart valvular lesions, and bronchoconstriction.9 Approximately 30% of patients with MTC develop diarrhea,6 being caused by increased gastrointestinal secretion and hypermotility due to the hormones secreted by the tumor. At present, symptoms of diarrhea and flushing in patients with MTC have been attributed to calcitonin5, prostaglandins,6 serotonin,7 or vasoactive intestinal peptide.8 The presence of chronic diarrhea is usually a sign of the advanced stage of MTC with metastatic disease.
Cushing’s syndrome is a rare complication of MTC and is due to ectopic adrenocorticotropic hormone (ACTH) secretion by tumor cells. Only 0.7% of patients with MTC develop ectopic Cushing syndrome, while MTC accounts for approximately 2.2%–7.5% of patients with ectopic ACTH.4,10 Cushing’s syndrome from MTC is associated with significant morbidity and mortality,11 with secondary complications of hypercortisolism accounting for 50% of the mortality in MTC.
Comorbidities of MTC Associated With MEN2
Three different clinical forms can be distinguished in MTC-MEN2 cases:
- MEN2A represents 80% of all MEN2 occurrences, being characterized by the presence of MTC in nearly 100% cases, pheochromocytomas (30%-50%), and primary hyperparathyroidism in (20%-30%).12
- MEN2B is observed in only 5% of the cases and is characterized by MTC and pheochromocytomas, while also presenting additional extra-endocrine features, such as mucosa and gut neuromas, medullated corneal nerve fibers, marfanoid body habitus, and intestinal tumors (mostly ganglioneuromas).13,14 Usually these individuals do not manifest hyperparathyroidism. Although rare, this is the most aggressive of MEN2 and often appears in the first decade of life.
- Familial MTC (FMTC) is a variant of MEN2A and accounts for 15% of hereditary MTCs. In this form, MTC is the only manifestation and has a later age of onset (typically middle age) and is less aggressive than MEN2A and MEN2B.15
Pheochromocytoma is a catecholamine-secreting tumor that develops in the chromaffin cells of the adrenal medulla. It occurs in approximately 30%-50% of individuals with MEN 2A or 2B, most frequently impacting those aged 35–45 years, although children under 10 can also be affected.2,16 Unlike sporadic pheochromocytoma which typically appears as a single unilateral lesion, adrenomedullary disease is mostly bilateral (up to 78% of cases) in MEN2.15,17
Pheochromocytomas are typically benign in individuals with MEN2, provided they are managed adequately in an expert center.15 However, clinical manifestations of pheochromocytoma may arise caused by episodic secretion of catecholamines, leading to paroxystic symptoms, such as hypertension, headaches, and excessive sweating.16
One of the clinical features characteristic of primary HPTH in the context of MEN2 syndromes is the younger age at presentation compared to the sporadic form. Prevalence of primary hyperparathyroidism has been reported in 20%-30 % of individuals with MEN2A aged 20 to 45 years.18,19 It has been reported that most patients present with mild manifestations secondary to hypercalcemia.
The gastrointestinal problems found in MTC are caused by diffuse intestinal ganglioneuromatosis and impaired colonic motility that leads to an intestinal pseudo-obstruction. Ultimately this may lead to megacolon development due to enteric and extrinsic nerve hyperplasia and ganglioneuromas of the submucosal and myenteric plexuses that cause distension of the colon.20 These intestinal manifestations have been suggested to be predictive of MTC aggressiveness, as a worse MTC prognosis was associated with more severe gastrointestinal signs.21
4. Barbosa SL-S, Rodien P, Leboulleux S, et al. Ectopic adrenocorticotropic hormone-syndrome in medullary carcinoma of the thyroid: a retrospective analysis and review of the literature. Thyroid. 2005;15(6):618-623. doi:10.1089/thy.2005.15.618
7. Hocevar M, Bergant D, Auersperg M, Golouh R. Medullary carcinoma of the thyroid with serotonin production and carcinoid-like syndrome. Eur J Surg Oncol. 2001;27(2):219-222. doi:10.1053/ejso.2000.1032
8. Said SI. Evidence for secretion of vasoactive intestinal peptide by tumours of pancreas, adrenal medulla, thyroid and lung: support for the unifying APUD concept. Clin Endocrinol (Oxf). 1976;5 Suppl:201S-204S. doi:10.1111/j.1365-2265.1976.tb03828.x
10. Nella AA, Lodish MB, Fox E, et al. Vandetanib successfully controls medullary thyroid cancer-related Cushing syndrome in an adolescent patient. J Clin Endocrinol Metab. 2014;99(9):3055-3059. doi:10.1210/jc.2013-4340
11. Valassi E, Tabarin A, Brue T, et al. High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: results from the ERCUSYN registry. Eur J Endocrinol. 2019;181(5):461-472. doi:10.1530/EJE-19-0464
13. Amodru V, Taieb D, Guerin C, et al. MEN2-related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives. Endocrine. 2020;69(3):496-503. doi:10.1007/s12020-020-02332-2
15. Wells SA, Pacini F, Robinson BG, Santoro M. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149-3164. doi:10.1210/jc.2013-1204
17. Maia AL, Siqueira DR, Kulcsar MA V, Tincani AJ, Mazeto GMFS, Maciel LMZ. Diagnosis, treatment, and follow-up of medullary thyroid carcinoma: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. Arq Bras Endocrinol Metabol. 2014;58(7):667-700. doi:10.1590/0004-2730000003427
19. Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab. 2013;98(2):E336-45. doi:10.1210/jc.2012-3192
20. Gibbons D, Camilleri M, Nelson AD, Eckert D. Characteristics of chronic megacolon among patients diagnosed with multiple endocrine neoplasia type 2B. United Eur Gastroenterol J. 2016;4(3):449-454. doi:10.1177/2050640615611630
21. Brauckhoff M, Gimm O, Weiss C-L, et al. Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg. 2004;28(12):1305-1311. doi:10.1007/s00268-004-7637-4
Reviewed by Kyle Habet, MD, on 7/1/2021.