Calculation and validation of a plasma calcitonin limit for early detection of medullary thyroid carcinoma in nodular thyroid disease

Abstract

Background: The early diagnosis of medullary thyroid carcinoma (MTC) is crucial for effective therapy. Elevated plasma calcitonin concentrations (pCT-Cs) are generally a specific and sensitive indicator for C-cell hyperplasia or MTC. The presence of thyroid nodules raises the possibility of MTC. Hence, in endemic goiter regions, there is a need for information regarding the pCT-C values that are indicative of C-cell hyperplasia or MTC. The aim of this study, therefore, was to determine an upper pCT-C to distinguish patients with and without MTC in a collective with nodular thyroid disease, and to give an estimation of the prevalence of MTC in an endemic goiter area.

Methods: Basal pCT-C was measured in 21,928 patients with thyroid nodules living in central Germany, an area with endemic goiter due to previous iodine deficiency. In 218 subjects with pCT-Cs exceeding 10 ng/L, stimulated pCT-C was additionally determined, as suggested by the German consensus recommendation. A nominal normal range for basal pCT-C was calculated with data from 21,900 subjects without known MTC. The predicted upper limit was then validated using the known diagnoses of 376 patients with pCT-Cs exceeding 10 ng/L, 28 of whom presented with MTC.

Results: For basal pCT-C, calculation of the three-sigma borders after logarithmic transformation revealed upper limits of the nominal normal range of 14.6 ng/L in females and 32.8 ng/L in males, respectively. However, three male patients with small MTCs had basal pCT-Cs between 15 and 33 ng/L. None of the patients with MTC had a basal pCT-C below 15 ng/L or an increase in pCT-C after pentagastrin stimulation that was less than 80 ng/L. In the basal pCT-C range between 15 and 50 ng/L (n = 192; eight with MTC), the positive predictive value for the detection of MTC was 4% in our group. Applying an upper limit for basal pCT-C of 15 ng/L in both sexes, 329 of the total of 21,928 patients exceeded this range. Among these, the final outcome is known in 231 subjects, including all 28 MTCs.

Conclusions: An upper limit of 15 ng/L instead of 10 ng/L for basal pCT-C is able to detect all MTC and reduce false-positive cases. The prevalence of MTC in nodular thyroid disease in our group was approximately 1.8 per thousand.