How to manage patients with undetectable thyroglobulin but thyroid residue after radioiodine ablative therapy in differentiated thyroid carcinoma, retreatment or observation?

Document Type : Original Article


1 Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Radiology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran


Introduction:Differentiated thyroid carcinoma (DTC) follow-up after thyroidectomy and radioiodine-ablation is performed mainly by thyroglobulin (Tg), diagnostic iodine-131 whole body scan (DxWBS) and sonography. Some patients with undetectable Tg have thyroid-bed uptake after ablation in whom decision making regarding the need for retreatment is still controversial.
Methods: In this study, we enrolled DTC patients with undetectable Tg but small thyroid residue in six-month-DxWBS following first radioiodine-ablation. Patients with detectable Tg, high TgAb, suspicious neck lymphadenopathy in sonography and metastasis were excluded. Ninety four patients were placed in two groups of cohort, i.e., radioiodine-retreatment group (n=36) versus observation (untreated) group (n=58). After six months, the clinical outcome was compared by evaluating DxWBS, Tg, TgAb and sonography.
Results: DxWBS showed sustained thyroid remnant in 47.2% of retreated patients while 34.5% of untreated group revealed negative DxWBS over the next period of follow-up. Also, only 6 cases (16.7%) in retreatment group and 12 cases (20.7%) in observation group revealed an additional finding other than local faint RAI uptake, including detectable serum Tg, rising TgAb or suspicious ultrasound finding, favoring no significant difference of the outcome as well as relative risk of new finding incidence between treated and untreated patients (CI 95% for relative risk: 0.58-2.41; p=0.630).

Conclusion: Regarding sonologic and laboratory follow-up evidences, RAI-retreatment shows no significant advantage over observation in DTC patients with Tg negative, remnant positive DxWBS. In addition, residual thyroid tissue was completely disappeared in about one third of patients without retreatment.


Main Subjects

  1. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19(11):1167-214.
  2. Francis GL, Waguespack SG, Bauer AJ Angelos P, Benvenga S, Cerutti JM, Dinauer CA, Hamilton J, Hay ID, Luster M, Parisi MT, Rachmiel M, Thompson GB, Yamashita S; American Thyroid Association Guidelines Task Force. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015 Jul;25(7):716-59.
  3. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD, Lee S, Davies TF, Arafah BM, Ladenson PW, Pinchera A. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab. 2003 Apr;88(4):1433-41.
  4. Kloos RT. Thyroid cancer recurrence in patients clinically free of disease with undetectable or very low serum thyroglobulin values. J Clin Endocrinol Metab. 2010 Dec;95(12):5241-8.
  5. Robbins RJ, Srivastava S, Shaha A, Ghossein R, Larson SM, Fleisher M, Tuttle RM. Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma. J Clin Endocrinol Metab. 2004 Dec;89(12):6010-6.
  6. Giovanella L, Treglia G, Sadeghi R, Trimboli P, Ceriani L, Verburg FA. Unstimulated highly sensitive thyroglobulin in follow-up of differentiated thyroid cancer patients: a meta-analysis. J Clin Endocrinol Metab. 2014 Feb;99(2):440-7.
  7. Chindris AM, Diehl NN, Crook JE, Fatourechi V, Smallridge RC. Undetectable sensitive serum thyroglobulin (<0.1 ng/ml) in 163 patients with follicular cell-derived thyroid cancer: results of rhTSH stimulation and neck ultrasonography and long-term biochemical and clinical follow-up. J Clin Endocrinol Metab. 2012 Aug;97(8):2714-23.
  8. Lee JI, Chung YJ, Cho BY, Chong S, Seok JW, Park SJ. Postoperative-stimulated serum thyroglobulin measured at the time of 131I ablation is useful for the prediction of disease status in patients with differentiated thyroid carcinoma. Surgery. 2013 Jun;153(6):828-35.
  9. Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, Limbert E, Lind P, Pacini F, Reiners C, Sánchez Franco F, Toft A, Wiersinga WM. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol. 2004 Feb;150(2):105-12.
