Download PDF
Exp Clin Endocrinol Diabetes 2004; 112(1): 52-58
DOI: 10.1055/s-2004-815727
Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

Calcitonin Measurement to Detect Medullary Thyroid Carcinoma in Nodular Goiter: German Evidence-Based Consensus Recommendation

W. Karges 1 , H. Dralle 2 , F. Raue 3 , K. Mann 4 , C. Reiners 5 , M. Grussendorf 6 , M. Hüfner 7 , B. Niederle 8 , G. Brabant 9 , German Society for Endocrinology (DGE) - Thyroid Section
  • 1Department of Internal Medicine, University of Ulm, Ulm, Germany
  • 2Department of General Surgery, Martin Luther University of Halle-Wittenberg, Halle, Germany
  • 3Endokrinologische Gemeinschaftspraxis, Heidelberg, Germany
  • 4Department of Internal Medicine, University of Essen, Essen, Germany
  • 5Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany
  • 6Endokrinologische Praxis, Stuttgart, Germany
  • 7Department of Internal Medicine, University of Göttingen, Göttingen, Germany
  • 8Department of General Surgery, University of Vienna, Vienna, Austria
  • 9Department of Internal Medicine, MHH Medical School Hannover, Hannover, Germany
Further Information

Publication History

Received: March 11, 2003 First decision: May 23, 2003

Accepted: June 4, 2003

Publication Date:
03 February 2004 (online)

Also available at
    Permissions and Reprints

Abstract

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter.

