【作者】 陈欣；

【导师】 滕理送；

【作者基本信息】 浙江大学 ， 肿瘤外科（专业学位）， 2013， 博士

【摘要】 背景甲状腺滤泡状癌属于分化型甲状腺癌的一种,其分期、治疗与甲状腺乳头状癌类似。但由于甲状腺滤泡状癌独特的生物学特征,侵袭性较高,转移方式以血运为主,易发生远处转移,预后较甲状腺乳头状癌差。部分专家认为应该采取积极的治疗方案,包括甲状腺全切或近全切除术,术后辅助以促甲状腺激素抑制治疗和放射性碘治疗。目前普遍接受对初治存在远处转移和广泛浸润型甲状腺滤泡状癌患者给予甲状腺全切/近全切除术加术后131I治疗,而微小浸润型甲状腺滤泡状癌的治疗存在较多争论。普遍认为其预后良好,但一旦出现早期复发、转移,将严重影响预后。临床缺乏统一的诊治指南来选择高危患者并给予合适的个体化治疗。甲状腺滤泡状癌早期诊断困难。术前细针穿刺活检和术中冰冻对甲状腺滤泡状癌的诊断价值有限,较多滤泡状肿瘤患者被迫接受诊断性甲状腺切除手术,部分患者诊断明确后由于初次手术切除范围不充分短期内还得接受二次手术以完成甲状腺全切。早期、快速的提供诊断信息,有助于避免不必要的手术干预,减轻患者痛苦,减少医疗资源浪费并改善预后。为提高甲状腺癌早期诊断率,临床出现较多利用分子标记物来鉴别甲状腺肿瘤良恶性的研究,其中蛋白标记物半乳糖凝集素-3是目前研究最为广泛的分子标记物之一。近几年出现了一些检测细针穿刺标本的半乳糖凝集素-3表达,以术前鉴别甲状腺滤泡状肿瘤良恶性的大型前瞻性多中心研究,大大增加了其临床可信度。为此,本研究通过建立浙江大学附属第一医院1997-2011年甲状腺癌临床数据库,整理我院1997年1月至2011年6月期间甲状腺癌的收治情况,分析15年来甲状腺癌发病趋势以及构成比变化。同时筛选数据库内滤泡状癌患者进行随访,评价甲状腺滤泡状癌和微小浸润型滤泡状癌的治疗效果,分析预后影响因素。同时检索PubMed、Cochrane Library、中国生物医学文献数据库、万方数据库、中文科技期刊全文数据库(维普数据库),检索利用检测半乳糖凝集素-3来鉴别细针穿刺提示甲状腺滤泡状肿瘤的良恶性的前瞻性研究文献,进行Meta分析,评价半乳糖凝集素-3检测对早期鉴别诊断甲状腺滤泡状肿瘤良恶性的应用价值,供临床参考。第一部分：浙江大学附属第一医院甲状腺癌临床数据库建立及1997年-2011年收治甲状腺癌构成比变化分析。目的：建立浙江大学附属第一医院甲状腺癌临床数据库,为临床、基础研究提供资料。同时筛选、分析库内甲状腺滤泡状癌临床数据,为第二部分研究做准备。方法：采用手工录入和电脑信息采集相结合的方法收集、整理浙江大学附属第一医院1997年1月至2011年6月年间收治的甲状腺癌患者临床数据,建立浙江大学附属第一医院甲状腺癌临床数据库。从中筛选、分析甲状腺滤泡状癌患者临床信息,为第二部分随访研究做准备。结果：(1)、1997年1月至2011年6月间,浙江大学附属第一医院共收治甲状腺癌患者2437例。其中乳头状癌2244例,占总收治人数的92.08%,滤泡状癌134例,占5.5%,髓样癌28例,占1.15%,未分化癌20例,占0.82%,其他特殊类型癌11例,占0.45%。1997-2001年共收治甲状腺癌患者227例,占总数的9.31%,其中乳头状癌200例(88.1%),滤泡状癌19例(8.4%),其余共8例(3.5%)；2002-2006年共收治578例,占23.71%,乳头状癌510例(88.2%),滤泡状癌45例(7.8%),其余23例(4%)；2007-2011年共收治1632例,占66.97%,乳头状癌1534例(94%),滤泡状癌70例(4.3%),其余28例(1.7%)。