Chinese Society of Clinical Oncology (CSCO) diagnosis and treatment guidelines for persistent/recurrent and metastatic differentiated thyroid cancer 2018 (English version).

1.  Diagnosis and dynamic assessment of persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC)

Differentiated thyroid cancer (DTC), including papillary, follicular and Hürthle cell types, accounts for nearly 95% of all thyroid carcinomas. The concept of DTC recurrence or persistence after surgery is still difficult to define due to its indolent nature. The recurrent or persistent tumors in this guideline refer to new lesions or residual tumors found during the follow-up after initial treatments.

1.1  Basic principles of diagnosis

The role of multidisciplinary team (MDT) should be emphasized during the diagnosis of prmDTC. A task force of specialists with complementary expertise (endocrinology, surgery, nuclear medicine, radiology, pathology, oncology, molecular diagnostics, and epidemiology) should be included in the MDT management of prmDTC. The diagnosis or further managements of prmDTC which may include surgical managment, radioiodine-131 (131I) therapy, thyroid stimulating hormone (TSH) suppressive therapy, as well as molecular targeted therapy (or being enrolled in certain clinical trial) or radiation therapy, etc., should be tailored according to comprehensive consideration of MDT.

1.2  Diagnostic methods

Laboratory tests, imaging studies and pathological examinations are recommended in the diagnosis of prmDTC ().

1.3  Ongoing assessment of response to therapy ()

As the risk of recurrence and cancer-related death in prmDTC may change over time, life long follow-up and periodical surveillance including laboratory and imaging evaluation are needed. Ongoing assessment of response to therapy should be used to guide the long-term surveillance and therapeutic management decision. In this guideline, we adopted the system of response to therapy which was put forward by 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer.

Multiple factors including clinical, biochemical, imaging (structural and functional) and cytopathology findings were taken into comprehensive consideration in this response system to assess the individual response to therapy during follow-up. It has been verified as an objective ongoing evaluation system to reflect the clinical outcomes from both the risk of recurrence and mortality (1). Four categories including excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR) and structural incomplete response (SIR) are used to describe clinical outcomes at any time after initial treatment (1).

References

Haugen, BR, Alexander EK, Bible KC, 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.

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Wang C, Zhang X, Li H, et al. Quantitative thyroglobulin response to radioactive iodine treatment in predicting radioactive iodine-refractory thyroid cancer with pulmonary metastasis. PLoS One 2017;12:e0179664.

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Cong H, Liang J, Li F, et al. Changes in thyroglobulin antibodies after treatment of differentiated thyroid cancer and its influence factors. Zhongguo Yi Xue Ke Xue Yuan Xue Bao (in Chinese) 2015;37:61-5.

Leenhardt L, Erdogan MF, Hegedus L, et al. 2013 European thyroid association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer. Eur Thyroid J 2013;2:147-59.

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Sheikh A, Polack B, Rodriguez Y, et al. Nuclear molecular and theranostic imaging for differentiated thyroid cancer. Mol Imaging Radionucl Ther 2017;26(Suppl 1):50-65.

Chen L, Luo Q, Shen Y, et al. Incremental value of 131I SPECT/CT in the management of patients with differentiated thyroid carcinoma. J Nucl Med 2008;49:1952-7.

Long B, Yang M, Yang Z, et al. Assessment of radioiodine therapy efficacy for treatment of differentiated thyroid cancer patients with pulmonary metastasis undetected by chest computed tomography. Oncol Lett 2016;11:965-8.

Song HJ, Qiu ZL, Shen CT, et al. Pulmonary metastases in differentiated thyroid cancer: efficacy of radioiodine therapy and prognostic factors. Eur J Endocrinol 2015;173:399-408.

Qiu ZL, Xue YL, Song HJ, et al. Comparison of the diagnostic and prognostic values of 99mTc-MDP-planar bone scintigraphy, 131I-SPECT/CT and 18F-FDG-PET/CT for the detection of bone metastases from differentiated thyroid cancer. Nucl Med Commun 2012, 33:1232-42.

Giraudet AL, Taïeb D. PET imaging for thyroid cancers: Current status and future directions. Ann Endocrinol (Paris) 2017;78:38-42.

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Haslerud T, Brauckhoff K, Reisæter L, et al. F18-FDG-PET for recurrent differentiated thyroid cancer: a systematic meta-analysis. Acta Radiol 2016;57:1193-200.

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Ambrosi F, Righi A, Ricci C, et al. Hobnail Variant of Papillary Thyroid Carcinoma: a Literature Review. Endocr Pathol 2017;28:293-301.

Professional Committee of Thyroid Cancer, Chinese Society of Clinical Oncology. Consensus on diagnosis and treatment of recurrent and metastatic differentiated thyroid cancer. China Oncology 2015;25:481-96.

Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab 2011;96:3390-7.

2.  Multidisciplinary treatment of prmDTC

2.1  Basic principles of treatment

Treatment options for prmDTCs usually include surgical resection, 131I therapy of lesions that can uptake 131I, external beam radiation therapy, active follow-up under L-T4 suppression therapy and other options (e.g., targeted medicines, radiofrequency or ethanol ablation). Among them, surgery should be the first choice for resectable lesions with surgical indications.

