Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Current practice in patients with differentiated thyroid cancer

Subjects

Abstract

Considerable changes have occurred in the management of differentiated thyroid cancer (DTC) during the past four decades, based on improved knowledge of the biology of DTC and on advances in therapy, including surgery, the use of radioactive iodine (radioiodine), thyroid hormone treatment and availability of recombinant human TSH. Improved diagnostic tools are available, including determining serum levels of thyroglobulin, neck ultrasonography, imaging (CT, MRI, SPECT–CT and PET–CT), and prognostic classifications have been improved. Patients with low-risk DTC, in whom the risk of thyroid cancer death is <1% and most recurrences can be cured, currently represent the majority of patients. By contrast, patients with high-risk DTC represent 5–10% of all patients. Most thyroid cancer-related deaths occur in this group of patients and recurrences are frequent. Patients with high-risk DTC require more aggressive treatment and follow-up than patients with low-risk DTC. Finally, the strategy for treating patients with intermediate-risk DTC is frequently defined on a case-by-case basis. Prospective trials are needed in well-selected patients with DTC to demonstrate the extent to which treatment and follow-up can be limited without increasing the risk of recurrence and thyroid cancer-related death.

Key points

  • Prognostic classifications currently distinguish the risk of differentiated thyroid cancer (DTC)-related death from the risk of recurrence.

  • The majority of patients with DTC have low-risk disease; postoperative administration of radioiodine is indicated in selected patients and thyroid hormone treatment maintains serum levels of TSH within the normal range.

  • Follow-up is based on determination of serum levels of thyroglobulin and neck ultrasonography.

  • Fluorodeoxyglucose PET–CT is useful for the detection of neoplastic foci in patients with high-risk DTC and in those with detectable serum levels of thyroglobulin that increases over time during follow-up.

  • Patients with distant metastases are first treated with radioiodine, and with focal treatment modalities as necessary; patients with progression might benefit from systemic targeted therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Indications and protocols for postoperative administration of 131I.
Fig. 2: Papillary thyroid cancer with miliary lung metastases in a 16-year-old girl.
Fig. 3: Poorly differentiated thyroid cancer in a 56-year-old man.
Fig. 4: Lymph node metastasis in a patient with poorly differentiated thyroid cancer.
Fig. 5: Left paratracheal lymph node metastasis in a patient with poorly differentiated thyroid cancer.
Fig. 6: Bone metastases in a patient with poorly differentiated thyroid cancer.

Similar content being viewed by others

References

  1. Mazzaferri, E. L., Young, R. L., Oertel, J. E., Kemmerer, W. T. & Page, C. P. Papillary thyroid carcinoma: the impact of therapy in 576 patients. Medicine 56, 171–196 (1977).

    Article  CAS  PubMed  Google Scholar 

  2. Mazzaferri, E. L. & Jhiang, S. M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am. J. Med. 97, 418–428 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Hay, I. D. et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the Mayo clinic during eight decades (1936–2015). World J. Surg. 42, 329–342 (2018).

    Article  PubMed  Google Scholar 

  4. Schlumberger, M. et al. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur. J. Endocrinol. 50, 105–112 (2004).

    Article  Google Scholar 

  5. Cady, B. Papillary carcinoma of the thyroid gland: treatment based on risk group definition. Surg. Oncol. Clin. N. Am. 7, 633–644 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Tubiana, M. et al. Long-term results and prognostic factors in patients with differentiated thyroid carcinoma. Cancer 55, 794–804 (1985).

    Article  CAS  PubMed  Google Scholar 

  7. Davies, L. & Welch, H. G. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA 295, 2164–2167 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Vaccarella, S. et al. Worldwide thyroid cancer epidemic? The increasing impact of overdiagnosis. N. Engl. J. Med. 375, 614–617 (2016).

    Article  PubMed  Google Scholar 

  9. Haugen, B. R. et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: American Thyroid Association Management Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 26, 1–133 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Filetti, S. et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 30, 1856–1883 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Lloyd, R. V., Osamura, R. Y., Kloppel, G. & Rosai, J. (eds) WHO Classification of Tumours of Endocrine Organs. 4th ed. (IARC, 2017).

