Appropriate and mindful measurement of serum calcitonin in patients with thyroid nodules. A white paper

Medullary thyroid carcinoma (MTC) is an infrequent malignant tumor originating from thyroid C cells. It was firstly described in 1951 [1] and the presence of “thyrocalcitonin” was later explored [2]. One in four cases is inherited as familial MTC or within multiple endocrine neoplasia (MEN) type 2 A or 2B syndromes [3]. 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 [3]. 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 [4]. 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 [5]. Most MTCs are solid and hypoechoic at ultrasound (US) and often have macrocalcifications [6]. 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 [7]. 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 [8]. 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 [9], its routine use in all patients with thyroid nodule(s) has not been universally accepted.

The 2006 consensus of European Thyroid Association (ETA) was in favor of routine serum Ctn testing during the initial assessment of patients diagnosed with thyroid nodule [10]. However, this recommendation was modified in the 2010 joint guidelines from ETA, American Association of Clinical Endocrinologists (AACE), and Associazione Medici Endocrinologi (AME) which recommended serum Ctn measurement for specific patient settings only, i.e., in the presence of relatives diagnosed with MTC and before surgery to avoid difficult follow-up in case of incidental histological diagnosis of MTC [11]. The 2015 American Thyroid Association (ATA) guidelines for the management of patients with thyroid nodules and differentiated thyroid cancer were neither in favor nor against routine serum Ctn measurement [12]. Similarly, the 2015 MTC ATA guidelines included the following recommendation: “Realizing that opinions of experts vary regarding the usefulness of measuring serum Ctn levels in patients with nodular goiters, the Task Force recommends that physicians decide whether the technique is useful in the management of patients in their clinic” [3]. More recently, the 2023 ETA guidelines for thyroid nodule management recommends measuring Ctn in specific scenarios, such as in patients scheduled for surgery or thermal-ablation, or with nodules with indeterminate cytology or suspicious sonographic pattern, or with family history of MTC or MEN. [13].

The lack of clarity on whether serum Ctn should be tested and in which circumstances prompted the authors of this white paper to critically reappraise the matter, considering recent advancements in this field. This document is then intended to be an easy-to-use guide for clinicians to appropriately consider the measurement of serum Ctn during the evaluation of their patients with thyroid nodules.

Routine serum Ctn measurement might not be cost-effective in many countries in unselected patients with thyroid nodules. However, serum Ctn might be helpful in selected scenarios with an expected higher prevalence of MTC:

MTC is rare but needs to be considered routinely when evaluating patients with thyroid nodules, as delayed diagnosis can have significant prognostic implications. Thyroid ultrasound and cytology have limited ability to identify a significant proportion of MTCs. Appropriate Ctn measurement in patients with thyroid nodules might help to overcome these relevant limitations in clinical practice.