Management of Distant Metastases in Differentiated Thyroid Cancer

  • Adrian Harvey
Part of the Head and Neck Cancer Clinics book series (HNCC)


Follicular cell-derived differentiated thyroid cancer (DTC) is a disease characterized by long-term survival and excellent prognosis. Large-scale studies have defined 10-year survival rates of 85 % in follicular thyroid cancer (FTC) and ~93 % in papillary thyroid cancer (PTC) [1–5]. Despite this, published series report that 6–20 % of patients will develop distant metastatic disease [3, 4, 6–16]. Outcomes in these patients with distant disease are significantly worse, with 10-year survival rates closely approximating 40 % [3, 4, 6, 7, 9, 10, 12–23]. Numerous risk factors have been linked to the development of both regional and distant disease. These include age, tumour size, extrathyroidal extension, multifocality and palpable lymphadenopathy [3, 8, 11, 24]. In 5–45 % of patients, distant disease will be discovered at the time of initial diagnosis on cross-sectional imaging or post-therapy radioactive iodine (RAI) scans [1, 6, 15, 18, 19, 22, 25, 26]. The remainder of patients will develop metastatic recurrence during follow-up. In this latter group, distant disease may be discovered more than 10 years after the initial treatment.


Thyroid Cancer Bone Metastasis External Beam Radiation Papillary Thyroid Cancer Differentiate Thyroid Cancer 
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.