  10. Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A. 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. 2002 Apr;87(4):1499-501.
  11. Durante C, Montesano T, Attard M, Torlontano M, Monzani F, Costante G, Meringolo D, Ferdeghini M, Tumino S, Lamartina L, Paciaroni A, Massa M, Giacomelli L, Ronga G, Filetti S; PTC Study Group. 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. 2012 Aug;97(8):2748-53.
  12. Ma C, Kuang A, Xie J, Ma T. Possible explanations for patients with discordant findings of serum thyroglobulin and 131I whole-body scanning. J Nucl Med. 2005 Sep;46(9):1473-80.
  13. Park EK, Chung JK, Lim IH, Park DJ, Lee DS, Lee MC, Cho BY. Recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy I-131 whole body scans. Eur J Nucl Med Mol Imaging. 2009 Feb;36(2):172-9.
  14. Tuttle RM, Haddad RI, Ball DW, Byrd D, Dickson P, Duh QY, Ehya H, Haymart M, Hoh C, Hunt JP, Iagaru A, Kandeel F, Kopp P, Lamonica DM, Lydiatt WM, McCaffrey J, Moley JF, Parks L, Raeburn CD, Ridge JA, Ringel MD, Scheri RP, Shah JP, Sherman SI, Sturgeon C, Waguespack SG, Wang TN, Wirth LJ, Hoffmann KG, Hughes M. Thyroid carcinoma, version 2.2014. J Natl Compr Canc Netw. 2014 Dec;12(12):1671-80.
  15. Lim DJ, O JH, Kim MH, Kim JH, Kwon HS, Kim SH, Kang MI, Cha BY, Lee KW, Son HY. Clinical significance of observation without repeated radioiodine therapy in differentiated thyroid carcinoma patients with positive surveillance whole-body scans and negative thyroglobulin. Korean J Intern Med. 2010 Dec;25(4):408-14.
  16. Kim EY, Kim WG, Kim WB, Kim TY, Ryu JS, Gong G, Yoon JH, Hong SJ, Lee JH, Baek JH, Shong YK. Clinical outcomes of persistent radioiodine uptake in the neck shown by diagnostic whole body scan in patients with differentiated thyroid carcinoma after initial surgery and remnant ablation. Clin Endocrinol (Oxf). 2010 Aug;73(2):257-63.
  17. Silberstein EB. The treatment of thyroid malignant neoplasms. In: Henkin RE, Bova D, Dillehay GL, Halama JR, Karesh SM, Wagner RH, Zimmer AM, eds. Nuclear medicine. Philadelphia: Mosby Elsevier; 2006. p. 1576–88.
  18. Tuttle RM, Becker DV, Hurley JR. Radioiodine treatment of thyroid diseases. In: Sandler MP, Coleman RE, Patton JA, Wackers FJ, Gottschalk A, eds. Diagnostic nuclear medicine. Philadelphia: Lippincott Williams & Wilkins; 2003. p. 653–70.
  19. Whitley RJ, Ain KB. Thyroglobulin: a specific serum marker for the management of thyroid carcinoma. Clin Lab Med. 2004 Mar;24(1):29-47.
  20. Biko J, Reiners C, Kreissl MC, Verburg FA, Demidchik Y, Drozd V. Favourable course of disease after incomplete remission on (131)I therapy in children with pulmonary metastases of papillary thyroid carcinoma: 10 years follow-up. Eur J Nucl Med Mol Imaging. 2011 Apr;38(4):651-5.
  21. Bachelot A, Leboulleux S, Baudin E, Hartl DM, Caillou B, Travagli JP, Schlumberger M. Neck recurrence from thyroid carcinoma: serum thyroglobulin and high-dose total body scan are not reliable criteria for cure after radioiodine treatment. Clin Endocrinol (Oxf). 2005 Mar;62(3):376-9.
  22. Ciappuccini R, Hardouin J, Heutte N, Vaur D, Quak E, Rame JP, Blanchard D, de Raucourt D, Bardet S. Stimulated thyroglobulin level at ablation in differentiated thyroid cancer: the impact of treatment preparation modalities and tumor burden. Eur J Endocrinol. 2014 Aug;171(2):247-52.