  12. Nikiforov, Y. E. et al. Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors. JAMA Oncol. 2, 1023–1029 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fagin, J. A. & Wells, S. A. Jr. Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375, 1054–1067 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014).

    Article  CAS  Google Scholar 

  15. Yoo, S. K. et al. Comprehensive analysis of the transcriptional and mutational landscape of follicular and papillary thyroid cancers. PLoS Genet. 12, e1006239 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Ganly, I. et al. Integrated genomic analysis of Hürthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell 34, 256–270 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Landa, I. et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Invest. 126, 1052–1066 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Xing, M. Genetic-guided risk assessment and management of thyroid cancer. Endocrinol. Metab. Clin. N. Am. 48, 109–124 (2019).

    Article  Google Scholar 

  19. Tuttle, R. M. & Alzahrani, A. S. Risk stratification in differentiated thyroid cancer: from detection to final follow-up. J. Clin. Endocrinol. Metab. 104, 4087–4100 (2019).

    Article  PubMed Central  Google Scholar 

  20. Durante, C. 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. 91, 2892–2899 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Liu, J. et al. The genetic duet of BRAF V600E and TERT promoter mutations robustly predicts loss of radioiodine avidity in recurrent papillary thyroid cancer. J. Nucl. Med. 61, 177–182 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Durante, C. et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism. J. Clin. Endocrinol. Metab. 92, 2840–2843 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Azouzi, N. et al. NADPH oxidase NOX4 is a critical mediator of BRAFV600E-induced down regulation of the sodium iodide symporter in papillary thyroid carcinomas. Antioxid. Redox. Signal. 26, 864–877 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chakravarty, D. et al. Small-molecule MAPK inhibitors restore radioiodine incorporation in mouse thyroid cancers with conditional BRAF activation. J. Clin. Invest. 121, 4700–4711 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Brierley, J. D., Gospodarowicz, M. K. & Wittekind, C. TNM Classification of Malignant Tumours 8th ed. (Wiley, 2017).

  26. Tuttle, R. M., Haugen, B. & Perrier, N. D. Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (eighth edition): what changed and why? Thyroid 27, 751–756 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tuttle, R. M. et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 20, 1341–1349 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Grani, G. et al. Real-world performance of the American Thyroid Association risk estimates in predicting 1-year differentiated thyroid cancer outcomes: a prospective multicenter study of 2000 patients. Thyroid https://doi.org/10.1089/thy.2020.0272 (2020).

    Article  PubMed  Google Scholar 

  29. Trimboli, P. et al. Patient age is an independent risk factor of relapse of differentiated thyroid carcinoma and improves the performance of the American Thyroid Association Stratification System. Thyroid 30, 713–719 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Momesso, D. P. et al. Dynamic risk stratification in patients with differentiated thyroid cancer treated without radioactive iodine. J. Clin. Endocrinol. Metab. 101, 2692–2700 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Miyauchi, A. & Ito, Y. Conservative surveillance management of low-risk papillary thyroid microcarcinoma. Endocrinol. Metab. Clin. N. Am. 48, 215–226 (2019).

    Article  Google Scholar 

  32. Leboulleux, S., Tuttle, R. M., Pacini, F. & Schlumberger, M. Papillary thyroid microcarcinoma: time to shift from surgery to active surveillance? Lancet Diabetes Endocrinol. 4, 933–942 (2016).

    Article  PubMed  Google Scholar 

  33. Zhang, M., Luo, Y., Zhang, Y. & Tang, J. Efficacy and safety of ultrasound-guided radiofrequency ablation for treating low-risk papillary thyroid microcarcinoma: a prospective study. Thyroid 26, 1581–1587 (2016).

