Distinguishing synchronous from metachronous manifestation of distant metastases: a prognostic feature in differentiated thyroid carcinoma

  • Amir Sabet
  • Ina Binse
  • Semih Dogan
  • Andrea Koch
  • Sandra J. Rosenbaum-Krumme
  • Hans-Jürgen Biersack
  • Kim Biermann
  • Samer EzziddinEmail author
Original Article



Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC.


We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7–11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring >12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan–Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p < 0.05.


The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of <45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type.


Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.


Differentiated thyroid cancer Radioiodine therapy Risk stratification Distant metastases 


Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Research involving human participants and/or animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not contain any studies with animals.

Informed consent

For this type of study, formal consent is not required.


  1. 1.
    Sherman SI. Thyroid carcinoma. Lancet. 2003;361:501–11.CrossRefGoogle Scholar
  2. 2.
    Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid. 2016;26:1–133. doi: 10.1089/thy.2015.0020.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214. doi: 10.1089/thy.2009.0110.CrossRefGoogle Scholar
  4. 4.
    Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16:109–42. doi: 10.1089/thy.2006.16.ft-1.CrossRefGoogle Scholar
  5. 5.
    Pacini F, Castagna MG, Brilli L, Pentheroudakis G. Differentiated thyroid cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009;20 Suppl 4:143–6. doi: 10.1093/annonc/mdp156.CrossRefGoogle Scholar
  6. 6.
    Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med. 1998;338:297–306. doi: 10.1056/NEJM199801293380506.CrossRefGoogle Scholar
  7. 7.
    Dean DS, Hay ID. Prognostic indicators in differentiated thyroid carcinoma. Cancer Control. 2000;7:229–39.CrossRefGoogle Scholar
  8. 8.
    Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–9. doi: 10.1210/jc.2005-2838.CrossRefGoogle Scholar
  9. 9.
    Sampson E, Brierley JD, Le LW, Rotstein L, Tsang RW. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer. 2007;110:1451–6. doi: 10.1002/cncr.22956.CrossRefGoogle Scholar
  10. 10.
    Lundgren CI, Hall P, Dickman PW, Zedenius J. Clinically significant prognostic factors for differentiated thyroid carcinoma: a population-based, nested case–control study. Cancer. 2006;106:524–31. doi: 10.1002/cncr.21653.CrossRefGoogle Scholar
  11. 11.
    Haq M, Harmer C. Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome. Clin Endocrinol (Oxf). 2005;63:87–93. doi: 10.1111/j.1365-2265.2005.02304.x.CrossRefGoogle Scholar
  12. 12.
    Menzel C, Grunwald F, Schomburg A, Palmedo H, Bender H, Spath G, et al. “High-dose” radioiodine therapy in advanced differentiated thyroid carcinoma. J Nucl Med. 1996;37:1496–503.Google Scholar
  13. 13.
    Grunwald F, Ruhlmann J, Ammari B, Knopp R, Hotze A, Biersack HJ. Experience with a high-dose therapy concept in metastatic differentiated thyroid cancer. Nuklearmedizin. 1988;27:266–71.CrossRefGoogle Scholar
  14. 14.
    Dietlein M, Dressler J, Eschner W, Grunwald F, Lassmann M, Leisner B, et al. Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 3). Nuklearmedizin. 2007;46:213–9.CrossRefGoogle Scholar
  15. 15.
    Dietlein M, Dressler J, Farahati J, Grunwald F, Leisner B, Moser E, et al. Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 2). Nuklearmedizin. 2004;43:115–20. doi: 10.1267/NUKL04040115.CrossRefGoogle Scholar
  16. 16.
    Dietlein M, Dressler J, Farahati J, Leisner B, Moser E, Reiners C, et al. Guidelines for radioiodine therapy (RIT) in differentiated thyroid cancer. Nuklearmedizin. 1999;38:221–2.Google Scholar
  17. 17.
    Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 1993;114:1050–7. discussion 7–8.Google Scholar
  18. 18.
    Gilliland FD, Hunt WC, Morris DM, Key CR. Prognostic factors for thyroid carcinoma. A population-based study of 15,698 cases from the Surveillance, Epidemiology and End Results (SEER) program 1973–1991. Cancer. 1997;79:564–73. doi: 10.1002/(SICI)1097-0142(19970201)79:3<564::AID-CNCR20>3.0.CO;2-0.CrossRefGoogle Scholar
  19. 19.
    Shoup M, Stojadinovic A, Nissan A, Ghossein RA, Freedman S, Brennan MF, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg. 2003;197:191–7. doi: 10.1016/S1072-7515(03)00332-6.CrossRefGoogle Scholar
  20. 20.
    Mihailovic JM, Stefanovic LJ, Malesevic MD, Erak MD, Tesanovic DD. Metastatic differentiated thyroid carcinoma: clinical management and outcome of disease in patients with initial and late distant metastases. Nucl Med Commun. 2009;30:558–64. doi: 10.1097/MNM.0b013e32832cc2ab.CrossRefGoogle Scholar
  21. 21.
    Orita Y, Sugitani I, Matsuura M, Ushijima M, Tsukahara K, Fujimoto Y, et al. Prognostic factors and the therapeutic strategy for patients with bone metastasis from differentiated thyroid carcinoma. Surgery. 2010;147:424–31. doi: 10.1016/j.surg.2009.10.009.CrossRefGoogle Scholar
  22. 22.
    Pitoia F, Bueno F, Urciuoli C, Abelleira E, Cross G, Tuttle RM. Outcomes of patients with differentiated thyroid cancer risk-stratified according to the American thyroid association and Latin American thyroid society risk of recurrence classification systems. Thyroid. 2013;23:1401–7. doi: 10.1089/thy.2013.0011.CrossRefGoogle Scholar
  23. 23.
    D’Avanzo A, Ituarte P, Treseler P, Kebebew E, Wu J, Wong M, et al. Prognostic scoring systems in patients with follicular thyroid cancer: a comparison of different staging systems in predicting the patient outcome. Thyroid. 2004;14:453–8. doi: 10.1089/105072504323150778.CrossRefGoogle Scholar
  24. 24.
    Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4. doi: 10.1245/s10434-010-0985-4.CrossRefGoogle Scholar
  25. 25.
    Mihailovic J, Stefanovic L, Malesevic M, Markoski B. The importance of age over radioiodine avidity as a prognostic factor in differentiated thyroid carcinoma with distant metastases. Thyroid. 2009;19:227–32. doi: 10.1089/thy.2008.0186.CrossRefGoogle Scholar
  26. 26.
    Lang BH, Wong KP, Cheung CY, Wan KY, Lo CY. Evaluating the prognostic factors associated with cancer-specific survival of differentiated thyroid carcinoma presenting with distant metastasis. Ann Surg Oncol. 2013;20:1329–35. doi: 10.1245/s10434-012-2711-x.CrossRefGoogle Scholar
  27. 27.
    Schlumberger M, Catargi B, Borget I, Deandreis D, Zerdoud S, Bridji B, et al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med. 2012;366:1663–73. doi: 10.1056/NEJMoa1108586.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Nuclear MedicineUniversity Duisburg-EssenEssenGermany
  2. 2.Department of Nuclear MedicineSaarland University HospitalHomburgGermany
  3. 3.Department of Nuclear MedicineUniversity HospitalBonnGermany
  4. 4.Department of Radiology and Nuclear MedicineConfessional Hospital “Barmherzige Brüder”TrierGermany

Personalised recommendations