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Determination of calcitonin levels in C-cell disease: clinical interest and potential pitfalls

Nature Clinical Practice Endocrinology & Metabolism volume 5, pages 35–44 (2009)Cite this article

Abstract

An elevated serum calcitonin level is a highly sensitive marker for medullary thyroid carcinoma (MTC) that can be used for screening, differential diagnosis, prognostic assessment, follow-up monitoring, and assessment of treatment response. Nevertheless, additional data are required to definitively support routine measurement of calcitonin levels in the initial work-up of patients with thyroid nodules, mainly because there is no convincing evidence that such testing actually reduces MTC-related mortality. By contrast, the prognostic value of measuring calcitonin levels preoperatively, postoperatively, and during follow-up of patients with MTC is widely acknowledged. Furthermore, determination of calcitonin levels is also used to evaluate the response of MTC to novel forms of systemic treatment, such as tyrosine kinase inhibitors. In this Review, we discuss the key issues surrounding the use of this laboratory test in the clinical management of patients with MTC.

Key Points

  • Serum calcitonin is a highly sensitive marker for medullary thyroid cancer

  • More evidence is necessary before routine calcitonin screening can be recommended in the initial management of thyroid nodular disease

  • Calcitonin screening for detection of medullary thyroid cancer in patients with thyroid nodules requires the availability of provocative tests (i.e. pentagastrin stimulation)

  • Calcitonin measurement can be used as a prognostic marker in postoperative follow-up of patients with medullary thyroid cancer

  • Determination of the calcitonin level is widely used to assess the efficacy of systemic treatment

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Figure 1: Preoperative calcitonin levels in patients with either C-cell hyperplasia or medullary thyroid carcinoma.
Figure 2: Correlation between serum calcitonin levels and disease progression.

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References

  1. Foster GV et al. (1964) Thyroid origin of calcitonin. Nature 202: 1303–1305

    Article  CAS  Google Scholar 

  2. Melvin KE et al. (1971) Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med 285: 1115–1120

    Article  CAS  Google Scholar 

  3. Pacini F et al. (2006) European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154: 787–803

    Article  CAS  Google Scholar 

  4. Cooper DS et al. (2006) Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16: 109–142

    Article  Google Scholar 

  5. AACE/AME Task Force on Thyroid Nodules (2006) American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 12: 63–102

  6. Leboulleux S et al. (2004) Medullary thyroid carcinoma. Clin Endocrinol (Oxf) 61: 299–310

    Article  Google Scholar 

  7. Baloch Z et al. (2003) Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13: 3–126

    Article  Google Scholar 

  8. Becker KL et al. (2004) Clinical review 167: procalcitonin and the calcitonin gene family of peptides in inflammation, infection, and sepsis: a journey from calcitonin back to its precursors. J Clin Endocrinol Metab 89: 1512–1525

    Article  CAS  Google Scholar 

  9. Leboeuf R et al. (2006) “Hook effect” in calcitonin immunoradiometric assay in patients with metastatic medullary thyroid carcinoma: case report and review of the literature. J Clin Endocrinol Metab 91: 361–364

    Article  CAS  Google Scholar 

  10. d'Herbomez M et al. (2007) Reference range of serum calcitonin levels in humans: influence of calcitonin assays, sex, age, and cigarette smoking. Eur J Endocrinol 157: 749–755

    Article  CAS  Google Scholar 

  11. Basuyau JP et al. (2004) Reference intervals for serum calcitonin in men, women, and children. Clin Chem 50: 1828–1830

    Article  CAS  Google Scholar 

  12. Tommasi M et al. (2001) False serum calcitonin high levels using a non-competitive two-site IRMA. J Endocrinol Invest 24: 356–360

    Article  CAS  Google Scholar 

  13. Uwaifo GI et al. (2001) A case of spurious hypercalcitoninemia: a cautionary tale on the use of plasma calcitonin assays in the screening of patients with thyroid nodules for neoplasia. J Endocrinol Invest 24: 361–369

    Article  CAS  Google Scholar 

  14. Wells SA Jr et al. (1978) Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg 188: 139–141

    Article  Google Scholar 

  15. Leboulleux S et al. (1999) Gastroenteropancreatic neuroendocrine tumor metastases to the thyroid gland: differential diagnosis with medullary thyroid carcinoma. Eur J Endocrinol 140: 187–191