    Article  PubMed  Google Scholar 

  34. Lamartina, L. et al. Follow-up of differentiated thyroid cancer – what should (and what should not) be done. Nat. Rev. Endocrinol. 14, 538–551 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Wang, T. S. & Sosa, J. A. Thyroid surgery for differentiated thyroid cancer – recent advances and future directions. Nat. Rev. Endocrinol. 14, 670–683 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Russell, M. D., Kamani, D. & Randolph, G. W. Modern surgery for advanced thyroid cancer: a tailored approach. Gland Surg. 9, S105–S119 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Fundakowski, C. E. et al. Surgical management of the recurrent laryngeal nerve in thyroidectomy: American Head and Neck Society consensus statement. Head Neck 40, 663–675 (2018).

    Article  PubMed  Google Scholar 

  38. Hartl, D. M. et al. Current concepts in the management of unilateral recurrent laryngeal nerve paralysis after thyroid surgery. J. Clin. Endocrinol. Metab. 9, 3084–3088 (2005).

    Article  CAS  Google Scholar 

  39. Hauch, A., Al-Qurayshi, Z., Randolph, G. & Kandil, E. Total thyroidectomy is associated with increased risk of complications for low- and high-volume surgeons. Ann. Surg. Oncol. 21, 3844–3852 (2014).

    Article  PubMed  Google Scholar 

  40. Adam, M. A. et al. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients. Ann. Surg. 260, 601–605 (2014).

    Article  PubMed  Google Scholar 

  41. Garsi, J. P. et al. Therapeutic administration of 131I for differentiated thyroid cancer, radiation dose to ovaries and outcome of pregnancies. J. Nucl. Med. 49, 845–852 (2008).

    Article  PubMed  Google Scholar 

  42. Bourcigaux, N. et al. Impact on testicular function of a single ablative activity of 3.7 GBq radioactive iodine for differentiated thyroid carcinoma. Hum. Reprod. 33, 1408–1416 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Pacini, F. et al. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine. J. Nucl. Med. 35, 1418–1422 (1994).

    CAS  PubMed  Google Scholar 

  44. Rubino, C. et al. Second primary malignancies in thyroid cancer patients. Br. J. Cancer 89, 1638–1644 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Verburg, F. A. et al. Errare humanum est, sed in errare perseverare diabolicum: methodological errors in the assessment of the relationship between I-131 therapy and possible increases in the incidence of malignancies. Eur. J. Nucl. Med. Mol. Imaging 47, 519–522 (2020).

    Article  PubMed  Google Scholar 

  46. Boucai, L. et al. Radioactive iodine-related clonal hematopoiesis in thyroid cancer is common and associated with decreased survival. J. Clin. Endocrinol. Metab. 103, 4216–4223 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Singer, M. C. et al. Salivary and lacrimal dysfunction after radioactive iodine for differentiated thyroid cancer: American Head and Neck Society Endocrine Surgery Section and Salivary Gland Section joint multidisciplinary clinical consensus statement of otolaryngology, ophthalmology, nuclear medicine and endocrinology. Head Neck 42, 3446–3459 (2020).

    Article  PubMed  Google Scholar 

  48. Lamartina, L., Durante, C., Filetti, S. & Cooper, D. S. Low-risk differentiated thyroid cancer and radioiodine remnant ablation: a systematic review of the literature. J. Clin. Endocrinol. Metab. 100, 1748–1761 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Sawka, A. M. et al. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer. Endocrinol. Metab. Clin. N. Am. 37, 457–480 (2008).

    Article  Google Scholar 

  50. Sacks, W., Fung, C. H., Chang, J. T., Waxman, A. & Braunstein, G. D. The effectiveness of radioactive iodine for treatment of low-risk thyroid cancer: a systematic analysis of the peer-reviewed literature from 1966 to April 2008. Thyroid 20, 1235–1245 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Jonklaas, J. et al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 16, 1229–1242 (2006).

