Annals of Surgical Oncology

, Volume 22, Issue 1, pp 96–102 | Cite as

Biochemical Cure after Reoperations for Medullary Thyroid Carcinoma: A Meta-analysis

  • Kathryn J. Rowland
  • Linda X. Jin
  • Jeffrey F. Moley
Endocrine Tumors



Despite meticulous surgical techniques, calcitonin levels remain detectable in 40 % to 66 % of patients after initial surgery for medullary thyroid carcinoma (MTC), and the optimal surgical management for persistent or recurrent disease remains controversial. Previous studies suggest that biochemical cure, defined by normalization of postoperative calcitonin measurements, predicts disease-free survival. Reoperative approaches range from targeted removal of detectable disease to comprehensive compartment-oriented lymph node clearance.


A proportional meta-analysis of clinical case series of postoperative calcitonin clearance after reoperation for MTC was performed. Studies were obtained from PubMed, Embase, Scopus, and the Cochrane Library.


Twenty-seven articles capturing data of 984 patients met the inclusion criteria for the meta-analysis. Overall, normalization of calcitonin after reoperation for MTC occurred in 16.2 % of patients [95 % confidence interval (CI) 14.0–18.5]. Stratified by operative procedure, targeted selective lymph node removal procedures had a normalization of calcitonin in 10.5 % of patients (95 % CI 6.4–14.7), while compartment-oriented procedures had a higher rate of normalization at 18.6 % (95 % CI 15.9–21.3).


The rate of calcitonin normalization after reoperation for MTC is enhanced through use of a meticulous compartment-oriented lymph node dissection. Compartment-oriented lymph node dissection results in calcitonin normalization in 18.6 % of reoperative MTC patients and is the procedure of choice in patients in whom the goal is biochemical cure.


Calcitonin Medullary Thyroid Carcinoma Calcitonin Level Recurrent Laryngeal Nerve Injury Biochemical Cure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



KJR was support by National Institutes of Health grant T32 CA009621.




