Medullary thyroid carcinoma (MTC) is an infrequent thyroid malignancy that is often diagnosed at advanced stage with consequent poor prognosis. Thus, the earlier the diagnosis of MTC, the better the prognosis. Unfortunately, the preoperative detection of MTC remains challenging in clinical practice. In fact, while ultrasound and fine-needle aspiration cytology have suboptimal performance in this context, measuring serum calcitonin (Ctn), fully recognized as the most reliable test to detect MTC, is not universally accepted as routine test in all patients with thyroid nodule(s). The authors of this paper reappraise critically the matter of Ctn measurement in view of the recent advancements in the literature to point out the essential information to be known, and then to prepare an easy-to-use guide for clinicians to appropriately consider the measurement of serum Ctn during clinical practice.
Medullary thyroid carcinoma (MTC) is an infrequent malignant tumor originating from thyroid C cells. It was firstly described in 1951  and the presence of “thyrocalcitonin” was later explored . One in four cases is inherited as familial MTC or within multiple endocrine neoplasia (MEN) type 2 A or 2B syndromes . MTC is often diagnosed with more advanced stage than well-differentiated thyroid cancer and is associated with poorer prognosis. Thus, the earlier the diagnosis of MTC, the better the prognosis . The early spread of MTC to regional lymph nodes makes generally necessary to treat MTCs with total thyroidectomy and lymph node dissection, of at least the central compartment. In fact, an incomplete initial resection significantly decreases the chance to achieve structural and biochemical complete response. Furthermore, patients diagnosed with advanced MTC can be treated with systemic therapies with only a minority of tumors –about 10% of RET-mutated tumors– achieving complete response with selective RET inhibitors; while the other 90% can expect a transitory partial response at best and a median progression free survival of 2–3 years with multikinase inhibitors and (probably) longer with selective RET inhibitors . Thus, early presurgical diagnosis of MTC has a direct impact on treatment’s outcomes and patient’s prognosis.
Unfortunately, the preoperative detection of MTC remains challenging in clinical practice . Most MTCs are solid and hypoechoic at ultrasound (US) and often have macrocalcifications . However, suspicious US features are less frequent in MTC than in papillary thyroid carcinoma, even if their prevalence among MTCs is higher than among follicular carcinomas. This makes sense, given that suspicious sonographic features were derived from cohorts in which >90% of the malignancies were papillary thyroid carcinomas . Furthermore, no sonographic features are specific of MTC. Therefore, depending on the sonographic classification used to set the threshold for biopsy, a significant proportion of MTCs may not be eligible for biopsy. Thus, delaying diagnosis with possible prognostic implications. If fine-needle aspiration cytology (FNAC) is performed, only about 50–60% of MTC cytological specimens allow a direct MTC diagnosis . The remainder of specimens are either non-diagnostic or classified into an indeterminate category of thyroid cytopathology; thus, being subject to either follow-up or diagnostic surgery, both of which can be detrimental to patient’s prognosis. In this context, while the measurement of serum calcitonin (Ctn) is fully recognized as the most reliable test to detect MTC , its routine use in all patients with thyroid nodule(s) has not been universally accepted.