    Article  PubMed  Google Scholar 

  52. Schvartz, C. et al. Impact on overall survival of radioactive iodine in low-risk differentiated thyroid cancer patients. J. Clin. Endocrinol. Metab. 97, 1526–1535 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. Nixon, I. J. et al. The results of selective use of radioactive iodine on survival and on recurrence in the management of papillary thyroid cancer, based on Memorial Sloan-Kettering Cancer Center risk group stratification. Thyroid 23, 683–694 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Verburg, F. A. et al. Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade. Eur. J. Nucl. Med. Mol. Imaging 47, 78–83 (2020).

    Article  CAS  PubMed  Google Scholar 

  55. Tuttle, R. M. et al. Controversies, consensus, and collaboration in the use of 131I therapy in differentiated thyroid cancer: a joint statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid 29, 461–470 (2019).

    Article  PubMed  Google Scholar 

  56. Durante, C. et al. Long-term surveillance of papillary thyroid cancer patients who do not undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement? J. Clin. Endocrinol. Metab. 97, 2748–2753 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Cailleux, A. F., Baudin, E., Travagli, J. P., Ricard, M. & Schlumberger, M. Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J. Clin. Endocrinol. Metab. 85, 175–178 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Pacini, F. et al. Diagnostic 131-iodine whole-body scan may be avoided in thyroid cancer patients who have undetectable stimulated serum Tg levels after initial treatment. J. Clin. Endocrinol. Metab. 87, 1499–1501 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Pacini, F. et al. Post-surgical use of radioiodine (131I) in patients with papillary and follicular thyroid cancer and the issue of remnant ablation. A consensus report. Eur. J. Endocrinol. 153, 651–659 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Schlumberger, M. et al. Strategies of radioiodine ablation in low-risk thyroid cancer patients. N. Engl. J. Med. 366, 1663–1673 (2012).

    Article  CAS  PubMed  Google Scholar 

  61. Mallick, U. et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N. Engl. J. Med. 366, 1674–1685 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Borget, I. et al. Quality of life and cost-effectiveness assessment of radioiodine ablation strategies in patients with thyroid cancer: results from the randomized phase III ESTIMABL trial. J. Clin. Oncol. 33, 2885–2892 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Schlumberger, M. et al. ESTIMABL1: favorable outcome after ablation in low risk thyroid cancer patients. Lancet Diabetes Endocrinol. 6, 618–626 (2018); author’s reply 686–687 (2018).

    Article  PubMed  Google Scholar 

  64. Dehbi, H. M. et al. Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial. Lancet Diabetes Endocrinol. 7, 44–51 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Matrone, A. et al. Postoperative thyroglobulin and neck ultrasound in the risk restratification and decision to perform 131I ablation. J. Clin. Endocrinol. Metab. 102, 893–902 (2017).

    PubMed  Google Scholar 

  66. Ahtiainen, V., Vaalavirta, L., Tenhunen, M., Joensuu, H. & Mäenpää, H. Randomised comparison of 1.1 GBq and 3.7 GBq radioiodine to ablate the thyroid in the treatment of low-risk thyroid cancer: a 13-year follow-up. Acta Oncol. 30, 1–8 (2020).

    Google Scholar 

  67. Tuttle, R. M. Distinguishing remnant ablation from adjuvant treatment in differentiated thyroid cancer. Lancet Diabetes Endocrinol. 7, 7–8 (2019).

    Article  PubMed  Google Scholar 

  68. Sugitani, I. & Fujimoto, Y. Does postoperative thyrotropin suppression therapy truly decrease recurrence in papillary thyroid carcinoma? A randomized controlled trial. J. Clin. Endocrinol. Metab. 95, 4576–4583 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Grani, G., Ramundo, V., Verrienti, A., Sponziello, M. & Durante, C. Thyroid hormone therapy in differentiated thyroid cancer. Endocrine 66, 43–50 (2019).

    Article  CAS  PubMed  Google Scholar 

  70. Durante, C. et al. Papillary thyroid cancer: time course of recurrences during postsurgery surveillance. J. Clin. Endocrinol. Metab. 98, 636–642 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Grani, G. et al. Thyroid cancer patients with no evidence of disease: the need for repeat neck ultrasound. J. Clin. Endocrinol. Metab. 104, 4981–4989 (2019).