2.2  Surgical management

PrmDTCs are commonly seen in clinical practice, approximately 95% of which occur in the neck (1). Since the difficulty and risk of reoperation increase significantly, the risks and benefits of surgery must always be balanced when selecting reoperation. Surgery should be performed by experienced specialists, and frequently even under multidisciplinary collaboration.

2.2.1  Preoperative clinical assessment

Preoperative clinical assessment includes the review of previous treatments, current status of the disease and vital organ function, which are the basis for the decision regarding intervention and extent of revision surgery. Structural lesions are required as a target for a surgical revision approach, therefore, imaging evaluation is of the utmost importance to surgeons to identify and localize the structural lesions ().

2.2.2  Principles of surgical treatment for prmDTC

The timing and extent of surgery are the most important issues which should be considered when the surgical management of prmDTC is decided. In general, the goal of revision surgery should be to try to cure or control the disease, improve survival, and preserve the function of the vital organs as far as possible ().

References

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Tufano RP, Clayman G, Heller KS, et al. Management of recurrent/persistent nodal disease in patients with differentiated thyroid cancer: a critical review of the risks and benefits of surgical intervention versus active surveillance. Thyroid 2015;25:15-27.

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Rondeau G, Fish S, Hann LE, et al. Ultrasonographically detected small thyroid bed nodules identified after total thyroidectomy for differentiated thyroid cancer seldom show clinically significant structural progression. Thyroid 2011;21:845-53.

Clayman GL, Agarwal G, Edeiken BS, et al. Long-term outcome of comprehensive central compartment dissection in patients with recurrent/persistent papillary thyroid carcinoma. Thyroid 2011;21:1309-16.

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Merdad M, Eskander A, Kroeker T, et al. Predictors of level II and Vb neck disease in metastatic papillary thyroid cancer. Arch Otolaryngol Head Neck Surg 2012;138:1030-3.

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2.3  131I therapy

131I therapy is one of the important adjuvant postoperative treatment modalities for prmDTC patients. It can reduce the risks of tumor recurrence, metastasis and death in high risk population (1,2), and significantly improve the 5- and 10-year survival for high-risk DTC patients with iodine-avid lesions (3-9).

131I therapy is recommended in patients with iodine-avid prmDTC lesions, and should be repeated at an interval of 6−12 months as long as the lesions continue to concentrate radioiodine and respond clinically. In addition, cumulative radioiodine activities, balance between benefits and risks, and patient preferences, are relevant to131I therapy decision-making. Patients with TSH stimulation and iodine preparation, whose lesions no longer concentrate 131I or respond to 131I therapy, are identified as radioactive iodine refractory DTC (RAIR-DTC) in four basic ways: 1) the malignant metastatic lesion does not ever concentrate RAI (no uptake outside the thyroid bed at the first therapeutic WBS); 2) the tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease (in the absence of stable iodine contamination); 3) RAI is concentrated in some lesions but not in others; and 4) disease progresses despite significant concentration of RAI (10).

2.3.1  Clinical assessment before 131I therapy

Clinical information, as well as the status exactly before 131I therapy should be considered for tailoring the management of prmDTC (). Further surgical consultation should be advised if a patient has lesions which might be amenable to surgery. While in terms of the clinical information, evaluation of the response to previous therapeutics is critical for subsequent 131I therapy of prmDTC, for instance, a previous 131I unresponsive patient would be unlikely to benefit from another repeated 131I therapy.

References

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Haugen BR, Alexander EK, Bible KC, 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.

Chinese Society of Nuclear Medicine. Clinical guidelines for 131I therapy of differentiated thyroid cancer. Zhonghua He Yi Xue Yu Fen Zi Ying Xiang Za Zhi (in Chinese) 2014;34:264-78.

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Yang X, Li J, Li X, et al. TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. J Nucl Med 2017;58:258-65.

2.3.2  Management of 131I therapy for prmDTC

Indications and dose determination of 131I therapy for prmDTC are addressed in terms of the sites of metastases ().

References

Chinese Society of Nuclear Medicine. Clinical guidelines for 131I therapy of differentiated thyroid cancer. Zhonghua He Yi Xue Yu Fen Zi Ying Xiang Za Zhi (in Chinese) 2014;34:264-78.

Haugen, BR, Alexander EK, Bible KC, 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.

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Song HJ, Qiu ZL, Shen CT, et al. Pulmonary metastases in differentiated thyroid cancer: efficacy of radioiodine therapy and prognostic factors. Eur J Endocrinol 2015;173:399-408.

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2.4  TSH suppression therapy

2.4.1  Strategy for TSH suppression therapy

For prmDTC that expresses TSH receptor, TSH suppression therapy is important in postoperative management of differentiated thyroid cancer. It has been realized the optimal degree of TSH suppression varies. An individually tailored approach to deciding TSH targets in prmDTC patients considering risk of side effects has been raised ().

