Abstract: In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Plain-language summary: We searched for evidence in the literature until June 2018 and identified a total of 16 studies. Studies were included if a routine calcitonin test (with or without the stimulation test) was performed in all included people with thyroid nodular disease. In total 72,638 people with thyroid nodular disease were enrolled in the analysed studies, of which 187 had medullary thyroid carcinoma. Our findings indicate that both basal and stimulated calcitonin testing are able to detect nearly all people with medullary thyroid carcinoma. However, because medullary thyroid carcinoma is very rare in persons with a thyroid nodule, there is large chance that calcitonin levels are false positives (i.e. the test indicates the disease, whereas in fact there is none). In practice this means that for every 10,000 persons with thyroid nodular disease, 23 persons will have medullary thyroid carcinoma. Of these, none will be missed using a basal calcitonin threshold of 10 pg/mL, while 280 people will have a false-positive test result. This might lead to unnecessary surgery of the thyroid with the need for life-long thyroid hormone supplementation and risk of complications. With the use of a stimulation test the chance of a false-positive test result may be reduced, however due to lack of sufficient studies this could not be calculated. The certainty of the evidence is importantly limited, because almost all studies did not report adequately on the outcome of people who had a negative calcitonin test. A number of patients who had medullary thyroid carcinoma were possibly not identified. The diagnostic accuracy can already be markedly affected when a small number of patients is missed because medullary thyroid carcinoma is very rare. Based on the available literature, there is insufficient evidence for a routine calcitonin test in all people with a thyroid nodule. Further studies are needed, with also adequate reporting of the people who have a negative calcitonin test, to determine the role of the calcitonin test in people with thyroid nodules for detection of medullary thyroid carcinoma.