Research Article
No access
Published Online: 26 April 2019

Individualized Follow-Up Strategy for Patients with an Indeterminate Response to Initial Therapy for Papillary Thyroid Carcinoma

Publication: Thyroid
Volume 29, Issue Number 2


Background: The concept of a dynamic risk-stratification scheme has been suggested for individualized management of patients with papillary thyroid carcinoma (PTC). However, there is no specified follow-up strategy for patients with an indeterminate response.
Methods: This study evaluated 403 PTC patients who had an indeterminate response during the first 12–24 months after initial therapy. All patients underwent total thyroidectomy with radioactive iodine remnant ablation. Patients were further classified into three groups based on risk of structural persistence/recurrence: a Tg+ group (detectable thyroglobulin [Tg], regardless of antithyroglobulin antibody [TgAb] or imaging findings; 196 patients), a TgAb+ group (positive results for TgAb with undetectable Tg, regardless of imaging findings; 46 patients), and an Image+ group (nonspecific findings on neck ultrasonography or faint uptake in the thyroid bed on whole-body scan, with undetectable Tg and negative results for TgAb; 161 patients).
Results: With a median of 9.6 years (interquartile range 7.7–11.2 years) of follow-up, 56 (14%) PTC patients had structural persistent/recurrent disease: 50 (89%) at locoregional sites and six (11%) at distant sites. The recurrence rate in Tg+, TgAb+, and Image + groups were 26.5%, 8.7%, and 0%, respectively. The median time to detection of structural persistent/recurrent disease from the initial thyroid surgery was 3.7 years (interquartile range 2.5–6.3 years). The optimal cutoff stimulated Tg level to predict structural persistent/recurrent disease was 3.1 ng/mL in the Tg+ group. This classification system revealed higher predictability of structural persistent/recurrent disease than the tumor-node-metastasis staging system and American Thyroid Association risk stratification (proportion of variation explained: 15.7% vs. 2.4% and 0.9%, respectively). Six (3%) patients with distant metastatic disease were all classified in the Tg+ group, and all had lung metastasis.
Conclusions: The findings suggest a more individualized follow-up strategy for patients with an indeterminate response. More careful evaluation, including early evaluation of distant metastasis, is necessary in patients with elevated Tg levels. However, for patients testing positive for TgAb or those with only nonspecific imaging findings, regular follow-ups of Tg and TgAb levels and neck ultrasonography are sufficient.

Get full access to this article

View all available purchase options and get full access to this article.