References

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2.4.2  Management of adverse effects of TSH suppression therapy

When TSH has to be suppressed below the normal range (i.e. subclinical thyrotoxicosis) for a long period, especially below 0.1 mU/L, it may cause adverse effects (AEs) ().

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2.5  External beam radiation therapy

External beam radiation therapy (EBRT) is an effictive and safe local therapy with benefit to local control and palliative care for prmDTC. EBRT, stereotactic radiation therapy (SBRT) and other local therapies can be used for symptomatic, weight-bearing, key site metastasis, and oligo-metastasis ().

References

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2.6  Systemic therapy

Close follow-up is recommended in patients identified as RAIR-DTC. The degree of disease progression should be factored into treatment decisions. Systemic therapy, including chemotherapy and molecular targeted therapy, should be considered in RAIR-DTC patients with rapidly progressive and/or symptomatic disease. Potential benefits and risks of systemic therapy should be thoroughly balanced in the candidates (, ).

References

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Chinese Society of Endocrinology, Chinese Society of General Surgery Endocrinology Group, China Anti-Cancer Association Head and Neck Tumor Professional Committee, et al. Guidelines on the Diagnosis and Treatment of Thyroid Nodules and Differentiated Thyroid Carcinomas. Zhonoghua Nei Fen Mi Dai Xie Za Zhi (in Chinse) 2012;28:779-97.

Perros P, Boelaert K, Colley S, et al. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf) 2014;81 Suppl 1:1-122.

Pacini F, Castagna MG, Brilli L, et al. Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012 Suppl 7;23:110-9.

Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomized, double-blind, phase 3 trial. Lancet 2014;384:319-28.

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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.

Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675-84.

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Working group members

Chair: Yansong Lin

Associate chair: Huiqiang Huang, Ye Guo, Libo Chen

Task force member (listed alphabetically by last name) (

Jiandong Bao　 Jiangsu Institute of Nuclear Medicine, Jiangsu Jiangyuan Hospital, Wuxi Institute of Thyroid Diseases

Ge Chen　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Libo Chen* 　 Shanghai Jiao Tong University Affiliated Sixth People’s Hospital

Yali Cui　 Affiliated Tumor Hospital, Harbin Medical University

Yong Ding* 　 Beijing People’s Liberation Army 307 Hospital

Haixia Guan* 　 The First Hospital of China Medical University

Ye Guo* 　 Shanghai East Hospital, Tongji University

Zairong Gao* 　 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Huiqiang Huang　 Affiliated Tumor Hospital, Sun Yat-sen University

Rui Huang* 　 West China Hospital, Sichuan University

Tao Huang　 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Xiaorong Hou* 　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xiayun He* 　 Cancer Hospital, Fudan University

Mei Li* 　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Shaohua Li　 Nanjing First Hospital

Xiaoyi Li* 　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xuena Li　 The First Hospital of China Medical University

Yujun Li　 Affiliated Hospital of Qingdao University, Qingdao University

Zhiyong Liang* 　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Yukun Luo　 Chinese People’s Liberation Army General Hospital

Yansong Lin* 　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jing Lyu　 Affiliated Hospital of Qingdao University, Qingdao University

Qingjie Ma　 China-Japan Union Hospital, Jilin University

Lijuan Niu* 　 Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Wenhai Sun　 Affiliated Hospital of Qingdao University, Qingdao University

Feng Wang　 Nanjing First Hospital

Renfei Wang* Tianjin Medical University General Hospital, Tianjin Medical University

Feng Wei　 First Affiliated Hospital, Baotou Medical College, Inner Mongolia University of Science and Technology

Yu Xia　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Aiming Yang　 The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an Jiaotong University

Bin Zhang* 　 Peking University Cancer Hospital & Institute

Bo Zhang* Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Guang Zhang* 　 China-Japan Union Hospital, Jilin University

Hong Zhang　 Sun Yat-sen Memorial Hospital, Sun Yat-Sen University

Li Zhang　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Xiangqian Zheng* 　 Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University

Review expert committee (listed alphabetically by last name)

Rui An　 Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Jugao Fang　 Beijing Tongren Hospital, Capital Medical University

Youben Fan Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University

Ming Gao　 Tianjin Medical University Cancer Institute & Hospital, Tianjin Medical University

Zhuming Guo　 Sun Yat-sen University Cancer Center, Sun Yat-sen University

Gang Huang　 Shanghai University of Medicine & Health Sciences

Qinghai Ji　 Fudan University Shanghai Cancer Certer, Fudan University

Ningyi Jiang　 Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

Yuxin Jiang Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Anren Kuang　 West China Hospital, Sichuan University

Fang Li　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Sijin Li　 First Hospital of Shanxi Medical University, Shanxi Medical University

Yaming Li　 The First Hospital of China Medical University

Shaoyan Liu　 Cancer Hospital Chinese Academy of Medical Sciences, Chinese Academy of Medical Sciences

Hui Sun　 China-Japan Union Hospital, Jilin University

Zhongyan Shan　 The First Hospital of China Medical University

Jian Tan　 Tianjin Medical University General Hospital, Tianjin Medical University