    Article  PubMed  Google Scholar 

  72. Baudin, E. et al. Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up following thyroid hormone withdrawal, in thyroid cancer patients. J. Clin. Endocrinol. Metab. 88, 1107–1111 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Pacini, F. et al. Outcome of differentiated thyroid cancer with detectable serum Tg and negative diagnostic (131)I whole body scan: comparison of patients treated with high (131)I activities versus untreated patients. J. Clin. Endocrinol. Metab. 86, 4092–4097 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Vaisman, F. et al. Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. Clin. Endocrinol. 77, 132–138 (2012).

    Article  CAS  Google Scholar 

  75. Ritter, A. et al. Detecting recurrence following lobectomy for thyroid cancer: role of thyroglobulin and thyroglobulin antibodies. J. Clin. Endocrinol. Metab. 105, 2145–2151 (2020).

    Article  Google Scholar 

  76. Hartl, D. M. et al. Influence of prophylactic neck dissection on rate of retreatment for papillary thyroid carcinoma. World J. Surg. 37, 1951–1958 (2013).

    Article  PubMed  Google Scholar 

  77. Hartl, D. M. et al. Optimization of staging of the neck with prophylactic central and lateral neck dissection for papillary thyroid carcinoma. Ann. Surg. 255, 777–783 (2012).

    Article  PubMed  Google Scholar 

  78. Rosario, P. W., de Souza Furtado, M., Mourão, G. F. & Calsolari, M. R. Patients with papillary thyroid carcinoma at intermediate risk of recurrence according to American Thyroid Association criteria can be reclassified as low risk when the postoperative thyroglobulin is low. Thyroid 25, 1243–1248 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Nascimento, C. et al. Post-operative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT): an important imaging modality in patients with aggressive histology of differentiated thyroid cancer. Thyroid 25, 437–444 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Beckham, T. H. et al. Intensity-modulated radiation therapy with or without concurrent chemotherapy in nonanaplastic thyroid cancer with unresectable or gross residual disease. Thyroid 28, 1180–1189 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tuttle, R. M. & Sabra, M. M. ATA high-risk thyroid cancer patients demonstrating an excellent response to therapy within a few weeks of initial therapy have better than expected clinical outcomes. Endocr. Pract. 25, 287–289 (2019).

    Article  PubMed  Google Scholar 

  82. Schlumberger, M., Mancusi, F., Baudin, E. & Pacini, F. 131I therapy for elevated thyroglobulin levels. Thyroid 7, 273–276 (1997).

    Article  CAS  PubMed  Google Scholar 

  83. Leboulleux, S. et al. Post-radioiodine treatment whole body scan in the era of fluorodesoxyglucose positron emission tomography for differentiated thyroid carcinoma with elevated serum thyroglobulin levels. Thyroid 22, 832–838 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Shah, S. & Boucai, L. Effect of age on response to therapy and mortality in patients with thyroid cancer at high risk of recurrence. J. Clin. Endocrinol. Metab. 103, 689–697 (2018).

    Article  PubMed  Google Scholar 

  85. Travagli, J. P. et al. Combination of radioiodine (131I) and probe-guided surgery for persistent or recurrent thyroid carcinoma. J. Clin. Endocrinol. Metab. 83, 2675–2680 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Hartl, D. M. et al. Charcoal suspension tattoo localization for differentiated thyroid cancer recurrence. Ann. Surg. Oncol. 16, 2602–2608 (2009).

    Article  PubMed  Google Scholar 

  87. Lamartina, L. et al. Surgery for neck recurrence of differentiated thyroid cancer: outcomes and risk factors. J. Clin. Endocrinol. Metab. 102, 1020–1031 (2017).

    PubMed  Google Scholar 

  88. Pacini, F. et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J. Surg. 18, 600–604 (1994).

    Article  CAS  PubMed  Google Scholar 

  89. Hay, I. D., Lee, R. A., Davidge-Pitts, C., Reading, C. C. & Charboneau, J. W. Long-term outcome of ultrasound-guided percutaneous ethanol ablation of selected “recurrent” neck nodal metastases in 25 patients with TNM stages III or IVA papillary thyroid carcinoma previously treated by surgery and 131I therapy. Surgery 154, 1448–1454 (2013); discussion 1454–1455 (2013).