    Article  CAS  Google Scholar 

  16. Verdy M et al. (1978) Calcium infusion and pentagastrin injection in diagnosis of medullary thyroid carcinoma. Can Med Assoc J 119: 29–35

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gharib H et al. (1987) Determination of silica-purified plasma calcitonin for the detection and management of medullary thyroid carcinoma: comparison of two provocative tests. Mayo Clin Proc 62: 373–378

    Article  CAS  Google Scholar 

  18. O'Connell JE et al. (1990) A comparison of calcium pentagastrin and TRH tests in screening for medullary carcinoma of the thyroid in MEN IIA. Clin Endocrinol (Oxf) 32: 417–421

    Article  CAS  Google Scholar 

  19. Russo D et al. (2004) Multiple endocrine neoplasia type 2. In Update in neuroendocrinology. From basic research to clinical practice, 292–296 (Eds Tamburano G et al.) Rome: Pubblicazioni Medico Scientifiche

    Google Scholar 

  20. Pacini F et al. (1994) Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 78: 826–829

    CAS  PubMed  Google Scholar 

  21. Rieu M et al. (1995) Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules. Clin Endocrinol (Oxf) 42: 453–460

    Article  CAS  Google Scholar 

  22. Niccoli P et al. (1997) Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab 82: 338–341

    Article  CAS  Google Scholar 

  23. Vierhapper H et al. (1997) Routine measurement of plasma calcitonin in nodular thyroid diseases. J Clin Endocrinol Metab 82: 1589–1593

    Article  CAS  Google Scholar 

  24. Ozgen AG et al. (1999) Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter. Thyroid 9: 579–582

    Article  CAS  Google Scholar 

  25. Hahm JR et al. (2001) Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases. Thyroid 11: 73–80

    Article  CAS  Google Scholar 

  26. Iacobone M et al. (2002) Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels. World J Surg 26: 886–890

    Article  Google Scholar 

  27. Elisei R et al. (2004) Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89: 163–168

    Article  CAS  Google Scholar 

  28. Karanikas G et al. (2004) Frequency and relevance of elevated calcitonin levels in patients with neoplastic and nonneoplastic thyroid disease and in healthy subjects. J Clin Endocrinol Metab 89: 515–519

    Article  CAS  Google Scholar 

  29. Gibelin H et al. (2005) Increased calcitonin level in thyroid nodules without medullary carcinoma. Br J Surg 92: 574–578

    Article  CAS  Google Scholar 

  30. Vierhapper H et al. (2005) Early diagnosis and curative therapy of medullary thyroid carcinoma by routine measurement of serum calcitonin in patients with thyroid disorders. Thyroid 15: 1267–1272

    Article  CAS  Google Scholar 

  31. Papi G (2006) Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest 29: 427–437

    Article  CAS  Google Scholar 

  32. Costante G et al. (2007) Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab 92: 450–455

    Article  CAS  Google Scholar 

  33. Yen TW et al. (2003) Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery 134: 890–899

    Article  Google Scholar 

  34. Scheuba C et al. (1999) Is medullary thyroid cancer predictable? A prospective study of 86 patients with abnormal pentagastrin tests. Surgery 126: 1089–1095

    Article  CAS  Google Scholar 

  35. Borget I et al. (2007) Editorial: Calcitonin determination in patients with nodular thyroid disease. J Clin Endocrinol Metab 92: 425–427

    Article  CAS  Google Scholar 

  36. Cheung K et al. (2008) Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab 93: 2173–2180

    Article  CAS  Google Scholar 

  37. Hodak SP and Burman KD (2004) The calcitonin conundrum—is it time for routine measurement of serum calcitonin in patients with thyroid nodules? J Clin Endocrinol Metab 89: 511–514

    Article  CAS  Google Scholar 

  38. Castro MR and Gharib H (2005) Continuing controversies in the management of thyroid nodules. Ann Intern Med 142: 926–931

    Article  Google Scholar 

  39. US Preventive Services Task Force (2008) Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med 149: 185–191

  40. Lin K et al. (2008) Benefits and harms of prostate-specific antigen screening for prostate cancer: an evidence update for the US Preventive Services Task Force. Ann Intern Med 149: 192–199