Wen Tian　 Chinese People’s Liberation Army General Hospital

Jing Wang　 Xijing Hospital, Fourth Military Medical University

Tie Wang　 Beijing Chaoyang Hospital, Capital Medical University

Xiaoping Xing　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Zhengang Xu　 Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College

Fuquan Zhang　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jiajun Zhao　 Shandong Provincial Hospital

Yupei Zhao　 Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences

Jingqiang Zhu　 West China Hospital, Sichuan University

Secretary(listed alphabetically by last name)

Hui Li　 Peking Union Medical College Hospital, Peking Union Medical College, Academy of Medical Science

Jiao Li　 Affiliated Hospital of Qingdao University, Qingdao University

Li Li　 Peking University International Hospital

Yingjie Zhang　 Shandong Cancer Hospital & Institute

Teng Zhao　 Beijing Chaoyang Hospital, Capital Medical University

Sonographic features of persistent/recurrent and metastatic differentiated thyroid cancers (prmDTCs). (A, B) Local recurrence of thyroid bed (among cursors and arrows); (C−E) Suspicious metastatic lymph nodes; (F, G) Recurrence in soft tissue (among cursors); (H) Venous tumor thrombus; (I) Tracheal invasion (arrow point). M, mass; IJV, internal jugular vein; CCA, common carotid artery.

1

Diagnostic methods of prmDTC

Methods	Level I recommendation	Level II recommendation
a, Thyroglobulin (Tg) monitoring facilitates postoperative assessment and risk stratification. Low serum Tg level has a high negative predictive value in the absence of thyroglobulin antibody (TgAb) interference after initial treatment (1). Thyroglobulinemia out of proportion to what is seen on 131I-whole body scan (WBS) indicates the presence of distant metastasis (1-3). Tg also holds value in predicting the response or resistance to 131I therapy (4,5). b, Simultaneous monitoring of Tg and TgAb levels is needed. The presence of TgAb will falsely lower serum Tg determinations in immunometric assays, and in this clinical setting, the serial monitoring of TgAb level may serve as a surrogate prognostic marker (6,7). c, Ultrasound (US) is considered the first-line imaging study for assessing locoregional lesions of persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC), and experienced radiologists may enhance the diagnostic credibility in the management of such patients (1,8-11). d, The assessment of cervical ultrasonography includes cervical lymph nodes, thyroid beds, soft tissue, blood vessels, trachea and esophagus. Sonographic features of prmDTC are as follows (Figure 1). e, Frequently, it is not easy to distinguish thyroid bed recurrence from benign nodules. Interpretation of neck US should take into account clinical and biological data. f, Cross-sectional imaging studies, computed tomography (CT) or magnetic resonance imaging (MRI) with intravenous (IV) contrast, are recommended for suspicious prmDTC (12,13). g, 131I-WBS and single photon emission computed tomography (SPECT)/CT can be used to locate the iodine-avid foci, which is helpful in tailoring the subsequent 131I therapy (14,15). h, CT is routinely recommended for assessing patients with pulmonary metastases, 131I-WBS may play a complementary role in some patients with micrometastatic lesions which may be missed by chest CT (16,17). i, MRI is routinely recommended for assessing cerebral metastases (1). j, Bone scan is recommended for assessing suspicious bone metastases (18). k, 18F-fluorodeoxyglucose (18F-FDG) PET/CT is recommended in patients with elevated Tg (generally >10 ng/mL) or TgAb, especially in patients with non-radioiodine-avid foci ( 1,19-22). It may also be considered as a part of initial staging in poorly or invasive DTC and serve as a prognostic tool in prmDTC, especially in predicting those who are unlikely to benefit from 131I therapy (1). l, The gross examination should include the following: specimen type, tumor location, tumor size, gross morphology, relationship between the tumor and adjacent tissue structures, number of lymph nodes detected, size, and group. m, Microscopic examination should include the following: morphological variants, tumor size, dissemination, invasion range, resection margin, vascular invasion, nerve invasion, lymph node metastasis and total number, and TNM staging. For cases with morphological PTC, if possible, the possible histologic subtypes that may indicate poor prognosis, such as tall cell variant, columnar cell variant, diffuse sclerosing variant and hobnail variant, should be further reported (23). n, Commonly used immunohistochemical markers for determining the origin include CK, Tg, TTF-1, TTF-2, PAX-8, Syn, CgA, Calcitonin and CEA (24). Commonly used immunohistochemical markers for distingushing malignancy from benign lesion include galectin-3, HBME-1, CK19, CD56, E-cadherin, p27, cyclinD1, p53, Ki-67 index, etc. (24). o, Common molecular markers used to indicate malignancy or benign lesion include BRAFV600E, NRAS 61 codon, HRAS 61 codon and KRAS 12/13 codon mutations, RET/PTC and PAX8/PPARγ rearrangements, etc. (25).
Laboratory diagnosis	Serum Tga and TgAbb (2A)	Tg washout determination (2A)
Imaging diagnosis	Various image detections are as follows:
Suspected local lesions	Neck ultrasoundc−e (2A), contrast CT or contrast MRIf (2A)	Ultrasound-guided fine needle aspiration cytology (2A), 131I-WBS + SPECT/CTg (2A), 18F-FDG PET/CT (2A)
Suspected distant metastasis	CTh (2A), 131I-WBS + SPECT/CT (2A), MRIi (suspected nervous system involvement) (2A), bone scanj (suspected bone involvement) (2A)	MRI (when organs other than the nervous system are involved) (2A), 18F-FDG PET/CTk (2A)
Pathological diagnosis
Previous pathology results	Confirmation of previous primary lesions	Review previous tissue specimens
Present pathology results	General inspectionl, microscopic examinationm of biopsy specimens	Immunohistochemistryn, molecular pathologyo (2A)