To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

Key words

Calcitonin - medullary thyroid cancer - consensus - goiter - thyroid

References

  • 1 Bennedbaek F N, Perrild H, Hegedus L. Diagnosis and treatment of the solitary thyroid nodule. Results of a European survey.  Clin Endocrinol (Oxf). 1999;  50 357-363
    CrossrefPubMedSearch in Google Scholar
  • 2 Bieglmayer C, Niederle B, Vierhapper H. Interference causes false high calcitonin levels with a commercial assay (Letter).  J Endocrinol Invest. 2002 a;  25 197
    PubMedSearch in Google Scholar
  • 3 Bieglmayer C, Scheuba C, Niederle B, Flores J, Vierhapper H. Screening for medullary thyroid carcinoma: experience with different immunoassays for human calcitonin.  Wien Klin Wochenschr. 2002 b;  114 267-273
    PubMedSearch in Google Scholar
  • 4 Brandi M L, Gagel R F, Angeli A, Bilezikian J P, Beck-Peccoz P, Bordi C, Conte-Devolx B, Falchetti A, Gheri R G, Libroia A, Lips C J, Lombardi G, Mannelli M, Pacini F, Ponder B A, Raue F, Skogseid B, Tamburrano G, Thakker R V, Thompson N W, Tomassetti P, Tonelli F, Wells Jr S A. Marx SJ. Guidelines for diagnosis and therapy of MEN type 1 and type 2.  J Clin Endocrinol Metab. 2001;  86 5658-5671
    CrossrefPubMedSearch in Google Scholar
  • 5 Brauckhoff M, Gimm O, Brauckhoff K, Ukkat J, Thomusch O, Dralle H. Calcitonin kinetics in the early postoperative period of medullary thyroid carcinoma.  Langenbecks Arch Surg. 2001;  386 434-439
    CrossrefPubMedSearch in Google Scholar
  • 6 Cohen R, Campos J M, Salaun C, Heshmati H M, Kraimps J L, Proye C, Sarfati E, Henry J F, Niccoli-Sire P, Modigliani E. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. Groupe d'Etudes des Tumeurs à Calcitonine (GETC).  J Clin Endocrinol Metab. 2000;  85 919-922
    CrossrefPubMedSearch in Google Scholar
  • 7 Delbridge L, Robinson B. Genetic and biochemical screening for endocrine disease: III. Costs and logistics.  World J Surg. 1998;  22 1212-1217
    CrossrefPubMedSearch in Google Scholar
  • 8 d'Herbomez M, Leclerc L, Vantyghem M C, Fourrier F, Proye C, Wemeau J L. Clinical evaluation of a new sensitive calcitonin assay: study of specificity.  Clin Chim Acta. 2001;  311 149-155
    CrossrefPubMedSearch in Google Scholar
  • 9 Dunn J T. When is a thyroid nodule a sporadic medullary carcinoma?.  J Clin Endocrinol Metab. 1994;  78 824-825
    CrossrefPubMedSearch in Google Scholar
  • 10 Engelbach M, Gorges R, Forst T, Pfutzner A, Dawood R, Heerdt S, Kunt T, Bockisch A, Beyer J. Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements.  J Clin Endocrinol Metab. 2000;  85 1890-1894
    CrossrefPubMedSearch in Google Scholar
  • 11 Erdogan M F, Gullu S, Baskal N, Uysal A R, Kamel N, Erdogan G. Omeprazole: calcitonin stimulation test for the diagnosis follow-up and family screening in medullary thyroid carcinoma.  J Clin Endocrinol Metab. 1997;  82 897-899
    CrossrefPubMedSearch in Google Scholar
  • 12 Escalada J, Teruel J L, Pavon I, Vila T, Navarro J, Varela C. Normal calcitonin response to pentagastrin stimulation in patients with chronic renal failure.  Acta Endocrinol. 1993;  129 39-41
    PubMedSearch in Google Scholar
  • 13 Gimm O, Sutter T, Dralle H. Diagnosis and therapy of sporadic and familial medullary thyroid carcinoma.  J Cancer Res Clin Oncol. 2001;  127 156-165
    CrossrefPubMedSearch in Google Scholar
  • 14 Grauer A, Raue F, Ziegler R. Clinical usefulness of a new chemiluminescent two-site immunoassay for human calcitonin.  Exp Clin Endocrinol Diabetes. 1998;  106 353-359
    PubMedSearch in Google Scholar
  • 15 Guyetant S, Wion-Barbot N, Rousselet M C, Franc B, Bigorgne J C, Saint-Andre J P. C-cell hyperplasia associated with chronic lymphocytic thyroiditis: a retrospective quantitative study of 112 cases.  Hum Pathol. 1994;  25 514-521
    CrossrefPubMedSearch in Google Scholar
  • 16 Guyetant S, Rousselet M C, Durigon M, Chappard D, Franc B, Guerin O, Saint-Andre J P. Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study.  J Clin Endocrinol Metab. 1997;  82 42-47
    CrossrefPubMedSearch in Google Scholar
  • 17 Hahm J R, Lee M S, Min Y K, Lee M K, Kim K W, Nam S J, Yang J H, Chung J H. Routine measurement of serum calcitonin is useful for early detection of medullary thyroid carcinoma in patients with nodular thyroid diseases.  Thyroid. 2001;  11 73-80