    Article  PubMed  Google Scholar 

  90. Kitamura, Y. et al. Immediate causes of death in thyroid carcinoma: clinicopathological analysis of 161 fatal cases. J. Clin. Endocrinol. Metab. 84, 4043–4049 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Hartl, D. M. et al. Surgery in the context of kinase inhibitor therapy for locally invasive thyroid cancer. Eur. J. Surg. Oncol. 46, 650–655 (2020).

    Article  PubMed  Google Scholar 

  92. Berdelou, A. et al. Treatment of refractory thyroid cancer. Endocr. Relat. Cancer 25, R209–R223 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. Tuttle, R. M. et al. Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer. Best Pract. Res. Clin. Endocrinol. Metab. 31, 295–305 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Miyauchi, A. et al. Prognostic impact of serum thyroglobulin doubling-time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy. Thyroid 21, 707–716 (2011).

    Article  PubMed  Google Scholar 

  95. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECISTguideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009).

    Article  CAS  PubMed  Google Scholar 

  96. Sabra, M. M., Sherman, E. J. & Tuttle, R. M. Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma. Cancer 123, 2955–2964 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Barat, M. et al. Thermal-ablation of vertebral metastases prevents adverse events in patients with differentiated thyroid carcinoma. Eur. J. Radiol. 119, 108650 (2019).

    Article  CAS  PubMed  Google Scholar 

  98. Quan, G. M., Pointillart, V., Palussière, J. & Bonichon, F. Multidisciplinary treatment and survival of patients with vertebral metastases from thyroid carcinoma. Thyroid 22, 125–130 (2012).

    Article  PubMed  Google Scholar 

  99. Farooki, A., Leung, V., Tala, H. & Tuttle, R. M. Skeletal-related events due to bone metastases from differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 97, 2433–2439 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Maxon, H. R. et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N. Engl. J. Med. 309, 937–941 (1983).

    Article  CAS  PubMed  Google Scholar 

  101. Pötzi, C. et al. Comparison of iodine uptake in tumour and nontumour tissue under thyroid hormone deprivation and with recombinant human thyrotropin in thyroid cancer patients. Clin. Endocrinol. 65, 519–523 (2006).

    Article  CAS  Google Scholar 

  102. Deandreis, D. et al. Comparison of empiric versus whole body/blood clearance dosimetry-based approach to radioactive iodine treatment in patients with metastases from differentiated thyroid cancer. J. Nucl. Med. 58, 717–722 (2017); correspondence 863–864 and 1531 (2017).

    Article  CAS  PubMed  Google Scholar 

  103. Sgouros, G. et al. Patient-specific dosimetry for 131I thyroid cancer therapy using 124I PET and 3-dimensional-internal dosimetry (3D-ID) software. J. Nucl. Med. 45, 1366–1372 (2004).

    CAS  PubMed  Google Scholar 

  104. Plyku, D. et al. Recombinant human thyroid-stimulating hormone versus thyroid hormone withdrawal in 124I PET/CT-based dosimetry for 131I therapy of metastatic differentiated thyroid cancer. J. Nucl. Med. 58, 1146–1154 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Klubo-Gwiezdzinska, J. et al. Efficacy of dosimetric versus empiric prescribed activity of 131I for therapy of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 96, 3217–3225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Robbins, R. J. et al. Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J. Clin. Endocrinol. Metab. 91, 498–505 (2006).

    Article  CAS  PubMed  Google Scholar 

  107. Schlumberger, M., Lacroix, L., Russo, D., Filetti, S. & Bidart, J. M. Defects in iodide metabolism in thyroid cancer and implications for the follow-up and treatment of patients. Nat. Rev. Endocrinol. 3, 260–269 (2007).

