Prevalence and significance of indeterminate calcitonin values in patients with thyroid nodules: A systematic review and meta-analysis

Abstract

Background Although calcitonin (Ctn) measurement is recognized as the most accurate diagnostic test for medullary thyroid carcinoma (MTC), its routine execution is not universally accepted for several reasons, including the lack of recommendations for managing indeterminate Ctn values (ICV); such as 10-to-100 pg/mL. This study aimed to gather data on 1) the frequency of ICV among patients undergoing Ctn test and 2) the MTC rate among patients with ICV. Methods This review was conducted according to the Meta-analyses Of Observational Studies in Epidemiology guidelines. PubMed and Cochrane databases were searched, with no language restrictions. The final search was completed on January 2023. Then, quality assessment and proportion meta-analyses were performed. Results The online search retrieved 233 articles and 15 were included for quantitative analysis. The risk of bias was low. The number of patients undergone Ctn testing was 29,533. The pooled percentage of those with ICV was 1.7% (95% confidence interval [CI]:1.2–2.3). The pooled proportion of MTC incidence among patients with ICV was 9.6% (95% CI:5–14.1). Heterogeneity was explained by the covariates of Ctn assay sensitivity and the resection rate. The subgroup with Ctn 10–20 pg/mL showed a significantly lower MTC rate than the subgroup with Ctn 20–100 pg/mL. Conclusions The percentage of ICV among patients with thyroid nodules who underwent Ctn testing is negligible. The rate of MTC in patients with ICV cannot be overlooked. Among the ICV intervals, the risk of MTC increases significantly when Ctn is above 20 pg/mL.

Determinants of circulating calcitonin value: analysis of thyroid features, demographic data, anthropometric characteristics, comorbidities, medications, and smoking habits in a population with histological full exclusion of medullary thyroid carcinoma

“…In addition, the other parameters may be considered in specific cases in whom skewed Ctn cannot be explained according to gender and anthropometrics (e.g., men with small thyroid size). In any case, according to high-evidence data about ultrasound and FNAC ( 2 , 20 – 22 ), careful management of patients with indeterminate Ctn must be focused on to avoid false negatives, and the next international guidelines are advised to prepare specific recommendations ( 25 ). Finally, companies producing Ctn assay are advised to develop clinically useful thresholds to help the decision-making process.…”

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

“…It should be taken into account that other non-thyroid malignancies (i.e., neuroendocrine neoplasia) can produce Ctn [ 18 ]. The rate of patients with indeterminate serum Ctn values, between 10 and 100 pg/mL, is negligible (1.7%); however, the prevalence of MTC in this setting is close to 10%, increasing significantly above 20 pg/mL [ 19 ]. This is the reason why some experts adopted in clinical practice different cut-offs to differentiate micro-MTC from C-cell hyperplasia and other unspecific Ctn elevations, such as 30 pg/mL in females and 60 pg/mL in males [ 20 ].…”

“… Unfortunately, there is no consensus about fixed cut-off of basal Cnt to be used in clinical practice. This is mainly due to the wide heterogeneity among studies enrolling series with different MTC prevalence [ 19 , 21 – 24 ]. Ctn levels above 500 pg/mL preoperatively and/or above 150 pg/mL postoperatively are suspicious for metastatic MTC, making necessary further imaging to rule out disease outside the neck [ 3 , 9 ].…”

“…Unfortunately, there is no consensus about fixed cut-off of basal Cnt to be used in clinical practice. This is mainly due to the wide heterogeneity among studies enrolling series with different MTC prevalence [ 19 , 21 – 24 ].…”

“…The clinical management of these cases can be challenging. The prevalence of indeterminate serum Ctn levels, however, is very low (<2%); whereas MTC prevalence is not negligible in this setting (around 10%), and increases with increasing serum Ctn levels [ 19 ]. Once interfering factors are ruled out, further diagnostic work-up can be discussed with both patient and surgeon considering the following issues: Serum Ctn levels are associated with the probability of MTC [ 3 ]; Serum Ctn levels correlate, in general, with the tumor burden.…”