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Meta-Analysis
. 2020 Mar 16;3(3):CD010159.
doi: 10.1002/14651858.CD010159.pub2.

Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules

Hans Hg Verbeek  1 , Jan Willem B de Groot  2 , Wim J Sluiter  3 , Anneke C Muller Kobold  4 , Edwin R van den Heuvel  5 , John Tm Plukker  6 , Thera P Links  1
Affiliations
Meta-Analysis

Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules

Hans Hg Verbeek et al. Cochrane Database Syst Rev. .

Abstract

Background: Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable.

Objectives: The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules.

Search methods: We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018.

Selection criteria: We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed).

Data collection and analysis: Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible.

Main results: 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) .

Authors' conclusions: 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.

PubMed Disclaimer

Conflict of interest statement

HHGV: none known. JWBdG: received personal fees for advisory roles from Bristol‐Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Pierre Fabre and Shire. WJS: none known. ACMK: none known. ERH: none known. JTMP: none known. TPL: none known.

Figures

1
1
The possible roles of calcitonin testing as triage (I), add‐on (II) or preoperative screening test (III) in the work‐up of thyroid nodules
2
2
Study flow diagram for selection of studies (search until June 2018).
3
3
Methodological quality graph: risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study
4
4
Forest plot showing sensitivity and specificity of reported basal calcitonin (bCT) cut‐off values (range 4.6 pg/mL to 100 pg/mL). (TP: true positive, FP: false positive, FN: false negative, TN: true negative, bCT: basal calcitonin). $Two different calcitonin assays were used during the study period, in which only 14 patients were measured with the second assay, therefore only the cut‐off value of 100 pg/mL was taken into account. # Gender‐specific cut‐off value was used (females: 4.6 pg/mL; males 11.5 pg/mL). * Two different assays with different cut‐off values were used during the study period.
5
5
Summary ROC Plot showing the summary curve of basal reported calcitonin cut‐off values (range 4.6 pg/mL to 100 pg/mL)
6
6
Forest plot showing sensitivity and specificity of basal calcitonin (bCT) cut‐off value of 10 pg/mL. (TP: true positive, FP: false positive, FN: false negative, TN: true negative, bCT: basal calcitonin)
7
7
Forest plot showing sensitivity and specificity of basal and stimulated reported calcitonin testing cut‐off values (range basal calcitonin 4.6 pg/mL to 35 pg/mL, range stimulated calcitonin 50 pg/mL to 100 pg/mL). (TP: true positive, FP: false positive, FN: false negative, TN: true negative, bCT: basal calcitonin, sCT stimulated calcitonin).# Gender‐specific cut‐off value was used (females: 4.6 pg/mL; males 11.5 pg/mL). * Two different assays with different cut‐off values were used during the study period.
8
8
Forest plot of basal calcitonin testing reported cut‐off values for females and males (range basal calcitonin 4.6 pg/mL to 35 pg/mL, range stimulated calcitonin 50 pg/mL to 100 pg/mL). (TP: true positive, FP: false positive, FN: false negative, TN: true negative, bCT: basal calcitonin).
1
1. Test
Basal reported cut‐off values.
2
2. Test
Basal calcitonin reported cut‐off values females.
3
3. Test
Basal calcitonin reported cut‐off values males.
4
4. Test
Basal and stimulated reported cut‐off values.
5
5. Test
Basal and stimulated reported calcitonin females.
6
6. Test
Basal and stimulated reported calcitonin males.
7
7. Test
Basal calcitonin and age 18‐39 years.
8
8. Test
Basal calcitonin and age 40‐49 years.
9
9. Test
Basal calcitonin and age 50‐64 years.
10
10. Test
Basal calcitonin and age > 65 years.
11
11. Test
Basal calcitonin 10 pg/mL.
12
12. Test
Basal calcitonin 10 pg/mL females.
13
13. Test
Basal calcitonin 10 pg/mL males.
14
14. Test
Basal calcitonin 10 pg/mL and basal or stimulated 100 pg/mL.
15
15. Test
Basal calcitonin 10 pg/mL and basal or stimulated 100 pg/mL females.
16
16. Test
Basal calcitonin 10 pg/mL and basal or stimulated 100 pg/mL males.
17
17. Test
Basal calcitonin 10 pg/mL and basal or stimulated 200 pg/mL.
18
18. Test
Basal calcitonin 10 pg/mL and basal or stimulated 200 pg/mL females.
19
19. Test
Basal calcitonin 10 pg/mL and basal or stimulated 200 pg/mL males.
20
20. Test
Basal calcitonin 15 pg/mL.
21
21. Test
Basal calcitonin 15 pg/mL females.
22
22. Test
Basal calcitonin 15 pg/mL males.
23
23. Test
Basal calcitonin 20 pg/mL.
24
24. Test
Basal calcitonin 20 pg/mL females.
25
25. Test
Basal calcitonin 20 pg/mL males.
26
26. Test
Basal calcitonin 20 pg/mL and basal or stimulated 100 pg/mL.
27
27. Test
Basal calcitonin 20 pg/mL and basal or stimulated 100 pg/mL females.
28
28. Test
Basal calcitonin 20 pg/mL and basal or stimulated 100 pg/mL males.
29
29. Test
Basal calcitonin 30 pg/mL.
30
30. Test
Basal calcitonin 30 pg/mL females.
31
31. Test
Basal calcitonin 30 pg/mL males.
32
32. Test
Basal calcitonin 50 pg/mL.
33
33. Test
Basal calcitonin 50 pg/mL females.
34
34. Test
Basal calcitonin 50 pg/mL males.
35
35. Test
Basal calcitonin 100 pg/mL.
36
36. Test
Basal calcitonin 100 pg/mL females.
37
37. Test
Basal calcitonin 100 pg/mL males.
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References

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