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中国临床肿瘤学会(CSCO)持续/复发及转移性甲状腺癌诊疗指南.2018.V1

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人民卫生出版社

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中国临床肿瘤学会指南工作委员会组织

正文

1　持续/复发及转移性分化型甲状腺癌的诊断及动态评估

由于生长缓慢等因素，有关分化型甲状腺癌（differentiated thyroid cancer，DTC）复发（recurrence）或术后残存肿瘤（persistence）的概念仍很难界定与区分，本指南中涉及的DTC复发或残存是指经过手术切除、¹³¹I清甲和（或）TSH抑制等治疗后，在随诊过程中所发现的新病灶或残存肿瘤，复发或残存肿瘤可以出现在甲状腺床，也可以通过淋巴道、血行或种植等途径出现在甲状腺床以外的部位，如颈部区域淋巴结转移、远处转移等。

1.1　诊断基本原则及MDT诊疗模式

默认分类

【注释】

a.持续/复发及转移性（metastatic）DTC的诊治应重视多学科团队（multidisciplinary team，MDT）的作用，推荐有条件的单位将此类患者的诊疗纳入MDT管理。

b.MDT的实施过程中由多个学科的专家共同分析患者的临床表现、影像、病理和分子生物学资料，对患者的一般状况、疾病的诊断、分期/侵犯范围、发展趋向和预后作出全面的评估，并根据当前的国内外治疗规范/指南或循证医学依据，结合现有的治疗手段，为患者制定最适合的整体治疗策略。

c.MDT原则应该贯穿每一位患者的治疗全程。

d.MDT团队应根据治疗过程中患者病情的变化、对之前治疗的反应而适时调整治疗方案，以期最大幅度地提高治愈率、改善生活质量和延长患者的生存。

1.2　诊断方法

默认分类

【注释】

a.Tg（Thyroglobulin）的监测有助于DTC的术后评估及风险分层。在全甲状腺切除后，无TgAb干扰下，低血清Tg水平具有较高的阴性预测价值，如促甲状腺激素（throtropin or thyroidstimulating hormone，TSH）抑制状态下Tg检测不到（＜0.2ng/ml）或刺激性Tg＜1ng/ml，预示疾病很可能达到完全缓解；Tg水平增高（如抑制性Tg＞1ng/ml）则提示存在DTC持续/复发的可能［1］。而与¹³¹I-全身显像（whole body scan，WBS）显示残余甲状腺不匹配的可疑增高清甲治疗前刺激性Tg（preablative stimulative Tg，ps-Tg）水平可能提示远处转移的存在，由于受到残余甲状腺组织、血清TSH及TgAb水平等因素的影响，目前尚无明确的最佳¹³¹I治疗前ps-Tg界值点用以指导¹³¹I治疗决策，国内有关ps-Tg预测远处转移的最佳界值为52.75ng/ml［1～2］，这将有助于为及时修正患者的¹³¹I治疗剂量、避免治疗不足提供分子证据［3］。Tg在¹³¹I治疗前预测疗效及动态疗效评估也有其价值，近期我国学者采用兼顾血清学及影像学的治疗疗效评估体系探索Tg与¹³¹I治疗疗效的关系，显示ps-Tg水平对DTC患者的治疗反应具有预测价值，ps-Tg＞26.75ng/ml时对治疗后结构性疗效不佳病灶（structural incomplete response）具有较好的预测价值，为¹³¹I治疗前评估、特别是高ps-Tg者¹³¹I治疗剂量的合理定制提供了依据［4］。在手术、¹³¹I等治疗后动态监测Tg的变化，有助于判断¹³¹I治疗疗效，对于远处转移性DTC患者Tg动态监测还有助于预测碘难治性DTC（RAI Refractory-DTC，RAIR-DTC）的出现［5］。

b.甲状腺球蛋白抗体（Tg antibody，TgAb）的存在会降低通过化学发光免疫分析方法检测血清Tg的测定值，从而影响通过Tg监测病情的准确性［6］，故须同时监测Tg和TgAb水平的变化。在治疗前TgAb明显增高者，TgAb的下降提示手术及¹³¹I治疗有效［7］。

c.在DTC治疗后，超声检查是监测持续/复发及转移性 DTC 的重要手段［1，8］。

d.超声检查应采用高分辨率超声仪器，并由有甲状腺超声检查经验的医生进行操作［9］。

e.颏下至锁骨上、胸骨上后方均是扫查范围，采用横切面及纵切面扫查侧方和中央区，可疑部位使用多切面及多普勒扫查。三个部位需要单独扫查：Ⅵ区、Ⅱ-Ⅵ区、ⅤA和ⅤB区。需特别关注咽后、咽旁及气管食管沟区域（图1）［10］。

示意图

图1　颈部淋巴结分区示意图

f.颈部超声评估内容包括颈部淋巴结、甲状腺床、颈部软组织、血管及气管食管。其主要超声成像特点如下（图2）：

默认分类

图2　①～②甲状腺床局部复发：①甲状腺乳头状癌术后，横切面显示左侧甲状腺床低回声结节，纵横比大于1；②纵切面显示肿瘤内可见血流信号；③～⑥可疑转移淋巴结：③淋巴结门消失，部分囊性变；④淋巴结内大部分囊性变；⑤淋巴结内可见高回声；⑥淋巴结边缘型血流

默认分类

图2（续）　⑦不能确定性质的淋巴结：Ⅲ区淋巴结，短轴长约5mm；⑧正常淋巴结；⑨～⑩肌肉软组织复发；⑪静脉瘤栓：右侧甲状腺床肿瘤组织延伸至右侧颈内静脉；⑫气管受侵：右侧甲状腺乳头状癌术后复发，侵及气管。（M：肿瘤；IJV：颈内静脉；CCA：颈总动脉；Trachea：气管）

默认分类

g.超声不易区别甲状腺床良性病变（术后瘢痕、缝线肉芽肿、食管气管憩室、断端神经瘤以及炎性反应增生性淋巴结等）和复发病灶。超声图像的正确解释需结合临床病史和化验指标。

h.颈部增强CT或MRI有助于评估超声可能无法完全探及的部位，如纵隔和Ⅱ区淋巴结，或者Tg阳性而超声检查阴性时［12］。颈部增强CT或MRI还有利于评估复发病灶或淋巴结与周围结构及器官的相对关系，如气管、食管、颈动脉鞘的关系，为手术范围提??

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2.2.1手术治疗前专科临床评估

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2.2.2无周围重要结构侵犯的局部持续/复发及转移病灶的外科治疗策略

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2.2.4　病灶侵犯周围重要结构的局部持续/复发及转移病灶的外科治疗策略

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13. Melliere DJ，Ben Yahia NE，Becquemin JP，et al.Thyroid carcinoma with tracheal or esophageal involvement：limited or maximal surgery？.Surgery，1993，113（2）：166-172.

14. Kebebew E，Clark OH.Locally advanced differentiated thyroid cancer.Surg Oncol，2003，12（2）：91-99.

15. Lee YS，Chung WY，Chang HS，et al.Treatment of locally advanced thyroid cancer invading the great vessels using a Y-shaped graft bypass.Interact Cardiovasc Thorac Surg，2010，10（6）：1039-1041.

16. Kamizono K，Ejima M，Taura M，et al.Internal jugular vein reconstruction：application of conventional type A and novel type K methods.J Laryngol Otol，2011，125（6）：643-648.

2.2.5　远处转移病灶的外科治疗策略

1. Porterfield JR，Cassivi SD，Wigle DA，et al.Thoracic metastasectomy for thyroid malignancies.Eur J Cardiothorac Surg，2009，36（1）：155-158.

2. Protopapas AD，Nicholson AG，Vini L，et al.Thoracic metastasectomy in thyroid malignancies.Ann Thorac Surg，2001，72（6）：1906-1908.

3. Khan JH，McElhinney DB，Rahman SB，et al.Pulmonary metastases of endocrine origin：the role of surgery.Chest，1998，114（2）：526-534.

4. Porterfield JR，Cassivi SD，Wigle DA，et al.Thoracic metastasectomy for thyroid malignancies.Eur J Cardiothorac Surg，2009，36（1）：155-158.

5. Moneke I，Kaifi JT，Kloeser R，et al.Pulmonary metastasectomy for thyroid cancer as salvage therapy for radioactive iodine-refractory metastases.Eur J Cardiothorac Surg，2017，doi：10.1093/ejcts/ezx367.［Epub ahead of print］

6. Jiang L, Ouyang H, Liu X, et al. Surgical treatment of 21 patients with spinal metastases of differentiated thyroid cancer. Chin. Med. J, 2014, 127（23）： 4092-4096.

7. Bernier MO，Leenhardt L，Hoang C，et al.Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas.J Clin Endocrinol Metab，2001，86（4）：1568-1573.

8. Orita Y，Sugitani I，Matsuura M，et al.Prognostic factors and the therapeutic strategy for patients with bone metastasis from differentiated thyroid carcinoma.Surgery，2010，147（3）：424-431.

9. Demura S，Kawahara N，Murakami H，et al.Total en bloc spondylectomy for spinal metastases in thyroid carcinoma.J Neurosurg Spine，2011，14（2）：172-176.

10. Chiu AC，Delpassand ES，Sherman SI.Prognosis and treatment of brain metastases in thyroid carcinoma.J Clin Endocrinol Metab，1997，82（11）：3637-3642.

11. McWilliams RR，Giannini C，Hay ID，et al.Management of brain metastases from thyroid carcinoma：a study of 16 pathologically confirmed cases over 25 years.Cancer，2003，98（2）：356-362.

12. Soyluk O，Selcukbiricik F，Erbil Y，et al.Prognostic factors in patients with papillary thyroid carcinoma.J Endocrinol Invest，2008，31（11）：1032-1037.

13. Reddy S，Wolfgang CL.The role of surgery in the management of isolated metastases to the pancreas.Lancet Oncol，2009，10（3）：287-293.

14. Niederle B，Roka R，Schemper M et al.Surgical treatment of distant metastases in differentiated thyroid cancer：indication and results.Surgery，1986，100（6）：1088-1097.

15. Djenic B，Duick D，Newell JO，et al.Solitary liver metastasis from follicular variant papillary thyroid carcinoma：A case report and literature review.Int J Surg Case Rep，2015，6C：146-149.

2.3.1　¹³¹I治疗前临床评估

1. Mazzaferri EL，Kloos RT.Clinical review 128：Current approaches to primary therapy for papillary and follicular thyroid cancer.J Clin Endocrinol Metab，2001，86（4）：1447-1463.

2. Mazzaferri EL，Jhiang SM.Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer.Am J Med，1994，97（5）：418-428.

3. Benbassat CA，Mechlis-Frish S，Hirsch D.Clinicopathological characteristics and long-term outcome in patients with distant metastases from differentiated thyroid cancer.World J Surg，2006，30（6）：1088-1095.

4. Schlumberger M，Tubiana M，De Vathaire F，et al.Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma.J Clin Endocrinol Metab，1986，63（4）：960-967.

5. Ruegemer JJ，Hay ID，Bergstralh EJ，et al.Distant metastases in differentiated thyroid carcinoma：a multivariate analysis of prognostic variables.J Clin Endocrinol Metab，1988，67（3）：501-508.

6. Wood WJ Jr，Singletary SE，Hickey RC.Current results of treatment for distant metastatic welldifferentiated thyroid carcinoma.Arch Surg，1989，124（12）：1374-1377.

7. Pacini F，Cetani F，Miccoli P，et al.Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine.World J Surg，1994，18（4）：600-604.

8. Lin JD，Huang MJ，Juang JH，et al.Factors related to the survival of papillary and follicular thyroid carcinoma patients with distant metastases.Thyroid，1999，9（12）：1227-1235.

9. Shoup M，Stojadinovic A，Nissan A，et al.Prognostic indicators of outcomes in patients with distant metastases from differentiated thyroid carcinoma.J Am Coll Surg，2003，197（2）：191-197.

10. 中华医学会核医学分会.131I治疗分化型甲状腺癌指南（2014版）.中华核医学与分子影像杂志，2014，34（4）：264-278.

11. 中国临床肿瘤学会甲状腺癌专业委员会.复发转移性分化型甲状腺癌诊治共识.中国癌症杂志，2015，25（7）：481-496.

12. Lesnik D，Cunnane ME，Zurakowski D，et al.Papillary thyroid carcinoma nodal surgery directed by a preoperative radiographic map utilizing CT scan and ultrasound in all primary and preoperative patients.Head Neck，2014，36（2）：191-202.

13. Kim E，Park JS，Son KR，et al.Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma：comparison of ultrasound，computed tomography，and combined ultrasound with computed tomography.Thyroid，2008，18（4）：411-418.

14. Padovani RP，Kasamatsu TS，Nakabashi CC，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，2012，22（9）：926-930.

15. 盛矢薇，陈立波，陆汉魁，等.含碘造影剂对分化型甲状腺癌肺转移病灶131I疗效的影响.上海交通大学学报：医学版，2010，30（3）：253-255.

16. 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）：1-133.

17. Yang K，Wang H，Liang ZY，et al. BRAFV600E mutation associated with non-radioiodine-avid status in distant metastatic papillary thyroid carcinoma.Clin Nucl Med，2014，39（8）：675-679.

18. 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（2）：258-265.

2.3.2　¹³¹I治疗在持续/复发及转移性DTC中的应用指征

1. 中华医学会核医学分会.131I治疗分化型甲状腺癌指南（2014版）.中华核医学与分子影像杂志，2014，34（4）：264-278.

2. 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）：1-133.

3. Piccardo A，Puntoni M，Bottoni G，et al.Differentiated Thyroid Cancer lymph-node relapse.Role of adjuvant radioactive iodine therapy after lymphadenectomy.Eur.J.Nucl.Med.Mol.Imaging，2017，44（6）：926-934.

4. 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（3）：399-408.

5. Ronga G，Filesi M，Montesano T，et al.Lung metastases from differentiated thyroid carcinoma.A 40 years' experience.Q J Nucl Med Mol Imaging，2014，48（1）：12-19.

6. Schlumberger M，Challeton C，de VF，et al.Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma.J Nucl Med，1996，37（4）：598- 605.

7. Ilgan S，Karacalioglu AO，Pabuscu Y，et al.Iodine-131 treatment and high-resolution CT：results in patients with lung metastases from differentiated thyroid carcinoma.Eur J Nucl Med Mol Imaging，2004，31（6）：825-830.

8. Hod N，Hagag P，Baumer M，et al.Differentiated thyroid carcinoma in children and young adults：evaluation of response to treatment.Clin Nucl Med，2005，30（6）：387-390.

9. Fatourechi V，Hay ID，Javedan H，et al.Lack of impact of radioiodine therapy in tg-positive，diagnostic whole-body scan-negative patients with follicular cell-derived thyroid cancer.J Clin Endocrinol Metab，2002，87（4）：1521- 1526.

10. Koh JM，Kim ES，Ryu JS，et al.Effects of therapeutic doses of 131I in thyroid papillary carcinoma patients with elevated thyroglobulin level and negative 131I whole-body scan：comparative study.Clin Endocrinol（Oxf），2003，58（4）：421- 427.

11. Bernier MO，Leenhardt L，Hoang C，et al.Survival and therapeutic modalities in patients with bone metastases of differentiated thyroid carcinomas.J Clin Endocrinol Metab，2001，86（4）：1568-1573.

12. Yim JH，Kim EY，Bae KW，et al.Long-term consequence of elevated thyroglobulin in differentiated thyroid cancer.Thyroid，2013，23（1）：58-63.

13. Wang W，Larson SM，Tuttle RM，et al.Resistance of ［18f］-fluorodeoxyglucose-avid metastatic thyroid cancer lesions to treatment with high-dose radioactive iodine.Thyroid，2001，11（12）：1169-1175.

14. Salvatore B，Paone G，Klain M，et al.Fluorodeoxyglucose PET/CT in patients with differentiated thyroid cancer and elevated thyroglobulin after total thyroidectomy and（131）I ablation.Q J Nucl Med Mol Imaging，2008，52（1）：2-8.

15. Robbins RJ，Wan Q，Grewal RK，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，2006，91（2）：498-505.

16. Miyauchi，A，Kudo T，Miya A，et al.Prognostic impactor of serum thyroglobulin doubling--time under thyrotropin suppression in patients with papillary thyroid carcinoma who underwent total thyroidectomy.Thyroid，2011，21（7）：707-716.

17. Van Tol KM，Jager PL，de Vries EG，et al.Outcome in patients with differentiated thyroid cancer with negative diagnostic whole-body scanning and detectable stimulated thyroglobulin.Eur J Endocrinol，2003，148（6）：589-596.

2.3.3　¹³¹I治疗前准备

1. 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）：1-133.

2. 李慧，丛慧，李从心，等.远处转移灶对分化型甲状腺癌患者停服左旋甲状腺素后TSH升高的影响.中华核医学与分子影像杂志，2015，35（4）：262-264.

3. 中华医学会核医学分会.131I治疗分化型甲状腺癌指南（2014版）.中华核医学与分子影像杂志，2014，34（4）：264-278.

4. 中国临床肿瘤学会甲状腺癌专业委员会.复发转移性分化型甲状腺癌诊治共识（2015版）.中国癌症杂志，2015，25（7）：481-496.

2.3.4　¹³¹I治疗剂量决策

1. 中华医学会核医学分会.131I治疗分化型甲状腺癌指南（2014版）.中华核医学与影像杂志，2014，34（4）：264-278.

2. 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）：1-133.

3. 中国临床肿瘤学会甲状腺癌专业委员会.复发转移性分化型甲状腺癌诊治共识（2015版）.中国癌症杂志，2015，25（7）：481-496.

4. National Comprehensive Cancer Network.NCCN guidelines.Thyroid Carcinoma.2017.V2.

2.3.5　重复¹³¹I治疗的最大剂量及安全性

1. Molenaar Remco J，Sidana Surbhi，Radivoyevitch T，et al.Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer.J.Clin.Oncol.，2017：JCO2017750232.

2.3.6　¹³¹I治疗后管理、随访及疗效评估

1. 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）：1-133.

2. 中国临床肿瘤学会甲状腺癌专业委员会.复发转移性分化型甲状腺癌诊治共识（2015版）.中国癌症杂志，2015，25（7）：481-496.

2.3.7　¹³¹I终止治疗指征

1. Haugen BR，Alexander EK，Bible KC，et al.2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer.Thyroid，2016，26（1）：1-133.

2. Schlumberger M，Brose M，Elisei R，et al.Definition and management of radioactive iodine-refractory differentiated thyroid cancer.Lancet Diabetes Endocrinol，2014，2（5）：356-358.

2.3.8　¹³¹I治疗的不良反应

1. 中国临床肿瘤学会甲状腺癌专业委员会.复发转移性分化型甲状腺癌诊治共识（2015版）.中国癌症杂志，2015，25（7）：481-496.

2. 中华医学会核医学分会.131I治疗分化型甲状腺癌指南（2014版）.中华核医学与影像杂志，2014，34（4）：264-278.

3. 王澎，孟召伟，谭建，等.维生素E对术后首次行131I治疗的分化型甲状腺癌患者唾液腺功能的保护作用.中华核医学与分子影像杂志，2016，36（5）：398-401.

4. Upadhyaya A，Zhou P，Meng Z，et al.Radioprotective effect of vitamin E on salivary glands after radioiodine therapy for differentiated thyroid cancer：a randomized-controlled trial.Nucl Med Commun，2017，38（11）：891-903.

5. 李慧，郭宁，张英杰，等.分化型甲状腺癌131I治疗前后外周血细胞的动态变化.中华核医学与分子影像杂志，2015，35（2）：116-119.

6. Hu T，Meng Z，Zhang G，et al.Influence of the first radioactive iodine ablation on peripheral complete blood count in patients with differentiated thyroid cancer.Medicine，2016，95（35）：e4451.

7. Molenaar RJ，Sidana S，Radivoyevitch T，et al.Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer.J Clin Oncol.2017 Dec 18：JCO2017750232.doi：10.1200/JCO.2017.75.0232.

2.4　TSH抑制治疗

1. Biondi B，Cooper DS. Benefits of thyrotropin suppression versus the risks of adverse effects in differentiated thyroid cancer. Thyroid，2010，20（2）：135.

2. Biondi B，Filetti S，Schlumberger M. Thyroid hormone therapy and thyroid cancer：a reassessment. Nat Clin Pract Endocrinol Metab，2005，1（1）：32-40.

3. Bach-Huynh TG，Nayak B，Loh J，et al. Timing of levothyroxine administration affects serum thyrotropin concentration. J Clin Endocrinol Metab，2009，94 （10）：3905-3912.

4. Biondi B，Wartofsky L. Treatment with thyroid hormone. Endocr Rev，2014，35（3）：433-512.

5. 中华医学会内分泌学分会，中华医学会外科学分会内分泌学组，中国抗癌协会头颈肿瘤专业委员会，中华医学会核医学分会. 甲状腺结节和分化型甲状腺癌诊治指南. 中华内分泌代谢杂志，2012，28（10）：779-797.

6. Diessl S，Holzberger B，Mder U，et al. Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma. Clin Endocrinol，2012，76（4）：586-592.

7. Carhill AA，Litofsky DR，Ross DS，et al. Long-term outcomes following therapy in differentiated thyroid carcinoma：NTCTCS registry analysis 1987-2012. J Clin Endocrinol Metab，2015，100（9）：3270.

8. Momesso DP，Tuttle RM. Update on differentiated thyroid cancer staging. Endocrinol Metab Clin North Am，2014，43（2）：401-421.

9. Haugen BR，Alexander EK，Bible KC，et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid dancer：the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid，2016，26（1）：1-133.

2.4.2　TSH抑制治疗不良反应及处理策略

1. Cooper DS，Biondi B. Subclinical thyroid disease. Lancet，2012，379（9821）：1142-1154.

2. Klein Hesselink EN，Klein Hesselink MS，de Bock GH，et al. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma：an observational study. J Clin Oncol，2013，31（32）：4046-4053.

3. Flynn RW，Bonellie SR，Jung RT，et al. Serum thyroid- stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab，2010，95（1）：186-193.

4. Haugen BR，Alexander EK，Bible KC，et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid dancer：the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid，2016，26（1）：1-133.

5. Rieben C，Segna D，da Costa BR，et al. Subclinical thyroid dysfunction and the risk of cognitive decline：a meta-analysis of prospective cohort studies. J Clin Endocrinol Metab，2016，101（12）：4945-4954.

6. Carlé A，Andersen SL，Boelaert K，et al. MANAGEMENT OF ENDOCRINE DISEASE：Subclinical thyrotoxicosis：prevalence，causes and choice of therapy. Eur J Endocrinol，2017，176（6）：325-337.

7. Jabbar A，Pingitore A，Pearce SH，et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol，2017，14（1）：39-55.

8. Ross DS，Burch HB，Cooper DS，et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid，2016，26（10）：1343-1421.

9. 中华医学会内分泌学分会，中华医学会外科学分会内分泌学组，中国抗癌协会头颈肿瘤专业委员会，中华医学会核医学分会. 甲状腺结节和分化型甲状腺癌诊治指南. 中华内分泌代谢杂志，2012，28（10）：779-797.

10. 中华医学会骨质疏松和骨矿盐疾病分会. 原发性骨质疏松症诊疗指南（2017）. 中华骨质疏松和骨矿盐疾病杂志，2017，10（5）：413-443.

2.5　外照射治疗

1. Chen PV，Osborne R，Ahn E，et al.Adjuvant external-beam radiotherapy in patients with high-risk well-differentiated thyroid cancer.Ear Nose Throat J，2009,88（7）：E01.

2. Nar Demirer A，Ayturk S，Tutuncu NB，et al.Unresectable huge sternal and mediastinal metastasis of follicular thyroid carcinoma；radiotherapy as first-line and palliative therapy.Exp Clin Endocrinol Diabetes，2009,117（4）：155-158.

3. Terezakis SA，Lee KS，Ghossein RA，et al.Role of external beam radiotherapy in patients with advanced or recurrent nonanaplastic thyroid cancer：Memorial Sloan-kettering Cancer Center experience.Int J Radiat Oncol Biol Phys，2009,73（3）：795-801.

4. Hamilton SN，Tran E，Berthelet E，et al.The role of external beam radiation therapy in welldifferentiated thyroid cancer.Expert Rev Anticancer Ther,2017，17（10）：905-910.

5. Mikalsen LTG，Arnesen MR，Bogsrud TV，et al.Combining radioiodine and external beam radiation therapy：the potential of integrated treatment planning for differentiated thyroid cancer.Acta Oncol，2017，56（6）：894-897.

6. Vulpe H，Kwan JYY，McNiven A，et al.Patterns of failure in anaplastic and differentiated thyroid carcinoma treated with intensity-modulated radiotherapy.Curr Oncol，2017，24（3）：e226-e232.

7. Kim TH，Chung KW，Lee YJ，et al.The effect of external beam radiotherapy volume on locoregional control in patients with locoregionally advanced or recurrent nonanaplastic thyroid cancer.Radiat Oncol，2010，5：69.

8. Mangoni M，Gobitti C，Autorino R，et al.External beam radiotherapy in thyroid carcinoma：clinical review and recommendations of the AIRO "Radioterapia Metabolica" Group.Tumori，2017，103（2）：114-123.

9. Schwartz DL，Lobo MJ，Ang KK，et al.Postoperative external beam radiotherapy for differentiated thyroid cancer：outcomes and morbidity with conformal treatment.Int J Radiat Oncol Biol Phys，2009，74（4）：1083-1091.

10. Lee EK，Lee YJ，Jung YS，et al.Postoperative simultaneous integrated boost-intensity modulated radiation therapy for patients with locoregionally advanced papillary thyroid carcinoma：preliminary results of a phase II trial and propensity score analysis.J Clin Endocrinol Metab，2015，100（3）：1009-1017.

11. Tam S，Amit M，Boonsripitayanon M，et al.Adjuvant External Beam Radiotherapy in Locally Advanced Differentiated Thyroid Cancer.JAMA Otolaryngol Head Neck Surg，2017，143（12）：1244-1251.

12. Rieber J，Streblow J，Uhlmann L，et al.Stereotactic body radiotherapy（SBRT）for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy".Lung Cancer，2016，97：51-58.

13. Lo SS，Lutz ST，Chang EL，et al.ACR Appropriateness Criteria（R）spinal bone metastases.J Palliat Med，2013，16（1）：9-19.

14. Lutz ST，Lo SS，Chang EL，et al.ACR Appropriateness Criteria（R）non-spine bone metastases.J Palliat Med，2012，15（5）：521-526.

15. Linskey ME，Andrews DW，Asher AL，et al.The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases：a systematic review and evidence-based clinical practice guideline.J Neurooncol，2010，96（1）：45-68.

16. Kalkanis SN，Kondziolka D，Gaspar LE，et al.The role of surgical resection in the management of newly diagnosed brain metastases：a systematic review and evidence-based clinical practice guideline.J Neurooncol，2010，96（1）：33-43.

17. Henriques de Figueiredo B，Godbert Y，Soubeyran I，et al.Brain metastases from thyroid carcinoma：a retrospective study of 21 patients.Thyroid，2014，24（2）：270-276.

18. Lutz S，Balboni T，Jones J，et al.Palliative radiation therapy for bone metastases：Update of an ASTRO Evidence-Based Guideline.Pract Radiat Oncol，2017，7（1）：4-12.

2.6.1　化疗

1. Sabra MM，Dominguez JM，Grewal RK，et al.Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.J Clin Endocrinol Metab，2013，98（5）：E829-836.

2. Schlumberger M，Brose M，Elisei R，et al.Definition and management of radioactive iodine-refractory differentiated thyroid cancer.Lancet Diabetes Endocrinol，2014，2（5）：356-358.

3. Shimaoka K，Schoenfeld DA，DeWys WD，et al.A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma.Cancer.1985；56（9）：2155-2160.

4. Droz JP，Schlumberger M，Rougier P，et al.Chemotherapy in metastatic nonanaplastic thyroid cancer：experience at the Institut Gustave-Roussy.Tumori，1990，76（5）：480-483.

5. Spano JP，Vano Y，Vignot S，et al.GEMOX regimen in the treatment of metastatic differentiated refractory thyroid carcinoma.Med Oncol，2012，29（3）：1421-1428.

2.6.2　分子靶向治疗

2. NCCN clinical practice guidelines in Oncology：Thyroid Carcinoma（version 2.2017）.NCCN.org.

3. 滕卫平，刘永锋，高明等.甲状腺结节和分化型甲状腺癌诊治指南.中华核医学与分子影像杂志，2013，33（2）：96-116.

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

5. Pacini F，Castagna MG，Brilli L，et al.Thyroid cancer：ESMO Clinical Practice Guidelines for diagnosis，treatment and follow-up.Ann Oncol，2012，23（7）：110-119.

6. Brose MS，Nutting CM，Jarzab B，et al.Sorafenib inradioactive iodine-refractory，locally advanced or metastatic differentiated thyroid cancer：a randomized，double-blind，phase 3 trial.Lancet，2014，384（9940）：319-328.

7. Chen L，Shen Y，Luo Q，et al.Response to sorafenib at a low dose in patients with radioiodine-refractory pulmonary metastases from papillary thyroid carcinoma.Thyroid，2011，21（2）：119-124.

8. Gupta-Abramson V，Troxel AB，Nellore A，et al.Phase II trial of sorafenib in advanced thyroid cancer.J Clin Oncol，2008，26（29）：4714-4719.

9. Kloos RT，Ringel MD，Knopp MV，et al.Phase II trial of sorafenib in metastatic thyroid cancer.J Clin Oncol，2009，27（10）：1675-1684.

10. Hoftijzer H，Heemstra KA，Morreau H，et al.Beneficial effects of sorafenib on tumor progression，but not on radioiodine uptake，in patients with differentiated thyroid carcinoma.Eur J Endocrinol，2009，161（6）：923-931.

11. Cabanillas ME，Waguespack SG，Bronstein Y，et al.Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer：the M.D.Anderson experience.J Clin Endocrinol Metab，2010，95（6）：2588-2595.

12. Shen Y，Ruan M，Luo Q，et al.Brain metastasis from follicular thyroid carcinoma：treatment with sorafenib.Thyroid，2012，22（8）：856-860.

13. Schlumberger M，Tahara M，Wirth LJ，et al.Lenvatinib versus placebo in radioiodine-refractory thyroid cancer .N Engl J Med，2015，372（7）：621-630.

14. Lin Y，Wang C，Gao W，et al.Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer .Oncotarget，2017，8（26）：42252-42261.

2.7　其他治疗

1. Dupuy DE，Monchik JM，Decrea C，et al.Radiofrequency ablation of regional recurrence from welldifferentiated thyroid malignancy.Surgery，2001，130（6）：971-977.

2. Dong G N，Lee J H，Jung S L，et al.Radiofrequency Ablation of Benign Thyroid Nodules and Recurrent Thyroid Cancers：Consensus Statement and Recommendations.Korean Journal of Radiology，1900，13（2）：117-125.

3. Garberoglio R，Aliberti C，Appetecchia M，et al.Radiofrequency ablation for thyroid nodules：which indications？ The first Italian opinion statement.Journal of Ultrasound，2015，18（4）：423-430.

4. 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）：1-133.

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