  1. 1.
    American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–214.Google Scholar
  2. 2.
    Eustatia-Rutten CF, Corssmit EP, Biermasz NR, et al. Survival and death causes in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2006;91:313–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Hundahl SA, Fleming ID, Fremgen AM, et al. A national cancer database report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995. Cancer. 1998;83:2638–48.PubMedCrossRefGoogle Scholar
  4. 4.
    Jonklaas J, Sarlis NJ, Litofsky D, et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid. 2006;16:1229–42.PubMedCrossRefGoogle Scholar
  5. 5.
    McConahey WM, Hay ID, Woolner LB, et al. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc. 1986;61:978–96.PubMedCrossRefGoogle Scholar
  6. 6.
    Benbassat CA, Mechlis-Frish S, Hirsch D. Clinicopathological characteristics and long-term outcome in patients with distant metastases from differentiated thyroid cancer. World J Surg. 2006;30:1088–95.PubMedCrossRefGoogle Scholar
  7. 7.
    Casara D, Rubello D, Saladini G, et al. Distant metastases in differentiated thyroid cancer: long-term results of radioiodine treatment and statistical analysis of prognostic factors in 214 patients. Tumori. 1991;77:432–6.PubMedGoogle Scholar
  8. 8.
    Clark JR, Lai P, Hall F, et al. Variables predicting distant metastases in thyroid cancer. Laryngoscope. 2005;115:661–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoie J, Stenwig AE, Kullmann G, et al. Distant metastases in papillary thyroid cancer. A review of 91 patients. Cancer. 1988;61:1–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Lin JD, Huang MJ, Juang JH, et al. Factors related to the survival of papillary and follicular thyroid carcinoma patients with distant metastases. Thyroid. 1999;9:1227–35.PubMedCrossRefGoogle Scholar
  11. 11.
    Machens A, Holzhausen HJ, Lautenschlager C, et al. Enhancement of lymph node metastasis and distant metastasis of thyroid carcinoma. Cancer. 2003;98:712–9.PubMedCrossRefGoogle Scholar
  12. 12.
    O’Neill CJ, Oucharek J, Learoyd D, et al. Standard and emerging therapies for metastatic differentiated thyroid cancer. Oncologist. 2010;15:146–56.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Ruegemer JJ, Hay ID, Bergstralh EJ, et al. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab. 1988;67:501–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Samaan NA, Schultz PN, Haynie TP, et al. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab. 1985;60:376–80.PubMedCrossRefGoogle Scholar
  15. 15.
    Sampson E, Brierley JD, Le LW, et al. Clinical management and outcome of papillary and follicular (differentiated) thyroid cancer presenting with distant metastasis at diagnosis. Cancer. 2007;110:1451–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Showalter TN, Siegel BA, Moley JF, et al. Prognostic factors in patients with well-differentiated thyroid cancer presenting with pulmonary metastasis. Cancer Biother Radiopharm. 2008;23:655–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Casara D, Rubello D, Saladini G, et al. Different features of pulmonary metastases in differentiated thyroid cancer: natural history and multivariate statistical analysis of prognostic variables. J Nucl Med. 1993;34:1626–31.PubMedGoogle Scholar
  18. 18.
    Durante C, Haddy N, Baudin E, 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.PubMedCrossRefGoogle Scholar
  19. 19.
    Haq M, Harmer C. Differentiated thyroid carcinoma with distant metastases at presentation: prognostic factors and outcome. Clin Endocrinol (Oxf). 2005;63:87–93.CrossRefGoogle Scholar
  20. 20.
    Lin JD, Chao TC, Chou SC, et al. Papillary thyroid carcinomas with lung metastases. Thyroid. 2004;14:1091–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Shaha AR, Ferlito A, Rinaldo A. Distant metastases from thyroid and parathyroid cancer. ORL J Otorhinolaryngol Relat Spec. 2001;63:243–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Shoup M, Stojadinovic A, Nissan A, et al. Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma. J Am Coll Surg. 2003;197:191–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Zettinig G, Fueger BJ, Passler C, et al. Long-term follow-up of patients with bone metastases from differentiated thyroid carcinoma—surgery or conventional therapy? Clin Endocrinol (Oxf). 2002;56:377–82.CrossRefGoogle Scholar
  24. 24.
    Welch Dinauer CA, Tuttle RM, Robie DK, et al. Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults. Clin Endocrinol (Oxf). 1998;49:619–28.CrossRefGoogle Scholar
  25. 25.
    Beasley NJ, Walfish PG, Witterick I, et al. Cause of death in patients with well-differentiated thyroid carcinoma. Laryngoscope. 2001;111:989–91.PubMedCrossRefGoogle Scholar
  26. 26.
    Harness JK, McLeod MK, Thompson NW, et al. Deaths due to differentiated thyroid cancer: a 46-year perspective. World J Surg. 1988;12:623–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Klubo-Gwiezdzinska J, Morowitz D, Van Nostrand D, et al. Metastases of well-differentiated thyroid cancer to the gastrointestinal system. Thyroid. 2010;20:381–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Lo CY, van Heerden JA, Soreide JA, et al. Adrenalectomy for metastatic disease to the adrenal glands. Br J Surg. 1996;83:528–31.PubMedCrossRefGoogle Scholar
  29. 29.
    McWilliams RR, Giannini C, Hay ID, et al. Management of brain metastases from thyroid carcinoma: a study of 16 pathologically confirmed cases over 25 years. Cancer. 2003;98:356–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Hindie E, Melliere D, Lange F, et al. Functioning pulmonary metastases of thyroid cancer: does radioiodine influence the prognosis? Eur J Nucl Med Mol Imaging. 2003;30:974–81.PubMedCrossRefGoogle Scholar