2

Stratification of ongoing assessment of response to therapy

Stratification		Definition (serology and imaging meet simultaneously)			Level I recommendation
		Serology	Imaging
Tg, thyroglobulin; TgAb, thyroglobulin antibody; TSH, thyroid stimulating hormone; FDG, fluorodeoxyglucose. a, The risk of recurrence ranged from 1% to 4% over 5−10 years among ER patients. b, 15%−20% of IDR patients are reclassified as persistent/recurrent disease over approximately 10 years. c, 8%−17% of BIR patients developing structurally identifiable disease over 5−10 years. d, Death from disease was seen in 11% of patients with a loco-SIR and in 57% of patients with distant SIR.
Excellent responsea (ER)		Suppressive Tg <0.2 ng/mL or stimulated Tg <1 ng/mL	Negative		Decrease of the intensity and frequency of follow-up and the degree of TSH suppression (1A)
Indeterminate responseb (IDR)		Non-stimulated Tg detectable, but less than 1 ng/mL. Stimulated Tg detectable, but less than 10 ng/mL. Or Tg antibodies stable or declining in the absence of structural or functional disease	Non-specific findings on imaging studies. Or faint uptake in thyroid bed on RAI scanning		Continuing observation with appropriate serial imaging of the nonspecific lesions and serum Tg monitoring. Nonspecific findings that become suspicious over time can be further evaluated with additional imaging or biopsy (1A)
Biochemical incomplete responsec (BIR)		Suppressed Tg >1 ng/mL, Stimulated Tg >10 ng/mL. Or rising TgAb levels	Negative		Those with stable or decreasing serum Tg levels may continue TSH suppression therapy and follow-up; patients with elevated serum Tg or TgAb should prompt additional investigations and potentially additional therapies (1A)
Structural incomplete responsed (SIR)		Serum Tg or TgAb at any level	Structural or functional evidence of disease		Additional treatments or ongoing observation depending on multiple clinicopathologic factors including the size, location, rate of growth, RAI avidity, 18FDG avidity, and specific pathology of the structural lesions (1A)

3

Recommendations of preoperative clinical assessment

Evaluation contenta	Level I recommendation	Level II recommendation	Level III recommendation
PTH, parathyroid hormone; CT, computed tomography; MRI, magnetic resonance imaging; WBS, whole body scan; SPECT, single photon emission computed tomography; FDG, fluorodeoxyglucose. a, Thyroglobulin (Tg), Tg antibody (TgAb) and imaging examinations can be used to evaluate the current state of disease. Neck ultrasonography is the most important technique to detect structural lesions (2,3).
Clinical data	Preoperative and pathological record review Complications of previous surgery, such as hematoma, infection, etc. Physical exam, esp. special signs for recurrent metastases.	—	—
Laboratory tests	Serum Tg, TgAb, see 1.2 Diagnostic methods (2A) Parathyroid function evaluation: serum calcium and PTH levels	—	—
Routine examination	Neck ultrasound (2A) Contrast neck CT or MRI, chest CT, etc. See 1.2 Diagnostic methods (2A) Assessment of vocal cords movement and recurrent laryngeal nerve function assessment Laryngoscopy, when trachea involvement is suspected. Esophagoscopy, when esophagus involvement is suspected.	CT angiogram or MR angiogram (MRA) when suspected of vascular involvement 131I-WBS + SPECT/CT and 18F-FDG PET/CT if necessary, see 1.2 Diagnostic methods (2A)	—