1. Luster M, Weber T, Verburg FA 2014 Differentiated thyroid cancer—personalized therapies to prevent overtreatment. Nat Rev Endocrinol 10:563.
2. Raue F, Frank-Raue K 2016 Thyroid cancer: risk-stratified management and individualized therapy. Clin Cancer Res 22:5012–5021.
3. Grant CS 2014 Papillary thyroid cancer: strategies for optimal individualized surgical management. Clin Ther 36:1117–1126.
4. 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 2016 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 26:1–133.
5. Yi KH 2016 The Revised 2016 Korean Thyroid Association guidelines for thyroid nodules and cancers: differences from the 2015 American Thyroid Association Guidelines. Endocrinol Metab (Seoul) 31:373–378.
6. Nabhan F, Ringel MD 2017 Thyroid nodules and cancer management guidelines: comparisons and controversies. Endocr Relat Cancer 24:R13–R26.
7. Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin JA, Shaha A 2010 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.
8. Jeon MJ, Kim WG, Park WR, Han JM, Kim TY, Song DE, Chung KW, Ryu JS, Hong SJ, Shong YK, Kim WB 2014 Modified dynamic risk stratification for predicting recurrence using the response to initial therapy in patients with differentiated thyroid carcinoma. Eur J Endocrinol 170:23–30.
9. Jeon MJ, Kim TY, Kim WG, Han JM, Jang EK, Choi YM, Song DE, Yoon JH, Chung KW, Hong SJ, Shong YK, Kim WB 2014 Differentiating the location of cervical lymph node metastasis is very useful for estimating the risk of distant metastases in papillary thyroid carcinoma. Clin Endocrinol (Oxf) 81:593–599.
10. Kim EY, Kim TY, Kim WG, Yim JH, Han JM, Ryu J-S, Hong SJ, Yoon JH, Gong G, Kim WB, Shong YK 2011 Effects of different doses of radioactive iodine for remnant ablation on successful ablation and on long-term recurrences in patients with differentiated thyroid carcinoma. Nuclear Medicine Communications 32:954–959.
11. Jeon MJ, Kim WG, Choi YM, Kwon H, Song DE, Lee Y-M, Sung T-Y, Yoon JH, Hong SJ, Baek JH, Lee JH, Ryu J-S, Kim TY, Shong YK, Chung K-W, Kim WB 2015 Recent changes in the clinical outcome of papillary thyroid carcinoma with cervical lymph node metastasis. J Clin Endocrinol Metab 100:3470–3477.
12. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer LM, Gress DM, Byrd DR, Winchester DP 2017 The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population‐based to a more “personalized” approach to cancer staging. CA Cancer J Clin 67:93–99.
13. Shin JH, Han BK, Ko EY, Kang SS 2007 Sonographic findings in the surgical bed after thyroidectomy: comparison of recurrent tumors and nonrecurrent lesions. J Ultrasound Med 26:1359–1366.
14. Epstein S, McEachern R, Khot R, Padia S, Patrie JT, Itri JN 2018 Papillary thyroid carcinoma recurrence: low yield of neck ultrasound with an undetectable serum thyroglobulin level. J Ultrasound Med 37:2325–2331.
15. Kim M, Jeon MJ, Oh HS, Park S, Song DE, Sung TY, Kim TY, Chung KW, Kim WB, Shong YK, Lee YM, Kim WG 2018 Prognostic implication of N1b classification in the eighth edition of the tumor-node-metastasis staging system of differentiated thyroid cancer. Thyroid 28:496–503.
16. Kim M, Kim WG, Oh HS, Park S, Kwon H, Song DE, Kim TY, Shong YK, Kim WB, Sung TY, Jeon MJ 2017 Comparison of the seventh and eighth editions of the American Joint Committee on Cancer/Union for International Cancer Control tumor-node-metastasis staging system for differentiated thyroid cancer. Thyroid 27:1149–1155.
17. Han JM, Kim WB, Yim JH, Kim WG, Kim TY, Ryu JS, Gong G, Sung TY, Yoon JH, Hong SJ, Kim EY, Shong YK 2012 Long-term clinical outcome of differentiated thyroid cancer patients with undetectable stimulated thyroglobulin level one year after initial treatment. Thyroid 22:784–790.
18. Lee JI, Chung YJ, Cho BY, Chong S, Seok JW, Park SJ 2013 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 153:828–835.
19. Lin JD, Huang MJ, Hsu BR, Chao TC, Hsueh C, Liu FH, Liou MJ, Weng HF 2002 Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas. J Surg Oncol 80:45–51.
20. Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC, Hong SJ, Shong YK 2005 Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 90:1440–1445.
21. Piccardo A, Arecco F, Puntoni M, Foppiani L, Cabria M, Corvisieri S, Arlandini A, Altrinetti V, Bandelloni R, Orlandi F 2013 Focus on high-risk DTC patients: high postoperative serum thyroglobulin level is a strong predictor of disease persistence and is associated to progression-free survival and overall survival. Clin Nucl Med 38:18–24.
22. Vaisman F, Momesso D, Bulzico DA, Pessoa CH, Dias F, Corbo R, Vaisman M, Tuttle RM 2012 Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy. Clin Endocrinol (Oxf) 77:132–138.
23. Xu J, Bergren R, Schneider D, Chen H, Sippel RS 2015 Thyroglobulin antibody resolution after total thyroidectomy for cancer. J Surg Res 198:366–370.
24. Kim WG, Yoon JH, Kim WB, Kim TY, Kim EY, Kim JM, Ryu JS, Gong G, Hong SJ, Shong YK 2008 Change of serum antithyroglobulin antibody levels is useful for prediction of clinical recurrence in thyroglobulin-negative patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 93:4683–4689.
25. Spencer CA 2011 Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab 96:3615–3627.
26. Chung JK, Park YJ, Kim TY, So Y, Kim SK, Park DJ, Lee DS, Lee MC, Cho BY 2002 Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf) 57:215–221.
27. Pacini F, Capezzone M, Elisei R, Ceccarelli C, Taddei D, Pinchera A 2002 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.
28. Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger M 2000 Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 85:175–178.
29. Taylor H, Hyer S, Vini L, Pratt B, Cook G, Harmer C 2004 Diagnostic 131I whole body scanning after thyroidectomy and ablation for differentiated thyroid cancer. Eur J Endocrinol 150:649–653.
30. Zaheer S, Tan A, Ang ES, Loke KSH, Kao YH, Goh A, Wong WY 2014 Post-thyroidectomy neck ultrasonography in patients with thyroid cancer and a review of the literature. Singapore Med J 55:177–183.
31. Chua WY, Langer JE, Jones LP 2017 Surveillance neck sonography after thyroidectomy for papillary thyroid carcinoma: pitfalls in the diagnosis of locally recurrent and metastatic disease. J Ultrasound Med 36:1511–1530.
32. Peiling Yang S, Bach AM, Tuttle RM, Fish SA 2015 Frequent screening with serial neck ultrasound is more likely to identify false-positive abnormalities than clinically significant disease in the surveillance of intermediate risk papillary thyroid cancer patients without suspicious findings on follow-up ultrasound evaluation. J Clin Endocrinol Metab 100:1561–1567.
33. Wu JX, Beni CE, Zanocco KA, Sturgeon C, Yeh MW 2015 Cost-effectiveness of long-term every three-year versus annual postoperative surveillance for low-risk papillary thyroid cancer. Thyroid 25:797–803.
34. Mehanna H, Al-Maqbili T, Carter B, Martin E, Campain N, Watkinson J, McCabe C, Boelaert K, Franklyn JA 2014 Differences in the recurrence and mortality outcomes rates of incidental and nonincidental papillary thyroid microcarcinoma: a systematic review and meta-analysis of 21 329 person-years of follow-up. J Clin Endocrinol Metab 99:2834–2843.

Information & Authors


Published In

cover image Thyroid®
Volume 29Issue Number 2February 2019
Pages: 209 - 215
PubMed: 30384812


Published online: 26 April 2019
Published in print: February 2019
Published ahead of print: 14 December 2018
Published ahead of production: 1 November 2018


Request permissions for this article.




Hye-Seon Oh
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Jong Hwa Ahn
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Eyun Song
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ji Min Han
Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea.
Won Gu Kim
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Tae Yong Kim
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Won Bae Kim
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Young Kee Shong
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Min Ji Jeon [email protected]
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.


Address correspondence to: Min Ji Jeon, MD, PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea [email protected]

Author Disclosure Statement

No competing financial interests exist.

Metrics & Citations



Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options


View PDF/ePub

Full Text

View Full Text







Copy the content Link

Share on social media

Back to Top