    CrossrefPubMedSearch in Google Scholar
  • 18 Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines.  BMJ. 2001;  323 334-336
    PubMedSearch in Google Scholar
  • 19 Hinze R, Gimm O, Brauckhoff M, Schneyer U, Dralle H, Holzhausen H J. “Physiologische” und “neoplastische” C-Zell-Hyperplasien der Schilddrüse. Morphologisch und biologisch distinkte Entitäten?.  Pathologe. 2001;  22 259-265
    CrossrefPubMedSearch in Google Scholar
  • 20 Horvit P K, Gagel R F. The goitrous patient with an elevated serum calcitonin - what to do?.  J Clin Endocrinol Metab. 1997;  82 335-337
    CrossrefPubMedSearch in Google Scholar
  • 21 Iacobone M, Niccoli-Sire P, Sebag F, De Micco C, Henry J F. Can sporadic medullary thyroid carcinoma be biochemically predicted? Prospective analysis of 66 operated patients with elevated serum calcitonin levels.  World J Surg. 2002;  26 886-890
    CrossrefPubMedSearch in Google Scholar
  • 22 Kaserer K, Scheuba C, Neuhold N, Weinhausel A, Vierhapper H, Haas O A, Niederle B. C-cell hyperplasia and medullary thyroid carcinoma in patients routinely screened for serum calcitonin.  Am J Surg Pathol. 1998;  22 722-728
    CrossrefPubMedSearch in Google Scholar
  • 23 Kaserer K, Scheuba C, Neuhold N, Weinhausel A, Vierhapper H. Recommendations for reporting C cell pathology of the thyroid.  Wien Klin Wochenschr. 2002;  114 274-278
    PubMedSearch in Google Scholar
  • 24 Kotzmann H, Schmidt A, Scheuba C, Kaserer K, Watschinger B, Soregi G, Niederle B, Vierhapper H. Basal calcitonin levels and the response to pentagastrin stimulation in patients after kidney transplantation or on chronic hemodialysis as indicators of medullary carcinoma.  Thyroid. 1999;  9 943-947
    CrossrefPubMedSearch in Google Scholar
  • 25 Lips C J, Hoppener J W, Thijssen J H. Medullary thyroid carcinoma: role of genetic testing and calcitonin measurement.  Ann Clin Biochem. 2001;  38 168-179
    CrossrefPubMedSearch in Google Scholar
  • 26 Lissak B, Baudin E, Cohen R, Barbot N, Meyrier A, Niccoli P, Bouyge N, Modigliani E. Pentagastrin testing in patients with renal insufficiency: normal responsivity of mature calcitonin.  Thyroid. 1998;  8 265-268
    CrossrefPubMedSearch in Google Scholar
  • 27 LiVolsi V A. C cell hyperplasia/neoplasia.  J Clin Endocrinol Metab. 1997;  82 39-41
    CrossrefPubMedSearch in Google Scholar
  • 28 Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U, Dralle H. Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis.  Cancer. 2000 a;  88 1909-1915
    CrossrefPubMedSearch in Google Scholar
  • 29 Machens A, Haedecke J, Holzhausen H J, Thomusch O, Schneyer U, Dralle H. Differential diagnosis of calcitonin-secreting neuroendocrine carcinoma of the foregut by pentagastrin stimulation.  Langenbecks Arch Surg. 2000 b;  385 398-401
    CrossrefPubMedSearch in Google Scholar
  • 30 Machens A, Hinze R, Thomusch O, Dralle H. Pattern of nodal metastasis for primary and reoperative thyroid cancer.  World J Surg. 2002;  26 22-28
    CrossrefPubMedSearch in Google Scholar
  • 31 Niccoli P, Brunet P, Roubicek C, Roux F, Baudin E, Lejeune P J, Berland Y, Conte-Devolx B. Abnormal calcitonin basal levels and pentagastrin response in patients with chronic renal failure on maintenance hemodialysis.  Eur J Endocrinol. 1995;  132 75-81
    PubMedSearch in Google Scholar
  • 32 Niccoli P, Wion-Barbot N, Caron P, Henry J F, de-Micco C, Saint-Andre J P, Bigorgne J C, Modigliani E, Conte-Devolx B. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group.  J Clin Endocrinol Metab. 1997;  82 338-341
    CrossrefPubMedSearch in Google Scholar
  • 33 Ozgen A G, Hamulu F, Bayraktar F, Yilmaz C, Tuzun M, Yetkin E, Tuncyurek M, Kabalak T. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter.  Thyroid. 1999;  9 579-582
    PubMedSearch in Google Scholar
  • 34 Pacini F, Fontanelli M, Fugazzola L, Elisei R, Romei C, Di-Coscio G, Miccoli P, Pinchera A. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma.  J Clin Endocrinol Metab. 1994;  78 826-829
    CrossrefPubMedSearch in Google Scholar
  • 35 Peix J L, Braun P, Saadat M, Berger N, El-Khazen M, Mancini F. Occult micro medullary thyroid carcinoma: therapeutic strategy and follow-up.  World J Surg. 2000;  24 1373-1376
    CrossrefPubMedSearch in Google Scholar
