Diagnosis and Differential Diagnosis of Medullary Thyroid Cancer

Medullary thyroid cancer (MTC) occurs in less than 1% of thyroid nodules and accounts for 5-10% of thyroid malignancies. It is a well-differentiated neuroendocrine carcinoma arising from parafollicular calcitonin-producing cells (C-cells) of the thyroid gland and is associated with elevated serum calcitonin levels. Among well-differentiated thyroid carcinomas, MTC is the most aggressive, with survival rates of 40-50% at 10 years (American Thyroid Association [ATA] Guidelines Task Force et al., 2009; Leboulleux et al., 2004). In about 2025% of cases, MTC can be part of an autosomal dominant inherited cancer syndrome called Multiple Endocrine Neoplasia type 2 (MEN2), caused by activating germline mutations of the RET proto-oncogene, where this tumor is isolated (Familial MTC – FMTC) or is associated to other tumors (parathyroid adenoma, pheochromocytoma and cutaneous lichen amyloidosis in MEN2A; pheochromocytoma, mucosal and intestinal ganglioneuromatosis, marfanoid habitus in MEN2B). In the remaining 75-80% of cases MTC is sporadic (ATA Guidelines Task Force et al., 2009; Brandi et al., 2001; Leboulleux et al., 2004). Depending on the type of the genetic syndrome, clinical features, therapeutic approaches and prognosis of MTC are very different (Brandi et al., 2001). Calcitonin is a small peptide secreted by C-cells. It is the most specific and sensitive marker of MTC in patients with one or more thyroid nodules, useful in the diagnosis and follow-up of this tumor (ATA Guidelines Task Force et al., 2009; Leboulleux et al., 2004). High serum calcitonin levels are physiological in neonates, followed by an age-related decline from birth to about 1 year of age (Leboulleux et al., 2004). Elevated basal serum calcitonin levels are found in subjects with C-cells hyperplasia (CCH) or MTC. Anyway, in some cases it is possible to observe false positive or false negative for serum calcitonin levels in adult individuals. After excluding conditions that may cause falsely positive high levels of calcitonin, it is necessary to exclude tumors associated to ectopic production of calcitonin, which may represent up to 15% of cases (Pacini et al., 2010; Toledo et al., 2009). Another tumor marker used in the follow-up of MTC is carcino-embryonic antigen (CEA), a cytosolic enzyme which is not a specific biomarker for MTC being generally expressed by many endocrine and non-endocrine tumors. In MTC, CEA is considered to have lower diagnostic accuracy than calcitonin (Meijer et al., 2010). There is no close relationship