  23. Dai J, Dent W, Atkinson JW, Cox JG, Dembinski TC. Comparison of three immunoassay kits for serum thyroglobulin in patients with thyroid cancer. Clin Biochem. 1996 Oct;29(5):461-5.
  24. Nascimento C, Borget I, Troalen F, Al Ghuzlan A, Deandreis D, Hartl D, Lumbroso J, Chougnet CN, Baudin E, Schlumberger M, Leboulleux S. Ultrasensitive serum thyroglobulin measurement is useful for the follow-up of patients treated with total thyroidectomy without radioactive iodine ablation. Eur J Endocrinol. 2013 Oct 4;169(5):689-93.
  25. Feldt-Rasmussen U, Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, Elisei R, Rimmele H, Seregni E, Smit JW, Theimer C, Giovanella L. Thyroglobulin autoantibodies as surrogate biomarkers in the management of patients with differentiated thyroid carcinoma. Curr Med Chem. 2014;21(32):3687-92.
  26. Verburg FA, Luster M, Cupini C, Chiovato L, Duntas L, Elisei R, Feldt-Rasmussen U, Rimmele H, Seregni E, Smit JW, Theimer C, Giovanella L. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid. 2013 Oct;23(10):1211-25.
  27. Spencer CA. Clinical review: Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab. 2011 Dec;96(12):3615-27.
  28. Giovanella L, Suriano S, Ceriani L, Verburg FA. Undetectable thyroglobulin in patients with differentiated thyroid carcinoma and residual radioiodine uptake on a postablation whole-body scan. Clin Nucl Med. 2011 Feb;36(2):109-12.
  29. Torréns JI, Burch HB. Serum thyroglobulin measurement. Utility in clinical practice. Endocrinol Metab Clin North Am. 2001 Jun;30(2):429-67.
  30. Lupoli GA, Okosieme OE, Evans C, Clark PM, Pickett AJ, Premawardhana LD, Lupoli G, Lazarus JH. Prognostic significance of thyroglobulin antibody epitopes in differentiated thyroid cancer. J Clin Endocrinol Metab. 2015 Jan;100(1):100-8.
  31. Gianoukakis AG. Thyroglobulin antibody status and differentiated thyroid cancer: what does it mean for prognosis and surveillance? Curr Opin Oncol. 2015 Jan;27(1):26-32.
  32. Chung JK, Park YJ, Kim TY, So Y, Kim SK, Park DJ, Lee DS, Lee MC, Cho BY. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf). 2002 Aug;57(2):215-21.
  33. M El-Refaei S1, W Yassin S, Salman K, Al Munshy T, Al-Ezzi M, M Al-Sayed Y, Abd Elkareem Husseni M. Comparison between low and high radioactive iodine (131I) reablation dose in patients with papillary thyroid cancer. Nucl Med Commun. 2015 Feb;36(2):114-9. 
  34. Giovanella L, Piccardo A, Paone G, Foppiani L, Treglia G, Ceriani L. Thyroid lobe ablation with iodine- ¹³¹I in patients with differentiated thyroid carcinoma: a randomized comparison between 1.1 and 3.7 GBq activities. Nucl Med Commun. 2013 Aug;34(8):767-70.
  35. Fallahi B, Beiki D, Takavar A, Fard-Esfahani A, Gilani KA, Saghari M, Eftekhari M. Low versus high radioiodine dose in postoperative ablation of residual thyroid tissue in patients with differentiated thyroid carcinoma: a large randomized clinical trial. Nucl Med Commun. 2012 Mar;33(3):275-82.
  36. Kim EY, Kim TY, Kim WG, Yim JH, Han JM, Ryu JS, Hong SJ, Yoon JH, Gong G, Kim WB, Shong YK. Effects of different doses of radioactive iodine for remnant ablation on successful ablation and on long-term recurrences in patients with differentiated thyroid carcinoma. Nucl Med Commun. 2011 Oct;32(10):954-9.