  • 36 Perry A, Molberg K, Albores-Saavedra J. Physiologic versus neoplastic C-cell hyperplasia of the thyroid: separation of distinct histologic and biologic entities.  Cancer. 1996;  77 750-756
    CrossrefPubMedSearch in Google Scholar
  • 37 Raue F, Zink A, Scherubl H. Regulation of calcitonin secretion and calcitonin gene expression.  Recent Results in Cancer Research. Berlin; Springer 1992: 1-18
    Search in Google Scholar
  • 38 Raue F. Routine calcitonin determination in thyroid nodules - an effective approach?.  Exp Clin Endocrinol Diabetes. 1998;  106 289-291
    Thieme ConnectPubMedSearch in Google Scholar
  • 39 Redding A H, Levine S N, Fowler M R. Normal preoperative calcitonin levels do not always exclude medullary thyroid carcinoma in patients with large palpable thyroid masses.  Thyroid. 2000;  10 919-922
    PubMedSearch in Google Scholar
  • 40 Rieu M, Lame M C, Richard A, Lissak B, Sambort B, Vuong-Ngoc P, Berrod J L, Fombeur J P. Prevalence of sporadic medullary thyroid carcinoma: the importance of routine measurement of serum calcitonin in the diagnostic evaluation of thyroid nodules.  Clin Endocrinol. 1995;  42 453-460
    CrossrefPubMedSearch in Google Scholar
  • 41 Rosai J, Carangiu M, DeLellis R A. Tumors of the thyroid gland.  Atlas of Tumor Pathology. Washington DC; Armed Forces Institute of Pathology 1992: 247-258
    Search in Google Scholar
  • 42 Saller B, Gorges R, Reinhardt W, Haupt K, Janssen O, Mann K. Sensitive calcitonin measurement by two-site immunometric assays: implications for calcitonin screening in nodular thyroid disease.  Clin Lab. 2002;  48 191-200
    PubMedSearch in Google Scholar
  • 43 Scheuba C, Kaserer K, Weinhausl A, Pandev R, Kaider A, Passler C, Prager G, Vierhapper H, Haas O A, Niederle B. Is medullary thyroid cancer predictable? A prospective study of 86 patients with abnormal pentagastrin tests.  Surgery. 1999;  126 1089-1095 discussion 1096-1096
    Search in Google Scholar
  • 44 Scheuba C, Kaserer K, Kotzmann H, Bieglmayer C, Niederle B, Vierhapper H. Prevalence of C-cell hyperplasia in patients with normal basal and pentagastrin-stimulated calcitonin.  Thyroid. 2000;  10 413-416
    PubMedSearch in Google Scholar
  • 45 Schmid K W, Ensinger C. “Atypical” medullary thyroid carcinoma with little or no calcitonin expression.  Virchows Arch. 1998;  433 209-215
    CrossrefPubMedSearch in Google Scholar
  • 46 Sheppard M C. Should serum calcitonin be measured routinely in all patients with nodular thyroid disease?.  Clin Endocrinol. 1995;  42 451-452
    PubMedSearch in Google Scholar
  • 47 SIGN .SIGN 50: a guideline developers' handbook (Edinburgh, SIGN www.sign.ac.uk/guidelines). 2001
    Search in Google Scholar
  • 48 Tommasi M, Brocchi A, Cappellini A, Raspanti S, Mannelli M. False serum calcitonin high levels using a non-competitive two-site IRMA.  J Endocrinol Invest. 2001;  24 356-360
    PubMedSearch in Google Scholar
  • 49 Uwaifo G I, Remaley A T, Stene M, Reynolds J C, Yen P M, Snider R H, Becker K L, Sarlis N J. 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. 2001;  24 361-369
    PubMedSearch in Google Scholar
  • 50 Vierhapper H, Raber W, Bieglmayer C, Kaserer K, Weinhausl A, Niederle B. Routine measurement of plasma calcitonin in nodular thyroid diseases.  J Clin Endocrinol Metab. 1997;  82 1589-1593
    CrossrefPubMedSearch in Google Scholar
  • 51 Vitale G, Ciccarelli A, Caraglia M, Galderisi M, Rossi R, Del-Prete S, Abbruzzese A, Lupoli G. Comparison of two provocative tests for calcitonin in medullary thyroid carcinoma: omeprazole vs pentagastrin.  Clin Chem. 2002;  48 1505-1510
    PubMedSearch in Google Scholar
  • 52 Vlaeminck-Guillem V, D'Herbomez M, Pigny P, Fayard A, Bauters C, Decoulx M, Wemeau J L. Pseudohypoparathyroidism Ia and hypercalcitoninemia.  J Clin Endocrinol Metab. 2001;  86 3091-3096
    CrossrefPubMedSearch in Google Scholar
  • 53 Whang K T, Steinwald P M, White J C, Nylen E S, Snider R H, Simon G L, Goldberg R L, Becker K L. Serum calcitonin precursors in sepsis and systemic inflammation.  J Clin Endocrinol Metab. 1998;  83 3296-3301
    CrossrefPubMedSearch in Google Scholar

PD Dr. med. Wolfram Karges

Department of Internal Medicine 1 · University of Ulm

Robert-Koch-Straße 8

89081 Ulm

Germany

Phone: + 4973150024732

Fax: + 49 7 31 50 02 43 02

Email: wolfram.karges@medizin.uni-ulm.de