    Article  Google Scholar 

  41. Eng C et al. (2001) Genetic testing for cancer predisposition. Annu Rev Med 52: 371–400

    Article  CAS  Google Scholar 

  42. Russo D et al. (1997) A case of metastatic medullary thyroid carcinoma: early identification before surgery of an RET proto-oncogene somatic mutation in fine-needle aspirate specimens. J Clin Endocrinol Metab 82: 3378–3382

    CAS  PubMed  Google Scholar 

  43. Machens A and Dralle H (2007) Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 31: 957–968

    Article  Google Scholar 

  44. Frank-Raue K et al. (2006) Long-term outcome in 46 gene carriers of hereditary medullary thyroid carcinoma after prophylactic thyroidectomy: impact of individual RET genotype. Eur J Endocrinol 155: 229–236

    Article  CAS  Google Scholar 

  45. Machens A et al. (2005) Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 90: 2029–2034

    Article  CAS  Google Scholar 

  46. Scheuba C et al. (2007) Medullary thyroid microcarcinoma recommendations for treatment—a single-center experience. Surgery 142: 1003–1010

    Article  Google Scholar 

  47. Cohen R et al. (2000) Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs a Calcitonine (GETC). J Clin Endocrinol Metab 85: 919–922

    Article  CAS  Google Scholar 

  48. Machens A et al. (2008) Medullary thyroid cancer responsiveness to pentagastrin stimulation: an early surrogate parameter of tumor dissemination? J Clin Endocrinol Metab 93: 2234–2238

    Article  CAS  Google Scholar 

  49. Brauckhoff M et al. (2001) Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma. Langenbecks Arch Surg 386: 434–439

    Article  CAS  Google Scholar 

  50. Modigliani E et al. (1998) Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine. Clin Endocrinol (Oxf) 48: 265–273

    Article  CAS  Google Scholar 

  51. Kebebew E et al. (2000) Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88: 1139–1148

    Article  CAS  Google Scholar 

  52. van Heerden JA et al. (1990) Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212: 395–400

    Article  CAS  Google Scholar 

  53. Pellegriti G et al. (2003) Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer 88: 1537–1542

    Article  CAS  Google Scholar 

  54. Giraudet AL et al. (2007) Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab 92: 4185–4190

    Article  CAS  Google Scholar 

  55. Therasse P et al. (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92: 205–216

    Article  CAS  Google Scholar 

  56. Giraudet AL et al. (2008) Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol 158: 239–246

    Article  CAS  Google Scholar 

  57. Barbet J et al. (2005) Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 90: 6077–6084

    Article  CAS  Google Scholar 

  58. Wang TS et al. (2008) Medullary thyroid carcinoma without marked elevation of calcitonin: a diagnostic and surveillance dilemma. Thyroid 18: 889–894

    Article  CAS  Google Scholar 

  59. Dora JM et al. (2008) Normal perioperative serum calcitonin levels in patients with advanced medullary thyroid carcinoma: case report and review of the literature. Thyroid 18: 895–899

    Article  CAS  Google Scholar 

  60. Schlumberger M et al. (2008) New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 4: 22–32

    Article  CAS  Google Scholar 

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Acknowledgements

The work of S Filetti is supported by grants from the Italian Ministry of Universities and Research (PRIN), the Fondazione Umberto Di Mario ONLUS and the Banca d'Italia.

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Authors and Affiliations

  1. G Costante is an Assistant Professor at the University “Magna Graecia”, Catanzaro, Italy,

    Giuseppe Costante

  2. C Durante is a Postdoctoral Fellow and S Filetti is a Professor of Internal Medicine and Chairman of the Department of Internal Medicine at the University “Sapienza”, Rome, Italy.,

    Cosimo Durante & Sebastiano Filetti

  3. Z Francis is a Resident in the Department of Nuclear Medicine and Endocrine Oncology at the Institut Gustave Roussy, Villejuif, France.,

    Zélia Francis

  4. Paris and Chairman of the Department of Nuclear Medicine and Endocrine Oncology, M Schlumberger is a Professor of Oncology at the University Paris-Sud 11, Institut Gustave Roussy, Villejuif, France.,

    Martin Schlumberger

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  1. Giuseppe Costante
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Correspondence to Sebastiano Filetti.

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Costante, G., Durante, C., Francis, Z. et al. Determination of calcitonin levels in C-cell disease: clinical interest and potential pitfalls. Nat Rev Endocrinol 5, 35–44 (2009). https://doi.org/10.1038/ncpendmet1023

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