  37. Du P, Jiao X, Zhou Y, Li Y, Kang S, Zhang D, Zhang J, Lv L, Patel R. Low versus high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: a meta-analysis of randomized controlled trials. Endocrine. 2015 Feb;48(1):96-105.
  38. Bal C, Chandra P, Kumar A, Dwivedi S. A randomized equivalence trial to determine the optimum dose of iodine-131 for remnant ablation in differentiated thyroid cancer. Nucl Med Commun. 2012 Oct;33(10):1039-47.
  39. Han JM, Kim WG, Kim TY, Jeon MJ, Ryu JS, Song DE, Hong SJ, Shong YK, Kim WB. Effects of low-dose and high-dose postoperative radioiodine therapy on the clinical outcome in patients with small differentiated thyroid cancer having microscopic extrathyroidal extension. Thyroid. 2014 May;24(5):820-5.
  40. Cheng W, Ma C, Fu H, Li J, Chen S, Wu S, Wang H. Low- or high-dose radioiodine remnant ablation for differentiated thyroid carcinoma: a meta-analysis. J Clin Endocrinol Metab. 2013 Apr;98(4):1353-60.
  41. Valachis A, Nearchou A. High versus low radioiodine activity in patients with differentiated thyroid cancer: a meta-analysis. Acta Oncol. 2013 Aug;52(6):1055-61.
  42. Rees GJ. Radioiodine ablation for differentiated thyroid cancer-none, one dose or two? Clin Oncol (R Coll Radiol). 2010 Mar;22(2):131-5.
  43. Fard-Esfahani A, Emami-Ardekani A, Fallahi B, Fard-Esfahani P, Beiki D, Hassanzadeh-Rad A, Eftekhari M. Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma. Nucl Med Commun. 2014 Aug;35(8):808-17.
  44. Esfahani AF, Fallahi B, Olamaie R, Eftekhari M, Beiki D, Saghari M. Semi-quantitative assessment of salivary gland function in patients with differentiated thyroid carcinoma after radioiodine-131 treatment. Hell J Nucl Med. 2004 Sep-Dec;7(3):206-9.         
  45. Esfahani AF, Eftekhari M, Zenooz N, Saghari M. Gonadal function in patients with differentiated thyroid cancer treated with (131)I. Hell J Nucl Med. 2004 Jan-Apr;7(1):52-5.            
  46. Fard-Esfahani A, Hadifar M, Fallahi B, Beiki D, Eftekhari M, Saghari M, Takavar A. Radioiodine treatment complications to the mother and child in patients with differentiated thyroid carcinoma. Hell J Nucl Med. 2009 Jan-Apr;12(1):37-40.      
  47. Fard-Esfahani A, Mirshekarpour H, Fallahi B, Eftekhari M, Saghari M, Beiki D, Ansari-Gilani K, Takavar A. The effect of high-dose radioiodine treatment on lacrimal gland function in patients with differentiated thyroid carcinoma. Clin Nucl Med. 2007 Sep;32(9):696-9.      
  48. Fard-Esfahani A, Farzanefar S, Fallahi B, Beiki D, Saghari M, Emami-Ardekani A, Majdi M, Eftekhari M. Nasolacrimal duct obstruction as a complication of iodine-131 therapy in patients with thyroid cancer. Nucl Med Commun. 2012 Oct;33(10):1077-80.
  49. Fallahi B, Adabi K, Majidi M, Fard-Esfahani A, Heshmat R, Larijani B, Haghpanah V. Incidence of second primary malignancies during a long-term surveillance of patients with differentiated thyroid carcinoma in relation to radioiodine treatment. Clin Nucl Med. 2011 Apr;36(4):277-82.
  50. Phan HT, Jager PL, van der Wal JE, Sluiter WJ, Plukker JT, Dierckx RA, Wolffenbuttel BH, Links TP. The follow-up of patients with differentiated thyroid cancer and undetectable thyroglobulin (Tg) and Tg antibodies during ablation. Eur J Endocrinol. 2008 Jan;158(1):77-83.
  51. Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 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 Jan;26(1):1-133.