  31. 31.
    Nixon IJ, Whitcher MM, Palmer FL, et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid. 2012;22:884–9.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Kitamura Y, Shimizu K, Nagahama M, et al. Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases. J Clin Endocrinol Metab. 1999;84:4043–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Bernier MO, Leenhardt L, Hoang C, et al. Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2001;86:1568–73.PubMedCrossRefGoogle Scholar
  34. 34.
    Schlumberger M, Challeton C, De Vathaire F, et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med. 1996;37:598–605.PubMedGoogle Scholar
  35. 35.
    Pittas AG, Adler M, Fazzari M, et al. Bone metastases from thyroid carcinoma: clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid. 2000;10:261–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Toubert ME, Hindie E, Rampin L, et al. Distant metastases of differentiated thyroid cancer: diagnosis, treatment and outcome. Nucl Med Rev Cent East Eur. 2007;10:106–9.PubMedGoogle Scholar
  37. 37.
    Fatourechi V, Hay ID, Mullan BP, et al. Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer? Thyroid. 2000;10:573–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Fatourechi V, Hay ID, Javedan H, et al. Lack of impact of radioiodine therapy in Tg-positive, diagnostic whole-body scan-negative patients with follicular cell-derived thyroid cancer. J Clin Endocrinol Metab. 2002;87:1521–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Galligan JP, Winship J, van Doorn T, et al. A comparison of serum thyroglobulin measurements and whole body 131I scanning in the management of treated differentiated thyroid carcinoma. Aust N Z J Med. 1982;12:248–54.Google Scholar
  40. 40.
    Ma C, Kuang A, Xie J. Radioiodine therapy for differentiated thyroid carcinoma with thyroglobulin positive and radioactive iodine negative metastases. Cochrane Database Syst Rev. 2009;(1):CD006988.Google Scholar
  41. 41.
    Pacini F, Lippi F, Formica N, et al. Therapeutic doses of iodine-131 reveal undiagnosed metastases in thyroid cancer patients with detectable serum thyroglobulin levels. J Nucl Med. 1987;28:1888–91.PubMedGoogle Scholar
  42. 42.
    Pacini F, Agate L, Elisei R, et al. Outcome of differentiated thyroid cancer with detectable serum Tg and negative diagnostic 131I whole body scan: comparison of patients treated with high 131I activities versus untreated patients. J Clin Endocrinol Metab. 2001;86:4092–7.Google Scholar
  43. 43.
    Courbon F, Zerdoud S, Bastie D, et al. Defective efficacy of retinoic acid treatment in patients with metastatic thyroid carcinoma. Thyroid. 2006;16:1025–31.PubMedCrossRefGoogle Scholar
  44. 44.
    Kebebew E, Peng M, Reiff E, et al. A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. Surgery. 2006;140:960–6; discussion 966–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Kebebew E, Lindsay S, Clark OH, et al. Results of rosiglitazone therapy in patients with thyroglobulin-positive and radioiodine-negative advanced differentiated thyroid cancer. Thyroid. 2009;19:953–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Tepmongkol S, Keelawat S, Honsawek S, et al. Rosiglitazone effect on radioiodine uptake in thyroid carcinoma patients with high thyroglobulin but negative total body scan: a correlation with the expression of peroxisome proliferator-activated receptor-gamma. Thyroid. 2008;18:697–704.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang Y, Jia S, Liu Y, et al. A clinical study of all-trans-retinoid-induced differentiation therapy of advanced thyroid cancer. Nucl Med Commun. 2007;28:251–5.PubMedCrossRefGoogle Scholar
  48. 48.
    Pineda JD, Lee T, Ain K, et al. Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab. 1995;80:1488–92.PubMedGoogle Scholar
  49. 49.
    Grunwald F, Schomburg A, Bender H, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography in the follow-up of differentiated thyroid cancer. Eur J Nucl Med. 1996;23:312–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Ito S, Kato K, Ikeda M, et al. Comparison of 18 F-FDG PET and bone scintigraphy in detection of bone metastases of thyroid cancer. J Nucl Med. 2007;48:889–95.PubMedCrossRefGoogle Scholar
  51. 51.
    Larson SM, Robbins R. Positron emission tomography in thyroid cancer management. Semin Roentgenol. 2002;37:169–74.PubMedCrossRefGoogle Scholar
  52. 52.
    Nanni C, Rubello D, Fanti S, et al. Role of 18 F-FDG-PET and PET/CT imaging in thyroid cancer. Biomed Pharmacother. 2006;60:409–13.PubMedCrossRefGoogle Scholar
  53. 53.
    Schluter B, Bohuslavizki KH, Beyer W, et al. Impact of FDG PET on patients with differentiated thyroid cancer who present with elevated thyroglobulin and negative 131I scan. J Nucl Med. 2001;42:71–6.Google Scholar
  54. 54.
    Wang H, Fu HL, Li JN, et al. Comparison of whole-body 18 F-FDG SPECT and post-therapeutic 131I scintigraphy in the detection of metastatic thyroid cancer. Clin Imaging. 2008;32:32–7.Google Scholar
  55. 55.
    Wang W, Macapinlac H, Larson SM, et al. [18 F]-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic 131I whole body scans and elevated serum thyroglobulin levels. J Clin Endocrinol Metab. 1999;84:2291–302.PubMedCrossRefGoogle Scholar
  56. 56.
    Wang W, Larson SM, Tuttle RM, et al. Resistance of [18f]fluorodeoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine. Thyroid. 2001;11:1169–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Feine U, Lietzenmayer R, Hanke JP, et al. Fluorine-18-FDG and iodine-131-iodide uptake in thyroid cancer. J Nucl Med. 1996;37:1468–72.PubMedGoogle Scholar