  1. 1.
    Williams ED. Histogenesis of medullary carcinoma of the thyroid. J Clin Pathol. 1966;19:114–8.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Wells SA Jr, Baylin SB, Linehan WM, Farrell RE, Cox EB, Cooper CW. Provocative agents and the diagnosis of medullary carcinoma of the thyroid gland. Ann Surg. 1978;188:139–41.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Al-Rawi M, Wheeler MH. Medullary thyroid carcinoma—update and present management controversies. Ann R Coll Surg Engl. 2006;88:433–8.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Normann T. Medullary thyroid carcinoma in Norway. Acta Pathol Microbiol Scand A. 1977;85:775–86.PubMedGoogle Scholar
  5. 5.
    Ruggiero FP, Fedok FG. Outcomes in reoperative thyroid cancer. Otolaryngol Clin North Am. 2008;41:1261–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Fialkowski EA, Moley JF. Current approaches to medullary thyroid carcinoma, sporadic and familial. J Surg Oncol. 2006;94:737–47.PubMedCrossRefGoogle Scholar
  7. 7.
    Ukkat J, Gimm O, Brauckhoff M, Bilkenroth U, Dralle H. Single center experience in primary surgery for medullary thyroid carcinoma. World J Surg. 2004;28:1271–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Weber T, Schilling T, Frank-Raue K, et al. Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery. 2001;130:1044–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Rendl G, Manzl M, Hitzl W, Sungler P, Pirich C. Long-term prognosis of medullary thyroid carcinoma. Clin Endocrinol. 2008;69:497–505.CrossRefGoogle Scholar
  10. 10.
    Melvin KE, Miller HH, Tashjian AH Jr. Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N Engl J Med. 1971;285:1115–20.PubMedCrossRefGoogle Scholar
  11. 11.
    de Groot JW, Plukker JT, Wolffenbuttel BH, Wiggers T, Sluiter WJ, Links TP. Determinants of life expectancy in medullary thyroid cancer: age does not matter. Clin Endocrinol. 2006;65:729–36.PubMedCrossRefGoogle Scholar
  12. 12.
    Pellegriti G, Leboulleux S, Baudin E, et al. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer. 2003;88:1537–42.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Fialkowski E, Debenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg. 2008;32:754–65.PubMedCrossRefGoogle Scholar
  14. 14.
    Dotzenrath C, Goretzki PE, Cupisti K, et al. Is there any consensus in diagnostic and operative strategy with respect to medullary thyroid cancer? A questionnaire answered by 73 endocrine surgical units. Langenbecks Arch Surg. 2001;386:47–52.PubMedCrossRefGoogle Scholar
  15. 15.
    Abdelmoumene N, Schlumberger M, Gardet P, et al. Selective venous sampling catheterisation for localisation of persisting medullary thyroid carcinoma. Br J Cancer. 1994;69:1141–4.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Ben Mrad MD, Gardet P, Roche A, et al. Value of venous catheterization and calcitonin studies in the treatment and management of clinically inapparent medullary thyroid carcinoma. Cancer. 1989;63:133–8.Google Scholar
  17. 17.
    Block MA, Jackson CE, Tashjian AH Jr. Management of occult medullary thyroid carcinoma: evidenced only by serum calcitonin level elevations after apparently adequate neck operations. Arch Surg. 1978;113:368–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Brumsen C, Haak HR, Goslings BM, van de Velde CJ. Should patients with medullary thyroid carcinoma undergo extensive lymph node (re)operation to improve long-term survival? Henry Ford Hosp Med J. 1992;40:271–5.PubMedGoogle Scholar
  19. 19.
    Buhr HJ, Kallinowski F, Raue F, Frank-Raue K, Herfarth C. Microsurgical neck dissection for metastasizing medullary thyroid carcinoma. Eur J Surg Oncol. 1995;21:195–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Buhr HJ, Lehnert T, Raue F. New operative strategy in the treatment of metastasizing medullary carcinoma of the thyroid. Eur J Surg Oncol. 1990;16:366–9.PubMedGoogle Scholar
  21. 21.
    De Groot JWB, Links TP, Jager PL, Kahraman T, Plukker JTM. Impact of 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in patients with biochemical evidence of recurrent or residual medullary thyroid cancer. Ann Surg Oncol. 2004;11:786–94.PubMedCrossRefGoogle Scholar
  22. 22.
    De Groot JWB, Links TP, Sluiter WJ, Wolffenbuttel BHR, Wiggers T, Plukker JTM. Locoregional control in patients with palpable medullary thyroid cancer: results of standardized compartment-oriented surgery. Head Neck. 2007;29:857–63.PubMedCrossRefGoogle Scholar
  23. 23.
    De Labriolle-Vaylet C, Cattan P, Sarfati E, et al. Successful surgical removal of occult metastases of medullary thyroid carcinoma recurrences with the help of immunoscintigraphy and radioimmunoguided surgery. Clin Cancer Res. 2000;6:363–71.PubMedGoogle Scholar
  24. 24.
    Decker RA. Long-term follow-up of a large North American kindred with multiple endocrine neoplasia type 2A. Surgery. 1992;112:1066–72.PubMedGoogle Scholar
  25. 25.
    Dralle H, Damm I, Scheumann GF, Kotzerke J, Kupsch E. Frequency and significance of cervicomediastinal lymph node metastases in medullary thyroid carcinoma: results of a compartment-oriented microdissection method. Henry Ford Hosp Med J. 1992;40:264–7.PubMedGoogle Scholar
  26. 26.
    Dralle H, Damm I, Scheumann GF, et al. Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma. Surg Today. 1994;24:112–21.PubMedCrossRefGoogle Scholar
  27. 27.
    Duh QY, Sancho JJ, Greenspan FS, et al. Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy. Arch Surg. 1989;124:1206–10.PubMedCrossRefGoogle Scholar
  28. 28.