    Article  CAS  Google Scholar 

  108. Schlumberger, M. et al. Definition and management of radioactive iodine-refractory differentiated thyroid cancer. Lancet Diabetes Endocrinol. 2, 356–358 (2014).

    Article  PubMed  Google Scholar 

  109. Brose, M. S. et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 384, 319–328 (2014); correspondence 228–229 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Schlumberger, M. et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 372, 621–630 (2015); correspondence 1868 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Brose, M. S., Worden, F. P., Newbold, K. L., Guo, M. & Hurria, A. Effect of age on the efficacy and safety of lenvatinib in radioiodine-refractory differentiated thyroid cancer in the phase III SELECT trial. J. Clin. Oncol. 35, 2692–2699 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Berdelou, A. et al. Lenvatinib for the treatment of radio-iodine refractory thyroid cancer in real-life practice. Thyroid 28, 72–78 (2018).

    Article  CAS  PubMed  Google Scholar 

  113. Locati, L. D. et al. Real-world efficacy and safety of lenvatinib: data from a compassionate use in the treatment of radioactive iodine-refractory differentiated thyroid cancer patients in Italy. Eur. J. Cancer 118, 35–40 (2019).

    Article  CAS  PubMed  Google Scholar 

  114. Locati, L. D. et al. Treatment of advanced thyroid cancer with axitinib: phase 2 study with pharmacokinetic/pharmacodynamic and quality-of-life assessments. Cancer 120, 2694–2703 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Cabanillas, M. E. et al. Cabozantinib as salvage therapy for patients with tyrosine kinase inhibitor-refractory differentiated thyroid cancer: results of a multicenter phase II International Thyroid Oncology Group trial. J. Clin. Oncol. 35, 3315–3321 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bible, K. C. et al. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. Lancet Oncol. 11, 962–972 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lamartina, L. et al. Anti-angiogenic tyrosine kinase inhibitors: occurrence and risk factors of hemoptysis in refractory thyroid cancer. J. Clin. Endocrinol. Metab. 101, 2733–2741 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Wirth, L. J. et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N. Engl. J. Med. 383, 825–835 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Hu, M. et al. Clinical activity of selective RET inhibitor, BLU-667, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study [abstract]. Thyroid 28 (Suppl. 1), A170 (2018).

    Google Scholar 

  120. Drilon, A., Hu, Z. I., Lai, G. G. Y. & Tan, D. S. W. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat. Rev. Clin. Oncol. 15, 151–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  121. Shah, M. H. et al. Results of randomized phase II trial of dabrafenib versus dabrafenib plus trametinib in BRAF-mutated papillary thyroid carcinoma [abstract]. J. Clin. Oncol. 35 (Suppl. 15), 6022 (2017).

    Article  Google Scholar 

  122. Ho, A. L. et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 368, 623–632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Rothenberg, S. M., McFadden, D. G., Palmer, E. L., Daniels, G. H. & Wirth, L. J. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin. Cancer Res. 21, 1028–1035 (2015).

    Article  CAS  PubMed  Google Scholar 

  124. Leboulleux, S. et al. Redifferentiation of a BRAF-K601E mutated poorly differentiated thyroid cancer patient with dabrafenib and trametinib treatment. Thyroid 29, 735–742 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Mehnert, J. M. et al. Pembrolizumab for advanced papillary or follicular thyroid cancer: preliminary results from the phase 1b KEYNOTE-028 study [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 6091 (2016).

    Article  Google Scholar 

  126. Lorch, J. H. et al. A phase II study of nivolumab (N) plus ipilimumab (I) in radioidine refractory differentiated thyroid cancer (RAIR DTC) with exploratory cohorts in anaplastic (ATC) and medullary thyroid cancer (MTC) [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 6513 (2020).

    Article  Google Scholar 

  127. Haugen, B. et al. Lenvatinib plus pembrolizumab combination therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC): results of a multicenter phase II international thyroid oncology group trial [absdtract]. J. Clin. Oncol. 38 (Suppl. 15), 6512 (2020).