4

Recommendations of surgical treatment principles

Lesions	Level I recommendation	Level II recommendation	Level III recommendation
Cervical lesions without invasion to surrounding vital structuresa
Central 　compartment	Preservation in situ or autotransplantation of parathyroid glandsb (2A)	Active follow-up: lesion <8 mm in the smallest dimension (2A) Consider reoperation: lesion ≥8 mm in the smallest dimension (2A) Preoperative FNA (2A) Completion of thyroidectomy and standardized central compartment neck dissection (2A) Intraoperative Neuromonitoring (IONM) of the recurrent laryngeal nerveb (2A)	Ipsilateral central neck dissection in patient without bilateral central compartment involvement (2B)
Lateral 　compartment	—	Active follow-up: lesion <10 mm in the smallest dimension (2A) Consider reoperation: lesion ≥10 mm in the smallest dimension (2A) Preoperative FNA (2A) Therapeutic modified radical neck dissection and preservation of vital structures for previously undissected compartments (2A) Limited neck dissection (generally includes levels II, III, IV, or 1-2 levels of them) for previously managed compartments, due to extensive scar and unclear anatomy (2A)	—
Cervical lesions with invasion to surrounding vital structuresc
Recurrent 　laryngeal nerve 　involvementd	Shave the tumor off as much as possible and preserve the nerve in patient without vocal cord paralysis (2A) Remove lesions and the affected nerve in patient with preoperative vocal cord paralysis or intraoperative finding of complete tumor encapsulation of the nerve (2A)	Nerve reinnervation simultaneously at surgery after resection or injury of the nerve, if feasible (2A) Second-look operation with nerve repair for postoperative identification of recurrent laryngeal nerve injury (2A)	—
Airway/digestive 　tract (larynx 　trachea/ 　esophagus) 　involvemente	—	Consider shaving tumor in patient with no intraluminal tumor invasion (2A) Resection of the lesion and involved organs in patient with intraluminal tumor invasion; If feasible, simultaneous airway/digestive tract repair and reconstruction, otherwise, tracheostomy (2A) Palliative surgery, such as tracheostomy or gastrostomy, in patients having asphyxiation or hemoptysis symptoms with unresectable lesions (2A)	—
Table 4 (continued)

5

Recommendations of pretherapeutic evaluation for initial/further 131I therapy in prmDTC patients

Evaluation content	Level I recommendation	Level II recommendation	Level III recommendation
prmDTC, persistent/recurrent and metastaticdifferentiated thyroid cancer; WBS, whole body scan; CT, computed tomography; MRI, magnetic resonance imaging; FDG, fluorodeoxyglucose; PET, positron emission tomography. a, Serum TSH should be >30 mIU/L through L-T 4 withdrawl before 131I therapy (11,12). Currently, thyrogen is not approved by CFDA. b, Diagnostic WBS (Dx-WBS) can be used for identifying radioiodine-avid lesions, tailoring dosage of 131I, and predicting the efficacy of 131I therapy (1). c, BRAFV600E mutation is the most common oncogenic mutation and related to aggressive disease, recurrence and mortality. BRAFV600E mutation in isolation or in combination with TERT mutation appears to be associated with more aggressive tumor behavior, and more likely to be refractory to 131I therapy (1,13,14).
Clinical information	Evaluate the response and adverse events to previous therapeutics, including surgery, 131I therapy, and TSH suppression, etc.a Physical examination	—	—
Laboratory tests	Thyroid hormones, TSH (2A) Tg, TgAb (2A) Complete blood count, hepatic and renal function test	Serum/Urine iodine measurement	—
Routine examination	Electrocardiogram (ECG)	Cardiac ultrasound or dynamic ECG	—
Imaging examination	Diagnostic 131I WBSb (2A) Cervical ultrasonography (2A) CT (2A)	Bone scan (2A) MRI (2A) 18F-FDG PET/CT (2A)	—
Pathological examination	—	BRAFV600E mutation detectionc (2A)	—

6

Recommendations for 131I administration in prmDTC patients

Items	Recommendation
	Level I	Level II	Level III
Indications of 131I therapy for prmDTC
Local lesions	—	131I therapy (iodine-avid lesions)a (2A)	—
Lung metastases	131I therapy (iodine-avid lesions)b (1B)	—	—
Bone metastases	—	131I therapy (iodine-avid lesions)c (2A)	—
Brain metastases	—	—	131I therapy (iodine-avid lesions)d (2B)
Tg(+)131I(−)	—	—	Empirical 131I therapye
Preparation for 131I therapy
TSH >30 mIU/L	Levothyroxine (L-T4) withdrawal for at least 2−4 weeks (2A)	Liothyronine (L-T3) may be substituted for L-T4 for at least 4 weeks, and then should be withdrawn for at least 2 weeks (2A) rhTSHf (2A)	—
Low iodine diet	Low iodine diet for at least 2 weeksg (2A)	—	—
Table 6 (continued)

7

Strategy for TSH suppression therapy

Treatment period	Level I recommendation	Level II recommendation
ER, excellent response; IDR, indeterminate response; BIR, biochemical incomplete response; SIR, structural incomplete response. a, If the tumor is poorly differentiated and no longer expresses thyroid stimulating hormone (TSH) receptor, only thyroid hormone replacement is needed (1,2). b, The initial treatment period refers to within one year after the persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC) being treated with surgery and/or radioactive iodine (3,4). c, The long-term follow-up period refers to one year after the prmDTC being treated with surgery and/or radioactive iodine (3,4). TSH suppression goals may not be uniform and should be adjusted according to results of surveillance (5-8).
Whole-coursea	Applicable patients: prmDTC expresses TSH receptor (category 1A) First-line medication: oral L-T4 agents (category 1A) Starting L-T4 dose: based on patient's age and co-existing diseases Final L-T4 dose: titrated according to patient’s TSH goal and results of monitoring (category 1A) Check TSH every 4−6 weeks during the L-T4 dose adjustment (category 1A)	— Extend intervals of TSH monitor to 3−6 months once TSH reaches the goal (category 2A)
Initial periodb	TSH target based on risks of TSH suppression therapy (category 1A) -Low risk: <0.1 mU/L (category 2A) -High risk: If tolerated, <0.1 mU/L to lower normal limit (category 2A)	—
Long-term follow-up periodc	TSH target based on dynamic assessments (category 2A)	-ER: lower normal limit to 2.0 mU/L (category 2A) -IDR: around the lower normal limit of TSH (category 2A) -BIR: 0.1 mU/L to lower normal limit; If risk of side effects of TSH suppression is low, <0.1 mU/L (category 2A) -SIR: If tolerated, <0.1 mU/L (category 2A)