    Fleming JB, Lee JE, Bouvet M, et al. Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg. 1999;230:697–707.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Frank-Raue K, Raue F, Buhr HJ, Baldauf G, Lorenz D, Ziegler R. Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: high sensitivity of selective venous catheterization. Thyroid. 1992;2:113–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Gimm O, Dralle H. Reoperation in metastasizing medullary thyroid carcinoma: is a tumor stage-oriented approach justified? Surgery. 1997;122:1124–30.PubMedCrossRefGoogle Scholar
  31. 31.
    Gimm O, Ukkat J, Dralle H. Determinative factors of biochemical cure after primary and reoperative surgery for sporadic medullary thyroid carcinoma. World J Surg. 1998;22:562–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Goltzman D, Potts JT Jr, Ridgway RC, Maloof F. Calcitonin as a tumor marker. Use of the radioimmunoassay for calcitonin in the postoperative evaluation of patients with medullary thyroid carcinoma. N Engl J Med. 1974;290:1035–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Jeng TK, Lee CH, Wang HC, Chiu JW, Lui WY. DNA analysis and persistent hypercalcitoninemia in medullary thyroid carcinoma. Zhonghua Yi Xue Za Zhi (Taipei). 1993;51:340–4.PubMedGoogle Scholar
  34. 34.
    Kallinowski F, Buhr HJ, Meybier H, Eberhardt M, Herfarth C. Medullary carcinoma of the thyroid—therapeutic strategy derived from fifteen years of experience. Surgery. 1993;114:491–6.PubMedGoogle Scholar
  35. 35.
    Kebebew E, Kikuchi S, Duh QY, Clark OH. Long-term results of reoperation and localizing studies in patients with persistent or recurrent medullary thyroid cancer. Arch Surg. 2000;135:895–901.PubMedCrossRefGoogle Scholar
  36. 36.
    Machens A, Dralle H. Benefit–risk balance of reoperation for persistent medullary thyroid cancer. Ann Surg. 2013;257(4):751–7.Google Scholar
  37. 37.
    Marzano LA, Porcelli A, Biondi B, et al. Surgical management and follow-up of medullary thyroid carcinoma. J Surg Oncol. 1995;59:162–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Medina-Franco H, Herrera MF, López Ch G, et al. Persistent hypercalcitoninemia in patients with medullary thyroid cancer: a therapeutic approach based on selective venous sampling for calcitonin. Rev Invest Clin. 2001;53:212–7.PubMedGoogle Scholar
  39. 39.
    Misso C, Calzolari F, Puxeddu E, et al. Persistent hypercalcitoninemia in patients with medullary thyroid cancer. Tumori. 2009;95:484–7.PubMedGoogle Scholar
  40. 40.
    Moley JF, Dilley WG, Debenedetti MK. Improved results of cervical reoperation for medullary thyroid carcinoma. Ann Surg. 1997;225:734–43.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Moley JF, Wells SA, Dilley WG, Tisell LE. Reoperation for recurrent or persistent medullary thyroid cancer. Surgery. 1993;114:1090–5.PubMedGoogle Scholar
  42. 42.
    Norton JA, Doppman JL, Brennan MF. Localization and resection of clinically inapparent medullary carcinoma of the thyroid. Surgery. 1980;87:616–22.PubMedGoogle Scholar
  43. 43.
    O’Riordain DS, O’Brien T, Weaver AL, et al. Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery. 1994;116:1017–23.PubMedGoogle Scholar
  44. 44.
    Pelizzo MR, Bernante P, Piotto A, et al. The extent of surgery for thyroid medullary cancer. Tumori. 1994;80:427–32.PubMedGoogle Scholar
  45. 45.
    Raue F, Winter J, Frank-Raue K, Lorenz D, Herfarth C, Ziegler R. Diagnostic procedure before reoperation in patients with medullary thyroid carcinoma. Horm Metab Res Suppl. 1989;21:31–4.PubMedGoogle Scholar
  46. 46.
    Schott M, Willenberg HS, Sagert C, et al. Identification of occult metastases of medullary thyroid carcinoma by pentagastrin-stimulated intravenous calcitonin sampling followed by targeted surgery. Clin Endocrinol. 2007;66:405–9.CrossRefGoogle Scholar
  47. 47.
    Tisell LE, Hansson G, Jansson S, Salander H. Reoperation in the treatment of asymptomatic metastasizing medullary thyroid carcinoma. Surgery. 1986;99:60–6.PubMedGoogle Scholar
  48. 48.
    Tisell LE, Jansson S. Recent results of reoperative surgery in medullary carcinoma of the thyroid. Wien Klin Wochenschr. 1988;100:347–8.PubMedGoogle Scholar
  49. 49.
    van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg. 1990;212:395–400.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Vila JMF, Peix JL, Mandry AC, Mezzadri NA, Lifante JC. Biochemical results of reoperations for medullary thyroid carcinoma. Laryngoscope. 2007;117:886–9.CrossRefGoogle Scholar
  51. 51.
    Voutilainen PE, Multanen M, Haapiainen RK, Haglund CH, Sane T, Sivula AH. Long term prognosis of medullary thyroid carcinoma in 39 patients. Ann Chir Gynaecol. 2000;89:292–7.PubMedGoogle Scholar
  52. 52.
    Yen TW, Shapiro SE, Gagel RF, Sherman SI, Lee JE, Evans DB. Medullary thyroid carcinoma: results of a standardized surgical approach in a contemporary series of 80 consecutive patients. Surgery. 2003;134:890–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Cupisti K, Wolf A, Raffel A, et al. Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution’s experience over 20 years. Ann Surg. 2007;246:815–21.PubMedCrossRefGoogle Scholar
  54. 54.
    Moses L. The series of consecutive cases as a device for assessing outcomes of interventions. In: Bailar J, Hoaglin D, editors. Medical uses of statistics. 3rd ed. New York: Wiley; 2009. p. 109–22.Google Scholar
  55. 55.
    Meijer JA, le Cessie S, van den Hout WB, et al. Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clin Endocrinol. 2010;72:534–42.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Kathryn J. Rowland
    • 1
  • Linda X. Jin
    • 1
  • Jeffrey F. Moley
    • 1
  1. 1.Division of Endocrine and Oncologic Surgery, Department of Surgery, Barnes Jewish HospitalWashington University School of MedicineSt. LouisUSA

Personalised recommendations