  58. 58.
    Coburn M, Teates D, Wanebo HJ. Recurrent thyroid cancer. Role of surgery versus radioactive iodine (131I). Ann Surg. 1994;219:587–93; discussion 593–5.Google Scholar
  59. 59.
    Hindie E, Zanotti-Fregonara P, Keller I, et al. Bone metastases of differentiated thyroid cancer: Impact of early 131I-based detection on outcome. Endocr Relat Cancer. 2007;14:799–807.Google Scholar
  60. 60.
    Ilgan S, Karacalioglu AO, Pabuscu Y, et al. Iodine-131 treatment and high-resolution CT: results in patients with lung metastases from differentiated thyroid carcinoma. Eur J Nucl Med Mol Imaging. 2004;31:825–30.PubMedCrossRefGoogle Scholar
  61. 61.
    Pacini F, Cetani F, Miccoli P, et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg. 1994;18:600–4.PubMedCrossRefGoogle Scholar
  62. 62.
    Liu YY, van der Pluijm G, Karperien M, et al. Lithium as adjuvant to radioiodine therapy in differentiated thyroid carcinoma: clinical and in vitro studies. Clin Endocrinol (Oxf). 2006;64:617–24.CrossRefGoogle Scholar
  63. 63.
    Spitzweg C, Morris JC. Gene therapy for thyroid cancer: current status and future prospects. Thyroid. 2004;14:424–34.PubMedCrossRefGoogle Scholar
  64. 64.
    Kurebayashi J, Tanaka K, Otsuki T, et al. All-trans-retinoic acid modulates expression levels of thyroglobulin and cytokines in a new human poorly differentiated papillary thyroid carcinoma cell line, KTC-1. J Clin Endocrinol Metab. 2000;85:2889–96.PubMedGoogle Scholar
  65. 65.
    Schmutzler C, Brtko J, Bienert K, et al. Effects of retinoids and role of retinoic acid receptors in human thyroid carcinomas and cell lines derived therefrom. Exp Clin Endocrinol Diabetes. 1996;104 Suppl 4:16–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. Cancer Res. 2000;60:3484–92.PubMedGoogle Scholar
  67. 67.
    Brown AP, Chen J, Hitchcock YJ, et al. The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 2008;93:504–15.PubMedCrossRefGoogle Scholar
  68. 68.
    Rubino C, de Vathaire F, Dottorini ME, et al. Second primary malignancies in thyroid cancer patients. Br J Cancer. 2003;89:1638–44.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Sawka AM, Thabane L, Parlea L, et al. Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and metaanalysis. Thyroid. 2009;19:451–7.PubMedCrossRefGoogle Scholar
  70. 70.
    Subramanian S, Goldstein DP, Parlea L, et al. Second primary malignancy risk in thyroid cancer survivors: a systematic review and meta-analysis. Thyroid. 2007;17:1277–88.PubMedCrossRefGoogle Scholar
  71. 71.
    Porterfield JR, Cassivi SD, Wigle DA, et al. Thoracic metastasectomy for thyroid malignancies. Eur J Cardiothorac Surg. 2009;36:155–8.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Protopapas AD, Nicholson AG, Vini L, et al. Thoracic metastasectomy in thyroid malignancies. Ann Thorac Surg. 2001;72:1906–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Chiu AC, Delpassand ES, Sherman SI. Prognosis and treatment of brain metastases in thyroid carcinoma. J Clin Endocrinol Metab. 1997;82:3637–42.PubMedCrossRefGoogle Scholar
  74. 74.
    Dahl PR, Brodland DG, Goellner JR, et al. Thyroid carcinoma metastatic to the skin: a cutaneous manifestation of a widely disseminated malignancy. J Am Acad Dermatol. 1997;36:531–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Koutkia P, Safer JD. Adrenal metastasis secondary to papillary thyroid carcinoma. Thyroid. 2001;11:1077–9.PubMedCrossRefGoogle Scholar
  76. 76.
    Bukowski RM, Brown L, Weick JK, et al. Combination chemotherapy of metastatic thyroid cancer. Phase II study. Am J Clin Oncol. 1983;6:579–81.PubMedCrossRefGoogle Scholar
  77. 77.
    Gottlieb JA, Hill Jr CS, Ibanez ML, et al. Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients. Cancer. 1972;30:848–53.PubMedCrossRefGoogle Scholar
  78. 78.
    Gottlieb JA, Hill Jr CS. Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients. N Engl J Med. 1974;290:193–7.PubMedCrossRefGoogle Scholar
  79. 79.
    Hoskin PJ, Harmer C. Chemotherapy for thyroid cancer. Radiother Oncol. 1987;10:187–94.PubMedCrossRefGoogle Scholar
  80. 80.
    Shimaoka K, Schoenfeld DA, DeWys WD, et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer. 1985;56:2155–60.PubMedCrossRefGoogle Scholar
  81. 81.
    Williams SD, Birch R, Einhorn LH. Phase II evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: a Southeastern Cancer Study Group Trial. Cancer Treat Rep. 1986;70:405–7.PubMedGoogle Scholar
  82. 82.
    Ford D, Giridharan S, McConkey C, et al. External beam radiotherapy in the management of differentiated thyroid cancer. Clin Oncol (R Coll Radiol). 2003;15:337–41.CrossRefGoogle Scholar
  83. 83.
    Eustatia-Rutten CF, Romijn JA, Guijt MJ, et al. Outcome of palliative embolization of bone metastases in differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2003;88:3184–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Vitale G, Fonderico F, Martignetti A, et al. Pamidronate improves the quality of life and induces clinical remission of bone metastases in patients with thyroid cancer. Br J Cancer. 2001;84:1586–90.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714–9.PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol. 2009;27:1675–84.PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Pennell NA, Daniels GH, Haddad RI, et al. A phase II study of gefitinib in patients with advanced thyroid cancer. Thyroid. 2008;18:317–23.PubMedCrossRefGoogle Scholar

Copyright information

© K. Alok Pathak, Richard W. Nason, Janice L. Pasieka, Rehan Kazi, Raghav C. Dwivedi 2015

Authors and Affiliations

  1. 1.Department of Surgery, Faculty of MedicineUniversity of CalgaryCalgaryCanada

Personalised recommendations