8

Management of adverse effects of TSH suppression therapy

Adverse events (AE)	Level I recommendation	Level II recommendation
a,When thyroid stimulating hormone (TSH) has to be suppressed below the normal range (i.e. subclinical thyrotoxicosis) for a long period, especially below 0.1 mU/L, it may cause AE, mainly involving cardiovascular system, as well as skeletal system in postmenopausal women (1-5). b, Patients with underlying heart diseases or high risk of cardiovascular events should be given appropriate treatments by specialists, and their TSH targets should be adjusted accordingly (6-9). c, Particular attention is warranted for female patients after menopause (10).
All AEa	Set individualized TSH targets, monitor AEs and adjust L-T4 doses in a timely manner (1A)	—
Cardiovascular AEb	Baseline cardiovascular assessment (2A), β blockers (2A)	—
Skeletal system AEc	Baseline skeletal assessment (2A), primary prevention of osteoporosis (OP); anti-OP treatment (2A)	—

9

Recommendation of external beam radiation therapy for prmDTC

Lesions	Level I recommendation	Level II recommendation	Level III recommendation
a, External beam radiation therapy (EBRT) and stereotactic radiation therapy (SBRT) can be considered for persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC), such as local recurrence and distant metastasis, especially for non-iodine-avid disease or RAI-rafractory throid cancer (1,2). b, The optimal target volume and dose for EBRT are still controversial (3,4). Conventional fractionation radiotherapy dose is: 1) Gross target volume (GTV, mainly including recurrent or residual tumor regions, metastase): 60−70 Gy; and 2) Clinical target volume (CTV, mainly including subclinical area): 50−60 Gy (5). Precise radiotherapy technologies, such as intensity-modulated radiotherapy (IMRT) and image guided radiotherapy (IGRT), are safe, effective, and less morbid (6,7). c, In the case of DTC lung metastases, EBRT or SBRT mainly applies to: 1) Single or oligo-metastasis (the definition of oligo-metastasis is not uniformly standardized, and it is generally considered that the number of metastases is ≤3−4); and 2) Lung metastases that do not intake iodine (8). d, EBRT or SBRT can be mainly considered for symptomatic skeletal metastases or those that are asymptomatic in weight-bearing sites. The main role is to relieve the pain symptoms, reduce the risk of pathological bone events, and improve the quality of life (9,10). e, EBRT or SBRT is one of the main treatments for brain metastases regardless of the number and size of lesions, or the iodine intake status. Once brain metastases are diagnosed, disease-specific mortality is very high (67%), with median survival of 12.4 months. Survival can be significantly improved by neurosurgical resection. With the development of radiotherapy techniques, SBRT can achieve similar results to neurosurgery (11-13).
Local recurrent lesions	—	EBRT (unresectable local recurrent lesions)a,b (2A)	—
Metastatic lesions	—	—	—
Lung metastases	—	EBRT/SBRT (single or oligo-metastasis)c (2A)	EBRT/SBRT (selective for multiple metastases) (2B)
Bone metastases	—	EBRT/SBRT (symptomatic or weight bearing bones)d (2A)	—
Brain metastases	EBRT/SBRT (single or oligo-metastasis)e (2A)	EBRT/SBRT (multiple metastases) (2B)	—
Other metastases	—	EBRT/SBRT (non-iodine-avid disease, palliative relief of local symptoms) (2B)	—

10

Stratified recommendations for potential systemic therapy in RAI-refractory prmDTC patients