    Article  Google Scholar 

  128. Burman, B. et al. Radioiodine (RAI) in combination with durvalumab for recurrent/metastatic thyroid cancers? [abstract]. J. Clin. Oncol. 38 (Suppl. 15), 6587 (2020).

    Article  Google Scholar 

  129. Van Herle, A. J., Uller, R. P., Matthews, N. I. & Brown, J. Radioimmunoassay for measurement of thyroglobulin in human serum. J. Clin. Invest. 52, 1320–1327 (1973).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Schlumberger, M. et al. Circulating thyroglobulin and thyroid hormones in patients with metastases of differentiated thyroid carcinoma: relationship to serum thyrotropin levels. J. Clin. Endocrinol. Metab. 51, 513–519 (1980).

    Article  CAS  PubMed  Google Scholar 

  131. Haugen, B. R. et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J. Clin. Endocrinol. Metab. 84, 3877–3885 (1999).

    CAS  PubMed  Google Scholar 

  132. Pacini, F. et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J. Clin. Endocrinol. Metab. 91, 926–932 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. Schlumberger, M., Ricard, M., De Pouvourville, G. & Pacini, F. How the availability of recombinant human TSH has changed the management of patients who have thyroid cancer. Nat. Rev. Endocrinol. 3, 641–650 (2007).

    Article  Google Scholar 

  134. Brassard, M. et al. Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients. J. Clin. Endocrinol. Metab. 96, 1352–1359 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Netzel, B. C. et al. Thyroglobulin (Tg) testing revisited: Tg assays, TgAb assays, and correlation of results with clinical outcomes. J. Clin. Endocrinol. Metab. 100, 1074–1083 (2015).

    Article  CAS  Google Scholar 

  136. Spencer, C. & Fatemi, S. Thyroglobulin antibody (TgAb) methods—strengths, pitfalls and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer. Best. Pract. Res. Clin. Endocrinol. Metab. 27, 701–712 (2013).

    Article  CAS  PubMed  Google Scholar 

  137. Leboulleux, S. et al. Ultrasound criteria of malignancy for cervical lymph nodes in patients followed up for differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 92, 3590–3594 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Leenhardt, L. et al. European Thyroid Association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur. Thyroid. J. 2, 147–159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Pacini, F. et al. Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: a clue to the diagnosis of metastatic differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 74, 1401–1404 (1992).

    CAS  PubMed  Google Scholar 

  140. Leboulleux, S., Schroeder, P. R., Schlumberger, M. & Ladenson, P. W. The role of PET in follow-up of patients treated for differentiated epithelial thyroid cancers. Nat. Rev. Endocrinol. 3, 112–121 (2007).

    Article  Google Scholar 

  141. Wu, D. et al. 124I positron emission tomography/computed tomography versus conventional radioiodine imaging in differentiated thyroid cancer: a review. Thyroid 29, 1523–1535 (2019).

    Article  PubMed  Google Scholar 

  142. Padovani, R. P. et al. One month is sufficient for urinary iodine to return to its baseline value after the use of water-soluble iodinated contrast agents in post-thyroidectomy patients requiring radioiodine therapy. Thyroid 22, 926–930 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Aide, N. et al. Clinical relevance of single-photon emission computed tomography/computed tomography of the neck and thorax in postablation (131)I scintigraphy for thyroid cancer. J. Clin. Endocrinol. Metab. 94, 2075–2084 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Martin Schlumberger.

Ethics declarations

Competing interests

M.S. and S.L. have received personal fees and research support from Bayer, Eisai, Exilixis-IPSEN and Sanofi-Genzyme. No financial support was received from these entities for writing this review.

Additional information

Peer review information

Nature Reviews Endocrinology thanks A. Shaha and F. Verburg for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Thyroid Cancer Genome Atlas (TCGA): https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga/studied-cancers/thyroid

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Schlumberger, M., Leboulleux, S. Current practice in patients with differentiated thyroid cancer. Nat Rev Endocrinol 17, 176–188 (2021). https://doi.org/10.1038/s41574-020-00448-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-020-00448-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing