中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
医药导报, 2019, 38(5): 550-554
doi: 10.3870/j.issn.1004-0781.2019.05.003
甲状腺功能亢进症合并甲状腺癌的诊断与治疗*
Diagnosis and Treatment of Hyperthyroidism and Comcurrent Thyroid Cancer
陈继东, 欧阳文奇, 张李, 方菲

摘要:

以往认为甲状腺功能亢进症(甲亢)很少甚至不合并甲状腺癌,近年来研究发现甲亢伴结节患者发生甲状腺癌的风险增加,甲状腺癌与甲亢早期密切相关,但结果间存在较大差异,因此有必要明确两者之间的关系,为临床诊断和治疗提供依据。尽管手术治疗为首选,但选取何种术式仍没有统一,甲状腺全切术既能根治甲亢又能有效治疗甲状腺癌,而针对部分碘难治性分化型甲状腺癌,靶向药物为其提供了新的思路。中医药治疗亦有效弥补了现代医学手段的不足,可很好地发挥辅助作用。

关键词: 甲状腺功能亢进症 ; 甲状腺癌 ; 手术治疗 ; 靶向治疗

Abstract:

The occurrence of thyroid malignancy was considered a rare event in hyperthyroid patients.Recent studies have found an increased risk of thyroid cancer in patients of hyperthyroidism with thyroid nodules.Thyroid cancer is closely related to the early period of hyperthyroidism.However,there were significant differences among the results.In order to provide the basis for clinical diagnosis and treatment,it is necessary to clarify the relationship between hyperthyroidism and thyroid cancer. Although surgery is the preferred treatment,there is still no consensus on the choice of surgical approach.We believe that total thyroidectomy can not only cure hyperthyroidism but also effectively treat thyroid cancer.And targeted drug treatment provides a new method for some radioactive iodine-refractory differentiated thyroid cancer.The traditional Chinese meclicine therapy plays a supplementary role to make up for the lack of medicine.

Key words: Hyperthyroidism ; Thyroid cancer ; Surgical therapy ; Target therapy

甲状腺功能亢进症(简称甲亢)是因甲状腺产生过多的甲状腺激素导致的一类疾病,其病因以弥漫性毒性甲状腺肿(Graves disease,GD)最为常见,约占所有甲亢患者的85%。甲状腺癌是近年来全球发病率迅速增长且最为常见的内分泌系统恶性肿瘤[1]。过去认为甲亢不合并或很少合并甲状腺癌,甚至认为长期甲亢是甲状腺癌的保护性因素[2]。自1966年OLEN等[3]的报道明确支持甲亢并不能排斥甲状腺癌以来,一些学者相继对此进行了研究,尤其是甲亢合并微小癌(肿瘤直径≤1 cm)的报道越来越多,但结果间存在较大差异,因此有必要明确两者之间的关系,为临床诊断和治疗提供依据。笔者就其有关发病情况等概述如下。

1 发病情况

一般认为,人群中彩超发现甲状腺结节的概率在20%~76%,而其中有5%~15%为甲状腺癌,但甲亢合并甲状腺癌多半是在行手术治疗中被发现,并没有大量的流行病学数据,且甲亢合并甲状腺结节也没有流行病学结果,无法对比发生率,因此对于发生率的高低有多种观点并存。

甲亢手术中发现甲状腺癌的概率较高。多个回顾性研究显示,与普通人群或甲状腺功能正常的人群相比,甲亢患者甲状腺癌发生率均增高,但结果差别很大,最高可达42.4%[4]。因此,STANIFORTH等[5]搜集并筛选了1946年1 月—2015 年2 月发表的GD手术患者合并甲状腺癌发生率的文献,对其中33项有病理结果的研究进行Meta分析,显示GD患者中甲状腺癌的发生率为7%[95%CI(0.04,0.12)],发现GD合并甲状腺结节的患者被诊断为甲状腺癌的可能性是没有合并甲状腺结节患者的5倍。

另外,最近也开展了针对甲亢随访患者的大样本队列研究,其结果也更有代表性。其中以SHU等[6]的研究随访时间最长,收集了瑞典在1964—2006年共18 156例在医院就诊的GD患者,平均随访时间为17年,结果显示GD患者在1年内合并甲状腺癌的风险增高,但当病程超过1年时则差异无统计学意义。另有两项基于我国台湾全民健康保险数据库(National Health Insurance Database,NHI)的研究在样本量上最大,YEH等[7]收集了其中2000—2005年间确诊的17 033例甲亢患者和34 066例非甲亢患者的4年随访数据,结果显示甲亢患者发生甲状腺癌的频率每年每万例为6.51,远高于非甲亢队列中仅每年每万例为0.88的甲状腺癌发生率。回归分析显示,甲状腺癌在甲亢患者中的风险为对照人群的6.8倍[HR=6.803;95%CI(3.584,12.91)P<0.05]。CHEN等[8]的研究跨度则相对较长,收集1997—2010共计13年的5025例GD患者和20 100例非GD患者随访数据,结果显示GD患者发生甲状腺癌的风险较非GD患者高10.4 倍,进一步确认GD与甲状腺癌存在一定的正相关关系。

综上所述,甲亢患者发生甲状腺癌的总体风险高于普通人群,尤其早期发生甲状腺癌的风险很高,但随着病程的延长和进展并不增加甲状腺癌的发生风险。最近也有学者提出不同观点,认为无论是针对随访数据的队列分析或是甲状腺手术中意外发现的甲状腺癌患者,甲亢与甲状腺癌无关[9,10]。所以对于甲亢是甲状腺癌的致病因素还是保护性因素需要进一步以及大样本的流行病学研究数据。

2 发病机制

甲亢和甲状腺癌之间确切的发病机制仍不十分清楚,目前认为可能与以下几个因素相关。

2.1 促甲状腺激素(thyroid stimulating hormone,TSH)

TSH是甲状腺癌发生和发展的重要促进因素。根据临床观察,高浓度的TSH可以刺激甲状腺癌术后残留的癌细胞生长,从而导致局部复发和转移,故术后采取服用左甲状腺素钠来抑制TSH分泌以防止复发。宋春峰等[11]回顾性分析959例甲状腺结节患者的病例资料,显示术前TSH水平是甲状腺乳头状癌(papillary thyroid cancer,PTC)发生的独立影响因素[OR=1.315,95%CI(1.171,1.477),P<0.001],认为术前TSH水平与甲状腺结节恶性风险有一定的相关性,随TSH水平的上升PTC的患病风险增加。甲亢患者在长期服用抗甲状腺药物中,可因过度抑制而导致TSH明显升高,从而刺激甲状腺引发甲状腺癌。

2.2 刺激甲状腺抗体(TSAb)

目前认为GD是由刺激甲状腺免疫球蛋白(thyroid stimulating immunoglobulin,TSI)引起的自身免疫性疾病。TSI是一种IgG,与TSH结构相似,能与甲状腺中的TSH受体相结合,并模仿TSH的作用导致甲状腺细胞增生和功能加强,产生过多的甲状腺激素,不受垂体反馈抑制,且作用比TSH更强烈和持久,从而刺激甲状腺组织导致癌变[12]。另外,刺激甲状腺抗体还可以刺激血管生成,促进肿瘤的发展。

2.3 基因突变与交叉信号

最近研究发现,促甲状腺激素受体(thyroid stimulting hormone receptor,TSHR)在突变激活的情况下可以导致甲状腺毒性结节和高功能甲状腺癌[13],而CROSS等[14]第一次在GD合并冷结节的甲状腺癌中发现了TSHR突变,认为突变激活的TSHR可能也参与侵袭性的发生,发现了分别位于RAS基因和TSHR基因上的两个突变点,其机制可能是突变的TSHR激活蛋白激酶A(protein kinase A,PKA)通路,而PKA通路与RAS激活的丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK) 通路有交叉和加强作用,促进细胞增生和基因不稳定性及降低细胞分化的能力,从而导致肿瘤高侵袭性。故交叉信号机制可能是GD合并分化型甲状腺癌具有侵袭性的原因之一。

临床上,甲亢与甲状腺癌并存可能有以下不同形式:一是合并桥本甲状腺炎的甲亢发生甲状腺癌;二是甲状腺癌导致的甲亢;三是甲亢同时发生了甲状腺癌。不同的情况下可能有不同的发病机制,需要进一步研究明确。

3 病理特点

甲亢合并甲状腺癌与单纯甲状腺癌相似,大多数为女性患者,病理类型以乳头状癌为主,具有多中心性等,且还有如下特点:与合并甲状腺结节有关;年龄较单纯GD患者大;病理类型以乳头状腺癌多见,多为微小癌,可表现为多灶性;肿瘤病灶多较小或为隐匿性,转移发生率低[15]。KRAIMPS等[16]对557例因Graves病行手术治疗的患者进行回顾性分析发现,GRAVES病患者中有25.1%合并甲状腺结节,其中15%为甲状腺癌,并且所有甲状腺癌均发生于结节内。

4 甲亢合并甲状腺癌的诊断

GD合并甲状腺癌的术前诊断非常困难,术前诊断率总体较低。因此对甲亢患者的可疑病变可以采用以下几种检查方法,以减少漏诊和提高术前诊断。

4.1 超声检查

超声检查可以探测结节的囊实性质、数量、位置、边界和血流,以及颈部淋巴结有无转移,为甲状腺癌术前诊断提供重要依据。所以,对所有GD患者,无论是否经抗甲状腺药物治疗,都应行超声检查以早期发现甲状腺结节,尤其是使用TI-RADS分类系统[17],从而为甲状腺癌的诊断提供线索。

4.2 细针穿刺抽吸活检(FNA)

FNA是鉴别甲状腺结节良恶性最准确的诊断性筛查手段[18],其准确率可达95%。而因为超声引导下的FNA检查得到广泛使用,从而提高了不同地区的甲状腺癌的诊断率[19,20]。因此,甲状腺超声检查联合细针穿刺细胞学检查是判断甲状腺结节良恶性较推崇的方法。

4.3 甲状腺核素扫描

甲状腺扫描可以帮助评估甲状腺的整体结构和功能。可用于识别甲状腺组织,测量腺体大小,评估结节范围,识别良恶性等。连小兰等[15]指出当甲亢同时伴有甲状腺单个冷结节时,更应警惕甲状腺癌存在的可能。

5 甲亢合并甲状腺癌的治疗
5.1 手术治疗

对于甲亢合并甲状腺癌的治疗,目前认为仍以手术治疗为首选。除此之外,也有学者采用消融术治疗。但最新指南认为采用手术治疗甲亢推荐甲状腺全切术,以杜绝甲亢的复发。而单纯甲状腺癌临床上采取的术式较多,根据保留甲状腺的多少可分为患癌侧腺叶切除术、侧叶加峡部切除术、甲状腺次全切除、甲状腺近全切除术及全切除术等。对于甲亢合并甲状腺癌术式的选择尚无统一的认识,如CHAO等[21]对61例原发性甲亢合并甲状腺癌的病例研究认为,癌肿直径<10 mm的可行甲状腺次全切除术。癌肿直径<2 cm,且癌肿未侵犯甲状腺包膜,属腺内型,行癌侧叶全切及峡部切除加对侧叶次全切除。双侧癌肿,癌肿直径>2 cm者均行全甲状腺切除。

近来,建议采取甲状腺全切术或近全切除术,认为该方法是治疗甲亢合并甲状腺癌较理想的疗法[22]。如邢曙光[23]认为甲亢合并甲状腺癌采取甲状腺全切除治疗方案可以明显降低术后出血发生率、术后喉返神经经损伤发生率,提高术后2年生存率,提高生活质量。除术中的收益外,术后同样也具有较多益处。张宪波等[24]认为具有如下优势:①全切后无甲状腺癌复发、残留及甲亢复发的风险。②如术后出现远处转移时无需再次行甲状腺手术,可直接行131 I治疗,避免再次手术及其带来的严重并发症。③甲状腺癌术后给予甲状腺素治疗,可降低复发及远处转移率。④有利于放射碘扫描和甲状腺球蛋白监测甲状腺癌复发和转移。⑤可改善高危人群生存期,降低病死率。而合并微小癌的治疗亦首选手术。

甲亢伴甲状腺癌具有发病率逐年增高的趋势,但针对甲亢合并甲状腺癌的术式和淋巴结清扫问题仍值得进行大样本的研究,以形成统一的认识,同时因未采取全切术导致术后仍有甲亢的患者的治疗方式选择未见详细的对比临床报道,需要深入研究。

5.2 药物治疗

对绝大多数分化型甲状腺癌(DTC)而言,手术加放射性碘治疗及TSH抑制治疗可达到较理想的临床治疗效果,患者20年生存率可达90%。但是,部分DTC患者由于失分化导致其癌组织聚碘能力丧失或TSHR表达降低,对上述治疗及放化疗均不敏感,被归入碘难治性分化型甲状腺癌(RAIR-DTC)[25],其15年生存率仅为6%,成为临床研究的难点和热点,而分子靶向治疗为其提供新的思路。

研究发现,甲状腺癌发生的分子机制主要涉及MAPK通路、磷脂酰肌醇3-激酶(phosphatidyl inositol 3-kinase,PI3K)等信号通路及相应的血管内皮生长因子(vascular endothelial growth factor,VEGF)、BRAF、RAS、RET / PTC、配对盒基因8(paired box gene 8,PAX8)/过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor,PPAR)γ、miRNA 等基因异常。目前,美国食品药品管理局已经批准索拉非尼、乐伐替尼、凡德他尼和卡博替尼等4种酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)用于临床。一项韩国的索拉菲尼多中心、真实世界的临床试验显示:中位生存期达到9.7个月,部分缓解和病情稳定无进展率分别达到25%和65%,稳定无进展大于6个月的达42%[26]。一项乐伐替尼针对RAIR-DTC患者的III期临床试验显示:长期剂量干预组的中位生存期为12.8个月[95%CI(9.3,16.5)],明显优于安慰药对照组[27]。但尚缺乏药物之间的对比研究。具有我国自主知识产权的靶向药物甲磺酸阿帕替尼[28,29]也正处于临床实验中,显示出较好的临床疗效。而PI3K抑制剂Buparlisib在针对RAIR-DTC的治疗中并未显示出良好疗效[30]

分子靶向治疗药物为难治性甲状腺癌提供新的治疗手段,但是此类药物具有较明显的不良反应,限制了部分的临床使用。因此,还需基于现有和新发现的靶点特性开发出更加高效、低毒的全新靶向治疗药物。

5.3 中医药治疗

甲状腺癌属于祖国医学“瘿瘤”“石瘿”的范畴。王芷乔等[31]调查183例甲状腺癌术后患者发现,中医证型分布以气阴两虚证比例最高(34.43%),其次为肝郁气滞证(26.23%)、痰瘀互结证(24.59%)和脾肾阳虚证(14.75%)。陈如泉[32]拟定“益气养阴,软坚散结,扶正解毒”的基本治则,用黄芪、党参、沙参、麦冬、生地、女贞子、旱莲草、鳖甲、当归、龙葵、白花蛇舌草、半枝莲、山慈菇、猫爪草等,其观点与上述调查一致。俞菲菲[33]运用益气养阴方治疗分化型甲状腺癌术后患者,显示能够改善临床症状,缩短不适症状改善的起效时间,提高术后生活质量,并可能具有抑制垂体分泌促甲状腺激素,促进甲状腺功能的恢复,预防肿瘤的复发和转移的辅助作用。

中医药具有减毒增效的独特优势,有效弥补现代医学手段的不足,可很好地在甲状腺癌的治疗过程中发挥辅助作用,但需以辨证论治为宗旨,做到因人制宜,而中医药抗肿瘤及抑制肿瘤复发转移的机制尚不清楚,还需进一步探索。

The authors have declared that no competing interests exist.

参考文献

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Objective: The coexistence of hyperthyroidism and thyroid cancer is considered a rare event. With the aim of assessing the clinical relevance of this association, we have retrospectively analyzed the incidence of thyroid cancer in 425 hyperthyroid patients seen and treated by surgery in our institutions. Methods: Among these hyperthyroid patients, we observed 241 (56.7&percnt;) cases of multinodular toxic goiter, 120 (28.3&percnt;) of uninodular toxic goiter and 64 (15&percnt;) cases of Graves&rsquo; disease. Results: Thyroid cancer was diagnosed in 7 (1.65&percnt;) hyperthyroid patients. Histological examination revealed the presence of papillary carcinoma in 5 cases and follicular carcinoma in 2 cases. Neoplasia was detected in 4 patients with nodular toxic goiter and in 3 with uninodular toxic goiter. None of the patients with Graves&rsquo; disease had thyroid cancer. During the follow-up of 74 months (range 4&ndash;154), there were no deaths or any recurrences. Conclusion: Although the occurrence of thyroid cancer in hyperthyroid patients is a rare event, the presence of a &lsquo;cold&rsquo; nodule in a hyperfunctioning thyroid should be carefully evaluated to exclude the presence of concurrent malignancy.
DOI:10.1159/000071875      PMID:22334393      URL    
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[2] ZALZAL H G,CHUNG J,PERINI J A.Remarkable presen-tation:anaplastic thyroid carcinoma arising from chronic hyperthyroidism[J].Case Rep Endocrinol,2018,2018:7261264.
Background. Undifferentiated anaplastic carcinoma rarely develops from chronic hyperthyroidism. Although acute hyperthyroidism can develop prior to anaplastic transformation, chronic hyperthyroidism was thought to be a protective measure against thyroid malignancy. Methods. A 79-year-old female presented acutely to the hospital with dyspnea. She had been taking methimazole for chronic hyperthyroidism due to toxic thyroid nodules, previously biopsied as benign. Upon admission, imaging showed tracheal compression, requiring a total thyroidectomy with tracheostomy for airway management. Results. Pathology demonstrated undifferentiated anaplastic thyroid carcinoma. The patient passed away shortly after hospital discharge. Despite treatment with methimazole for many years, abrupt enlargement of her toxic multinodular goiter was consistent with malignant transformation. Chronic hyperthyroidism and toxic nodules are rarely associated with thyroid malignancy, with only one previous report documenting association with anaplastic thyroid carcinoma. Conclusion. Progressive thyroid enlargement and acute worsening of previously controlled hyperthyroidism should promote concern for disease regardless of baseline thyroid function.
DOI:10.1155/2018/7261264      URL    
[本文引用:1]
[3] OLEN E,KLINCK G H.Hyperthyroidism and thyroid can-cer[J].Arch Pathol,1966,81(6):531-535.
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[4] KUNJUMOHAMED F P,AL-BUSAIDI N B,AL-MUSALHI H N,et al.The prevalence of thyroid cancer in patients with hyperthyroidism[J].Saudi Med J,2015,36(7):874-877.
To determine the prevalence of thyroid cancer in patients with hyperthyroidism.This is a retrospective observational study using the data of 71 Omani patients with a diagnosis of hyperthyroidism due to Grave's disease, toxic multinodular goiter, and solitary toxic adenoma. These patients underwent thyroidectomy at the Royal Hospital (RH), Muscat, Oman, and were followed up at the National Diabetes and Endocrine Center (NDEC) between 2007 and 2013. The details were collected from the medical records of both the RH and the NDEC. Patients who underwent thyroidectomy for other reasons like non-toxic goiter and hypothyroidism with cancer were excluded from the study.Thyroid cancer was identified in 32.8% (n=23) of patients with hyperthyroidism. Half of these patients 52.1% (n=12) had papillary micro-cancer (intra-thyroidal), and 3 patients with Grave's disease (13%) had lymph nodes metastasis (loco-regional infiltration. The cancer preponderance was higher in young (n=21, 91.3%) and female patients (n=18, 73.9%). Most patients with thyroid cancer had abnormal ultrasound neck findings and thyroid scintigraphy (99 mTc uptake).Many patients with hyperthyroidism in Muscat, Oman, especially those with Grave's disease, show malignancy, and hence a proper initial evaluation of these patients is required as part of long-term management.
DOI:10.15537/smj.2015.7.11463      PMID:26108596      URL    
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[5] STANIFORTH J U,ERDIRIMANNE S,ESLICK G D.Thyroid carcinoma in Graves' disease:A meta-analysis[J].Int J Surg,2016,27:118-125.
61The incidence of thyroid carcinoma is increasing worldwide.61Studies have suggested an increased risk of thyroid malignancy in Graves' disease.61Thyroid malignancy in Graves' disease requiring surgical treatment is important.
DOI:10.1016/j.ijsu.2015.11.027      PMID:26626367      URL    
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[6] SHU X,JI J,LI X,et al.Cancer risk in patients hospitali-sed for Graves' disease:a population-based cohort study in Sweden[J].Br J Cancer,2010,102(9):1397-1399.
DOI:10.1038/sj.bjc.6605624     
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[7] YEH N C,CHOU C W,WENG S F,et al.Hyperthyroidism and thyroid cancer risk:a population-based cohort study[J].Exp Clin Endocrinol Diabetes,2013,121(7):402-406.
DOI:10.1055/s-00000017      URL    
[本文引用:1]
[8] CHEN Y K,LIN C L,CHANG Y J,et al.Cancer risk in patients with Graves' disease:a nationwide cohort study[J].Thyroid,2013,23(7):879-884.
The possibility of an association of Graves' disease (GD) with subsequent cancers has been previously reported.Our study used the Taiwanese National Health Insurance Research Database (NHIRD), which identified 5025 newly diagnosed GD patients from 1997 to 2010, and 20,100 frequency matched non-GD patients. The risk of developing cancer for GD patients was measured using the Cox proportional hazard model.The incidence of developing cancer in the GD cohort was 4.92 per 1000 person-years and was 1.37-fold higher than in the comparison cohort (p<0.001). Compared with patients aged 20-34 years, older age groups demonstrated a higher risk of developing cancer (35-49 years: hazard ratio (HR)=4.15; 50-64 years: HR=7.39; 65 years: HR=13.4). After adjusting for sex, age, and comorbidities, the HR for developing breast cancer and thyroid cancer was 1.58- and 10.4-fold higher for patients with GD. Furthermore, the incidence rates (IRR) were the highest in the first three years: 2.06 [confidence interval (CI)=1.87-2.27] and 15.6 [CI=13.9-17.5] in breast cancer and thyroid cancer with GD respectively. Specifically, a 16-fold hazard of developing thyroid cancer was present in the first three years in the GD cohort compared to the non-GD cohort [CI=7.95-32.1].GD patients have a higher risk of cancer, particularly thyroid and breast cancer sequent within six and three years respectively. Strategies for preventing thyroid and breast cancer are proposed.
DOI:10.1089/thy.2012.0568      PMID:23421548      URL    
[本文引用:1]
[9] KITAHARA C M,D K R F,JORGENSEN J O L,et al.Benign thyroid diseases and risk of thyroid cancer:a nationwide cohort study[J].J Clin Endocrinol Metab,2018,103(6):2216-2224.
Abstract Context: Thyroid nodules, adenomas, and goiter have consistently been associated with thyroid cancer risk. Few studies have assessed whether thyroid dysfunction and thyroid autoimmunity influence this risk. Objective: To examine thyroid cancer risk following diagnoses of a wide range of benign thyroid conditions. Design: Hospital and cancer registry linkage cohort study for the years 1978-2013. Setting: Nationwide (Denmark). Participants: Patients diagnosed with hyperthyroidism (n=85,169), hypothyroidism (n=63,143), thyroiditis (n=12,532), nontoxic nodular goiter (n=65,782), simple goiter (n=11,582), other/unspecified goiter (n=21,953), or adenoma (n=6,481) among 8,258,807 residents of Denmark during the study period. Main Outcome Measures: We computed standardized incidence ratios (SIRs) for differentiated thyroid cancer, excluding the first 12 months of follow-up after benign thyroid disease diagnosis. Results: SIRs were significantly elevated for all benign thyroid diseases apart from hypothyroidism. SIRs were higher for men than women and in the earlier follow-up periods. Elevated SIRs were observed for localized and regional/distant thyroid cancer. After excluding the first 10 years of follow-up, hyperthyroidism (n=27 thyroid cancer cases, SIR=2.00, 95% CI 1.32-2.92), nontoxic nodular goiter (n=83, SIR=4.91, 95% CI 3.91-6.09), simple goiter (n=8, SIR=4.33, 95% CI 1.87-8.53), other/unspecified goiter (n=20, SIR=3.94, 95% CI 2.40-6.08), and adenoma (n=9, SIR=6.02, 95% CI 2.76-11.5) remained positively associated with thyroid cancer risk. Conclusions: We found an unexpected increased risk of differentiated thyroid cancer, including regional/distant disease, following diagnosis of hyperthyroidism and thyroiditis that could not be solely attributed to increased medical surveillance. Hypothyroidism was less clearly associated with thyroid cancer risk.
DOI:10.1210/jc.2017-02599      PMID:29590402      URL    
[本文引用:1]
[10] JIA Q,LI X,LIU Y,et al.Incidental thyroid carcinoma in surgery-treated hyperthyroid patients with Graves' disease:a systematic review and meta-analysis of cohort studies[J].Cancer Manag Res,2018,10:1201-1207.
DOI:10.2147/CMAR      URL    
[本文引用:1]
[11] 宋春峰,刘满想,倪传斗,.术前TSH水平与甲状腺结节恶性风险的相关性[J].中国普外基础与临床杂志,2018,25(9):1060-1064.
目的探究术前TSH水平与甲状腺结节恶性风险的相关性。方法回顾性分析959例甲状腺结节患者的病例资料,通过SPSS 17.0软件进行统计学分析。结果 959例患者中,良性结节组746例,甲状腺乳头状癌(PTC)组213例。PTC患者术前的血清TSH水平高于良性结节患者[(2.32±1.65)mU/L比(1.76±1.20)mU/L,P0.001],并随TSH水平上升,PTC的患病风险增加。术前TSH水平与PTC肿瘤直径、病灶数量和淋巴结转移情况无相关性(P0.05)。logistic回归分析结果显示,术前TSH水平是PTC发生的独立影响因素[OR=1.315,95%CI为(1.171,1.477),P0.001]。TSH诊断PTC的最佳临界值为1.575 mU/L,此时灵敏度为62.0%,特异度为53.4%,受试者工作特征(ROC)曲线下面积为0.602(P0.001)。结论术前TSH水平与甲状腺结节恶性风险有一定的相关性,随TSH水平的上升PTC的患病风险增加。
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[12] ROWE C W,PAUL J W,GEDYE C,et al.Targeting the TSH receptor in thyroid cancer[J].Endocr Relat Cancer,2017,24(6):R191-R202.
Abstract Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway, and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.
DOI:10.1530/ERC-17-0010      PMID:28351942      URL    
[本文引用:1]
[13] JAESCHKE H,UNDEUTSCH H,PATYRA K,et al.Hyperthyroidism and papillary thyroid carcinoma in thyrotropin receptor D633H mutant mice[J].Thyroid,2018,28(10):1372-1386.
DOI:10.1089/thy.2018.0041      URL    
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[14] CROSS G A,SUAREZ H,PITOIA F,et al.Fatal outcome of a young woman with papillary thyroid carcinoma and graves' disease:possible implication of “cross-signalling” mechanism[J].Arq Bras Endocrinol Metabol,2008,52(7):1194-1200.
A 29 yrs-old patient was referred to our hospital due to generalized convulsions. She had hyperthyroidism treated with methimazole. Her MRI showed 4 metastatic lesions in the brain. She had a goiter with a cold nodule and a palpable ipsilateral lymph node. The FNAB disclosed a papillary thyroid carcinoma. Under 5 mg of MMI treatment, she had a subclinical hyperthyroidism and TRAb were 47.8% (n.v. 10%). The CT scan also showed lung metastasis. She underwent a total thyroidectomy with a modified neck dissection and she received an accumulated radioiodine dose of 700 mCi during the following two years. She died from the consequences of multiple metastatic lesions. Studies were performed in DNA extracted from paraffin-embedded tissue from the tumor, the metastatic lymph node and the non-tumoral thyroid. The genetic analysis of tumoral DNA revealed point mutations in two different genes: the wild type CAA at codon 61 of N-RAS mutated to CAT, replacing glycine by histidine (G61H) and the normal GCC sequence at codon 623 of the TSHR gene was replaced by TCC, changing the alanine by serine (A623S). In the non-tumoral tissue no mutations were found. In vitro studies showed a constitutive activation of the TSHR. It is very probable that this activating mutation of the TSHR is unable to reach the end point of the PKA cascade in the tumoral tissue. One possibility that could explain this is the presence of a cross-signaling mechanism generating a deviation of the TSH receptor cascade to the more proliferative one involving the MAPKinase, giving perhaps a more aggressive behavior of this papillary thyroid cancer.brPaciente de 29 anos foi encaminhada ao Hospital de Clínicas por causa de convuls01es generalizadas. Apresentava hipertiroidismo tratado com metimazol (MMI). A resson09ncia magnética mostrava quatro les01es metastáticas cerebrais. Possuía bócio com nódulo frio e linfonodo palpável ipsilateral. Usando 5 mg de MMI, a paciente apresentava hipertiroidismo subclínico e TRAb = 47,8% (normal 10%). A tomografia computadorizada também mostrava metástases pulmonares. A paciente foi submetida a tiroidectomia total com dissec0400o cervical modificada e recebeu dose acumulada de radioiodo de 700 mCi durante o período de dois anos. Foi analisado o DNA extraído de tecido emblocado em parafina do tumor, do linfonodo metastático e de tecido tiroidiano n00o-tumoral. Foram encontradas muta0401es pontuais em dois genes: uma substitui0400o do genótipo selvagem CAA no códon 61 de /N-RAS/ por CAT, substituindo a glicina pela histidina (G61H) e uma substitui0400o da seqüência normal GCC no códon 623 do gene TSHR por TCC, trocando a alanina pela serina (A623S). N00o foram encontradas muta0401es no tecido n00o-tumoral. Estudos in vitro mostraram ativa0400o constitutiva de TSHR. Já que esta muta0400o ativadora de TSHR foi incapaz de atingir o final da cascata PKA no tecido tumoral, sugere-se que um mecanismo de cross-signaling possa explicar o desvio da cascata do receptor de TSH para outra mais proliferativa, envolvendo MAPKinase e levando ao comportamento mais agressivo deste c09ncer papilífero.
DOI:10.1590/S0004-27302008000700018      PMID:19082310      URL    
[本文引用:1]
[15] 连小兰,白耀,唐伟松,.甲状腺功能亢进症合并甲状腺癌的临床分析[J].中国医学科学院学报,2000,22(3):273-275.
目的 了解甲状腺功能亢进症(甲亢)合并甲状腺癌的状况。方法 对本院1983年1月~1998年6月,接受手术方法治疗的394例甲亢和经手术病理诊断的245例甲状腺一并进行回顾性分析。结果 共发现甲亢合并甲状腺癌12例,占甲亢的3.0%(12/394),占甲状腺癌的4.9%(12/245),Graves病合并甲状腺癌6例,毒性结节必 腺肿合并甲状腺癌6例。12例患者中,甲状腺呈弥漫性肿大3例甲,弥漫性
DOI:10.1007/s11769-000-0028-3      URL    
[本文引用:2]
[16] KRAIMPS J L,BOUIN-PINEAU M H,MATHONNET M,et al.Multicentre study of thyroid nodules in patients with Graves' disease[J].Br J Surg,2000,87(8):1111-1113.
Abstract BACKGROUND: The association of Graves' disease with thyroid nodules and thyroid carcinoma is rarely reported. The incidence seems to be increasing according to recent literature. The aim of this multicentre study was to review patients who had surgery for Graves' disease associated with thyroid nodules, and to evaluate the risk of thyroid carcinoma. METHODS: A retrospective study was made of 557 consecutive patients who underwent operation for Graves' disease between 1991 and 1997 in five endocrine surgery departments. Each patient underwent clinical, biochemical, ultrasonographic and scintigraphic evaluation. None of the patients had had previous radioactive iodine therapy or external irradiation. Surgery consisted of either a subtotal or total thyroidectomy. RESULTS: Nodules were observed before operation in 140 patients (25.1 per cent). Thyroid carcinoma was diagnosed in 21 patients (15.0 per cent), always inside a nodule. The incidence of thyroid carcinoma associated with Graves' disease was 3.8 per cent (21 of 557 patients): 20 papillary and one follicular carcinoma. The carcinoma was multifocal in two patients. Tumour diameter ranged from 2 to 25 mm. A nodule was palpable in four patients. CONCLUSION: This multicentre study of patients having thyroidectomy for Graves' disease showed that 3.8 per cent had a carcinoma; the rate of carcinoma in cold nodules was 15.0 per cent. Surgery should be advised in any patient with Graves' disease and a thyroid nodule; the operation should be total thyroidectomy.
DOI:10.1046/j.1365-2168.2000.01504.x      PMID:10931060      URL    
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[17] MACEDO B M,IZQUIERDO R F,GOLBERT L,et al.Reliability of Thyroid Imaging Reporting and Data System(TI-RADS),and ultrasonographic classification of the American Thyroid Association(ATA) in differentiating benign from malignant thyroid nodules[J].Arch Endocrinol Metab,2018,62(2):131-138.
DOI:10.20945/2359-3997000000018      PMID:29641731      URL    
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[18] MELANY M,CHEN S.Thyroid cancer:ultrasound imaging and fine-needle aspiration biopsy[J].Endocrinol Metab Clin North Am,2017,46(3):691-711.
DOI:10.1016/j.ecl.2017.04.011      URL    
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[19] LEE K L,CHEN T J,WON G S,et al.The use of fine needle aspiration and trends in incidence of thyroid cancer in Taiwan[J].J Chin Med Assoc,2018,81(2):164-169.
react-text: 154 Ultrasound (US) elastography can provide information about the hardness of calcification and might help decide treatment strategy. The purpose of this study was to evaluate the hardness of the calcific area within rotator cuffs by US elastography as an aid for the selection of aspiration or fine-needle repeated puncture for the treatment of rotator cuff calcific tendinosis. This prospective... /react-text react-text: 155 /react-text [Show full abstract]
DOI:10.1016/j.jcma.2017.09.008      PMID:29174930      URL    
[本文引用:1]
[20] CHO Y J,KIM D Y,PARK E C,et al.Thyroid fine-needle aspiration biopsy positively correlates with increased diagnosis of thyroid cancer in South Korean patients[J].BMC Cancer,2017,17(1):114.
The incidence of thyroid cancer among South Koreans is more than 10-fold greater than its incidence in other countries, although its associated mortality rate is similar. Amidst concerns regarding the over-diagnosis of thyroid cancer related to gradually expanded medical testing in South Korea, we hypothesized that the number of thyroid fine-needle aspiration biopsies has led to increased diagnosis of thyroid cancer. We used data from the National Health Insurance Service National Sample Cohort 2003–2013, which included all medical claims filed for the 1,122,456 people in a nationally representative sample. We performed a Poisson regression analysis using generalized estimating equation to investigate the relationship between the number of thyroid fine-needle aspiration biopsies and the newly diagnosed cases of thyroid cancer. The study included 60 annual patients per 100,000 individuals out of 11,024,548 person-years. The number of biopsies per 100,000 patients positively correlated with increased incidence of thyroid cancer diagnosis (per 100 biopsy cases: RR65=651.108; 95% CI: 1.090–1.126;P<650.0001). Such relationships were greater in males, patients with a higher socioeconomic status, and patients from regions with relatively less accessibility to biopsies. Our findings suggest that a higher number of thyroid fine-needle aspiration biopsies per 100,000 individuals in a specific Si-Gun-Gu is positively associated with excessively increased diagnosis of thyroid cancer. Regarding the continually increasing thyroid cancer incidence in South Korea, healthcare professionals and policy makers should consider proper guidelines for recognizing the role of thyroid fine-needle aspiration biopsies in the potential over-diagnosis of thyroid cancer. The online version of this article (doi:10.1186/s12885-017-3104-0) contains supplementary material, which is available to authorized users.
DOI:10.1186/s12885-017-3104-0      PMID:28173779      URL    
[本文引用:1]
[21] CHAO T C,LIN J D,CHEN M F.Surgical treatment of thyroid cancers with concurrent Graves disease[J].Ann Surg Oncol,2004,11(4):407-412.
Background: Thyroid cancers with concurrent Graves disease are relatively rare. Accordingly, the natural history and optimal surgical treatment of thyroid cancers with Graves disease are controversial. Methods: Sixty-one thyroid cancers with concurrent Graves disease were retrospectively reviewed. Histopathologic diagnoses included 58 papillary thyroid carcinomas (95.1%), 1 follicular carcinoma (1.6%), 1 medullary carcinoma (1.6%), and 1 Hürthle cell carcinoma (1.6%). Results: The sample included 54 females and seven males. Subjects’ ages ranged from 20 to 73 years (mean ± SD, 35.9 ± 10.6 years; median, 37 years). Average tumor size was 10.7 ± 15.9 mm (range, 1–70 mm). Forty-nine tumors (80.3%) were 10 mm or smaller. Surgical procedures included subtotal thyroidectomy (40 patients), total thyroidectomy (16 patients), total thyroidectomy plus neck dissection (2 patients), near-total thyroidectomy (1 patient), and lobectomy with contralateral subtotal lobectomy (1 patient). Thirty-seven patients (60.7%) underwent postoperative 131 I ablation for thyroid remnant. Neck lymph node metastases occurred in three patients and lung metastases in two patients. Patients who developed metastases were younger and had significantly larger tumors and higher pretreatment serum T3 level than those who did not develop metastases. No deaths occurred during the 6.2 ± 4.1 year follow-up period (range, 1 year and 2 months to 18 years and 11 months). Conclusions: Most thyroid cancers with concurrent Graves disease were 10 mm or smaller. Subtotal thyroidectomy is adequate for patients with Graves disease with concurrent carcinoma 10 mm or smaller.
DOI:10.1245/ASO.2004.06.011      PMID:15070601      URL    
[本文引用:1]
[22] DIGONNET A,WILLEMSE E,DEKEYSER C,et al.Near total thyroidectomy is an optimal treatment for graves' disease[J].Eur Arch Otorhinolaryngol,2010,267(6):955-960.
Surgical management of Graves’ disease is still debated. We report our current experience with thyroidectomy for Graves’ disease at a tertiary center. A retrospective database of 132 patients who underwent surgery for Graves’ disease from January 1985 to December 2008 was collected. During that period, 16 patients underwent subtotal thyroidectomy and 116 patients underwent near total thyroidectomy. Eighty-seven patients (66%) underwent surgery for recurrent disease after medical therapy. Forty-five patients (34%) had surgery as a primary treatment, the indications were large goiter size in 22 (17%), patient preference in 19 (14%), and associated cold nodule in 3 (2%). The incidence of cancer was 4.4%. Permanent hypoparathyroidism was observed in one patient who underwent a second surgery for recurrence. Unilateral transitory vocal cord palsy was observed in nine patients (7%), bilateral transitory vocal cord palsy was observed in one patient, and no definitive vocal cord palsy was observed. Two patients (1.5%) experienced post-operative hemorrhagia requiring surgical revision. Near total thyroidectomy for Graves’ disease provides an immediate and definitive treatment with a low complication rate. Near total thyroidectomy offers an appropriate treatment for coexisting malignancy. This procedure can be safely recommended as a primary treatment, in experienced hands.
DOI:10.1007/s00405-009-1174-6      PMID:20035341      URL    
[本文引用:1]
[23] 邢曙光. 甲状腺全切除治疗原发性甲状腺功能亢进症合并甲状腺癌的临床分析[J].世界最新医学信息文摘,2018,18(54):43.
目的研究分析甲状腺全切除治疗原发性甲状腺功能亢进症合并甲状腺癌的临床效果。方法在2016年1月到2017年1月,在我院选取50例原发性甲状腺功能亢进症合并甲状腺癌患者,纳入患者均在我院进行采用甲状腺全切除治疗,分析临床治疗效果。结果纳入患者中甲状腺乳头状腺癌、滤泡状腺癌、伴有颈部淋巴结转移患者占比分别为84.0%、14.0%、2.0%。手术后暂时性声音嘶哑、低血钙患者占比分别为2.0%。占比为4.0%。手后随访,出现甲状腺功能减退占比为2.0%。结论对原发性甲状腺功能亢进症合并甲状腺癌患者采用甲状腺全切除治疗,临床效果显著,具有临床应用价值。
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[24] 张宪波,许践刚,颜育祥,.原发性甲状腺功能亢进症合并甲状腺癌的治疗[J].山东医药,2008,48(10):48-49.
报告21例原发性甲状腺功能亢进症(原发性甲亢)合并甲状腺癌患者,术前均诊断为原发性甲 亢,术中快速病理检查均确诊为甲状腺癌,其中17例行甲状腺全切。结果术中及住院期间无死亡,均无手术并发症,随访均未发现癌及甲亢复发。认为甲状腺全切 加术后终生服用甲状腺素是治疗原发性甲亢合并甲状腺癌较理想的疗法。
[本文引用:1]
[25] JIN Y,VAN NOSTRAND D,CHENG L,et al.Radioiodine refractory differentiated thyroid cancer[J].Crit Rev Oncol Hematol,2018,125:111-120.
Differentiated thyroid cancer (DTC) is usually curable with surgery, radioactive iodine (RAI), and thyroid-stimulating hormone (TSH) suppression. However, local recurrence and/or distant metastases occur in approximately 15% of cases during follow-up, and nearly two-thirds of these patients will become RAI-refractory (RR-DTC) with a poor prognosis. This review focuses on the most challenging and rapidly evolving aspects of RR-DTC, and we discuss the considerable improvement in more accurately defining RR-DTC, more effective therapeutic strategies, and describe the diagnosis, pathogenesis, and future prospects of RR-DTC. Along with the detection of serum thyroglobulin and anatomic imaging modalities, such as ultrasound and computer tomography, radionuclide molecular imaging plays a vital role in the evaluation of RR-DTC. In addition, continual progress has been made in the management of RR-DTC, including watchful waiting under appropriate TSH suppression, local treatment approaches, and systemic therapies (molecular targeted therapy, redifferentiation therapy, gene therapy, and cancer immunotherapy). These all hold promise to change the natural history of RR-DTC.
DOI:10.1016/j.critrevonc.2018.03.012      PMID:29650270      URL    
[本文引用:1]
[26] KIM M,KIM T H,SHIN D Y,et al.Tertiary care experie-nce of sorafenib in the treatment of progressive radioiodine-refractory differentiated thyroid carcinoma:a korean multicenter study[J].Thyroid,2018,28(3):340-348.
To control the production schedule for mold making, it is important to collect the actual results of machining operations, yet machine operators seldom record the results. Some die and mold shops have constructed a system which interfaces with NC controllers and which identifies the status of the machining operation from signals. This method depends totally on the NC controller and requires... [Show full abstract]
DOI:10.1089/thy.2017.0356      PMID:29350109      URL    
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[27] TAHARA M,BROSE M S,WIRTH L J,et al.Impact of dose interruption on the efficacy of lenvatinib in a phase 3 study in patients with radioiodine-refractory differentiated thyroid cancer[J].Eur J Cancer,2019,106:61-68.
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[28] LIN Y,WANG C,GAO W,et al.Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer[J].Oncotarget,2017,8(26):42252-42261.
Currently, patients with radioiodine refractory differentiated thyroid cancer (RAIR-DTC) have limited treatment options. In this study, we aimed to assess the short-term efficacy and safety of apatinib in RAIR-DTC. Ten adult patients were prospectively enrolled to receive oral apatinib (750 mg q.d). The primary endpoints were change in serum thyroglobulin (Tg) concentration, disease control rate (DCR) and objective response rate (ORR) based on RECIST 1.1 criteria. The secondary endpoints included change in glucose metabolism, evaluated by maximum standard uptake value (SUVmax), and safety. As early as 2 weeks after apatinib treatment, the serum Tg concentration decreased by 21.0% in 8 patients available for detection without interference, and a further sharp decline by 81.4% compared with the baseline level occurred at 8 weeks post-treatment. The DCR and ORR were 100% (10/10) and 90% (9/10), respectively. The sum of tumor diameter shrank to 22.8 8.1 mm from 38.8 15.7 mm (P=0.001). Moreover, a significant decrease in SUVmax was observed from 6.53 5.14 to 2.56 1.67 and 2.45 1.48 at 4-week and 8-week time-points after treatment (P=0.032 and 0.020), respectively. The common grade 3 adverse events (AEs) included hand-foot-skin reaction (50%), hypertension (30%), and hypocalcemia (20%). No severe AE related to apatinib was observed during treatment. Hence, apatinib seems to be a promising therapeutic option for RAIR-DTC patients. Apart from RECIST 1.1 criteria, the biochemical marker (Tg) and glucose metabolism index (SUVmax) could be adopted in assessing the early response to TKI in RAIR-DTC.
DOI:10.18632/oncotarget.15036      PMID:28178685      URL    
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[29] ZHANG X,WANG C,LIN Y.Pilot dose comparison of apatinib in Chinese patients with progressive radioiodine-refractory differentiated thyroid cancer[J].J Clin Endocrinol Metab,2018,103(10):3640-3646.
DOI:10.1210/jc.2018-00381      URL    
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[30] BORSON-CHAZOT F,DANTONY E,ILLOUZ F,et al.Effect of buparlisib,a pan-Class I PI3K Inhibitor,in refractory follicular and poorly differentiated thyroid cancer[J].Thyroid,2018,28(9):1174-1179.
DOI:10.1089/thy.2017.0663      URL    
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[31] 王芷乔,吕萌,周玉,.183例甲状腺癌术后患者中医证候临床调查[J].北京中医药大学学报,2015,38(9):645-648.
目的 对甲状腺癌术后患者的中医证候进行调查,明确证候分布及症状表现,为甲状腺癌的中医辨证论治提供依据。方法 结合文献研究和中医理论,制定“甲状腺癌中医证候学调查表”,对183例甲状腺癌术后患者进行中医证候横断面调查。结果 183例甲状腺癌术后患者中气阴两虚证63例(34.43%),肝郁气滞证48例(26.23%),痰瘀互结证45例(24.59%),脾肾阳虚证27例(14.75%)。不同年龄与不同病程的甲状腺癌患者,中医证候分型无统计学差异(<i>P</i>&lt;0.05)。结论 甲状腺癌术后患者中医证型的分布规律对于临床辨证具有一定指导意义。
DOI:10.3969/j.issn.1006-2157.2015.09.014      Magsci     URL    
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[32] 赵勇,徐文华,陈如泉.陈如泉运用益气养阴扶正法治疗甲状腺癌术后经验[J].湖北中医杂志,2013,35(11):24-25.
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[33] 俞菲菲. 益气养阴方在分化型甲状腺癌术后的应用研究[D].南京:南京中医药大学,2018:1-20.
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关键词(key words)
甲状腺功能亢进症
甲状腺癌
手术治疗
靶向治疗

Hyperthyroidism
Thyroid cancer
Surgical therapy
Target therapy

作者
陈继东
欧阳文奇
张李
方菲

CHEN Jidong
OUYANG Wenqi
ZHANG Li
FANG Fei