Stratificationa	Level I recommendation	Level II recommendation	Level III recommendation
a, Patients with very indolent disease who are asymptomatic may not be appropriate for systemic therapy, and the follow-up strategy of every 3−6 months is recommended. Whereas patients with more rapidly progressive disease may benefit from systemic therapy (1,2). b, The following points should be taken into consideration when patients are tentatively regarded as candidates for molecular targeted therapy (3-7): 1) The benefit of molecular targeted therapy may primarily yield the prolongation of progression-free survival (PFS) rather than overall survival (OS); 2) Molecular targeted drugs may induce adverse effects and result in low quality of life (QoL); and 3) Despite radioactive iodine refractory (RAIR), the disease may remain stable for several months to several years. c, Sorafenib is the first targeted drug applied in a completed randomized, double-blind, phase 3 trial for the treatment of locally advanced or metastatic RAIR-DTC (8). It was approved by China Food and Drug Administration (CFDA) in March 2017 for the treatment of progressive RAIR-DTC (9). Considering the balance of efficacy and side effects, 400 mg b.i.d. has been commonly utilized in most clinical trials (10-13); but the applications of low-dose sorafenib (200 mg b.i.d.) for treatment of RAIR-DTC could also achieve well efficacy with slight side effects, which may improve the compliance of patients and reduce medical costs (9,14). d, The indications of clinical trials in this entity may include: 1) Locally advanced or metastatic RAIR-DTC patients with disease progression determined by Response Evaluation Criteria In Solid Tumors (RECIST); and 2) Patients with BRAF, PPARγ or other tumor-related gene mutations which could be targeted by molecular drugs. e, Chemotherapy is only a palliative or experimental method for persistent/recurrent and metastatic differentiated thyroid cancer (prmDTC) with no response to other treatment. Adriamycin is the only chemotherapeutic drug approved by the US FDA (15,16). f, Molecular targeted therapy-induced adverse effects are common, and may lead to dose reduction and drug discontinuation. Common adverse effects reported include skin toxicity, hypertension, gastrointestinal toxicity, proteinuria, fatigue, thyroid-stimulating hormone inhibitory disorders, and impaired thyroid function. Before treatment, comprehensive assessment of certain risk factors that may increase the risk of adverse effects and necessary intervention to control concomitant diseases are recommended. For adverse effects during treatment, multidisciplinary consultation should be considered to protect important organs, improve the quality of life, and maximize the effects of targeted drugs. If the degree of adverse reactions is low and the function of important organs is well, the sustained targeted therapy is recommended to obtain the maximum curative effect and survival benefit from targeted drugs; if grade 3−4 adverse effects or the damage of important organs occur, the dose reduction or drug discontinuation should be promptly adopted until the weakening or disappearance of adverse effects, and then the therapy should restart from a lower dose.
Asymptomatic, stable or slow progression	Regular follow-up (2A)	Participation in clinical trialsd (2A)	—
Symptomatic or rapid progression	Sorafenibb,c (1)	Adriamycine (2A); Participation in clinical trials (2A)	—
Termination of targeted therapy	Tumor response evaluated to be progressive disease (PD) according to RECIST (1A) Serious drug-related adverse reactions that cannot be tolerated for continued treatmentf (1A)	Tg continues to rise or fail to decrease without disease remission according to RECIST (2A)	—

11

Efficacy of molecular targeted drugs for thyroid cancer therapeutics

Medicines	Pathological type	Experimental design	Number of cases	ORR	Median PFS (month)	References
ORR, objective response rate; PFS, proression-free survival; RAIR-DTC, radioactive iodine refractory differentiated thyroid cancer; MTC, medullary thyroid carcinoma; RCT, randomized controlled clinical trial; PLC, placebo; SOR, sorafenib; LEN, lenvatinib; VAN, vandetanib; NR, not reported; NE, not evaluated. a, The SELEC study showed that lenvatinib significantly prolonged PFS in RAIR-DTC compared with placebo (17). Lenvatinib mesylate has been approved by the European Commission for the treatment of invasive, locally advanced or metastatic DTCs. b, A single-arm prospective clinical trial had been conducted to evaluate the efficacy and safety of apatinib in the treatment of advanced RAIR-DTC, suggesting well tolerance with rapid-onset efficacy and high-rate of objective response in the first 8-week therapy (18).
Sorafenib	RAIR-DTC	Phase III RCT vs. PLC	207 SOR, 210 PLC	12.2% vs. 0.5%	10.8 vs. 5.8	Lancet 2014; 384:319-28.
Lenvatiniba	RAIR-DTC	Phase III RCT vs. PLC	261 LEN, 131 PLC	64.8% vs. 1.5%	18.3 vs. 3.6	New England journal of medicine 2015;372: 621-30.
Apatinibb	RAIR-DTC	Phase II	10	90%	NR	Oncotarget 2017;8:42252-61.
Pazopanib	RAIR-DTC	Phase II	37	49%	11.7	The Lancet Oncology 2010;11:962-72.
Sunitinib	RAIR-DTC	Phase II	23	26%	8	European Journal of Endocrinology 2016;174:373-80.
	RAIR-DTC/MTC	Phase II	27 RAIR-DTC, 7 MTC	31%	NR	Clinical cancer research 2010;16:5260-8.
Axitinib	RAIR-DTC/MTC	Phase II	45 RAIR-DTC, 11 MTC	30%	16.1	Cancer 2014;120:2694-703.
	RAIR-DTC/MTC	Phase II	45 RAIR-DTC, 6 MTC	35%	15	Cancer Chemotherapy and Pharmacology 2014;74:1261-70.
Vandetanib	RAIR-DTC	Phase II RCT vs. PLC	72 VAN, 73 PLC	8% vs. 5%	11.1 vs. 5.9	The Lancet Oncology 2012;13:897-905.
Cabozantinib	RAIR-DTC	Phase I	15	53%	NE	Thyroid 2014;24:1508-14.