(2)、1997-2011年共收治甲状腺滤泡状癌患者134名,中位年龄45岁,男女比为1：3.1；年龄≥45岁患者71人,<45岁63人；肿瘤直径≥4.0cm为35人,<4.0cmm为99人,TNM分期分别为I期95人、II期16人、Ⅲ期17人、Ⅳ期6人；接受淋巴结清扫术患者25人,未清扫109人,接受全切术患者82人,腺叶切除患者52人。结论：(1)、浙江大学附属第一医院收治甲状腺癌患者例数逐年上升,尤其近5年上升特别明显。其分型仍以乳头状癌为主,但所占比例上升,从1997-2001年的88.1%上升到2007-2011年的94.0%。其次为滤泡状癌,而其所占比例有所下降,从1997-2001年间的8.4%下降到2007-2011年间的4.3%。(2)、1997-2011年浙一医院收治的甲状腺滤泡状癌患者疾病一般情况较好,治疗较多采用甲状腺全切术式,淋巴结清扫相对较少。第二部分：甲状腺滤泡状癌临床研究及预后影响因素分析。目的：分析甲状腺滤泡状癌及微小浸润型滤泡状癌的预后及其影响因素。方法：对浙江大学医学院附属第一医院1997年1月至2011年6月期间收治的134例甲状腺滤泡状癌患者进行筛选,总结、分析甲状腺滤泡状癌和微小浸润型滤泡状癌患者的5年、10年、15年累计生存率、无病生存率及其影响因素。主要分析指标有：年龄、性别、复发转移情况(无病生存率分析不进行此项分组)、肿瘤直径、TNM分期、是否多灶、手术切除方式、淋巴清扫范围。统计学方法应用Kaplan-Meier法对累计生存率及无病生存率情况进行分析,生存曲线差异使用Log-rank检验,预后相关因素分析采用Cox比例回归模型。双侧检验,P<0.05为具有统计学意义。结果：(1)、排除不符合本研究纳入标准的患者后进行随访；共125例甲状腺滤泡状癌患者纳入本部分研究,102例患者获得随访。患者总体5年、10年、15年生存率分别为：97%、91.6%、69%。>45岁患者5年、10年生存率分别为94.3%、82.5%,<45岁患者10年生存率为100%。12例M0患者随访期间发生转移、复发,4例为远处转移,8例为局部复发或区域淋巴结转移。总体5年、10年无病生存率分别为87.8%、75%,>45岁患者5年、10年无病生存率为83.1%、56.1%,<45岁患者5年、10年无病生存率为92.9%、88%。甲状腺滤泡状癌患者的预后与年龄、是否复发转移、TNM分期相关。年龄大于45岁,有复发、转移,TNM分期靠后的患者预后相对较差。(2)、共86例微小浸润型甲状腺滤泡状癌患者获得随访,总体5年、10年年生存率分别为：97.7%、89.6%。≥45岁患者5年、10年生存率为97.1%、87.4%,<45岁患者5年、10年生存率均为100%。8例M0患者随访期间发生转移或复发,3例发生远处转移,其余5例为原位复发或者区域淋巴转移。总体5年、10年无病生存率为87.7%、83.3%。≥45岁患者5年、10年无病生存率为81.8%、71.6%,<45岁患者5年、10年无病生存率为94%。微小浸润型滤泡状癌患者预后的主要影响因素是复发转移和TNM分期,发生复发转移和TNM分期大于I期的患者预后较差。肿瘤直径≥4.0cm是影响微小浸润型滤泡状癌患者无病生存率的独立影响因素。结论：甲状腺滤泡状癌和微小浸润型滤泡状癌整体预后良好,早期诊断、早期治疗和密切随访是提高患者预后的关键。第三部分：术前Galectin-3检测对细针穿刺提示甲状腺滤泡性肿瘤良恶性鉴别诊断价值的系统评价。目的：评价术前Galectin-3检测对鉴别细针穿刺提示甲状腺滤泡性肿瘤良恶性的诊断价值。方法：检测PUBMED、Cochrane图书馆、中国生物医学文献数据库、中国期刊全文数据库、中文科技期刊全文数据库,检索时间为1995.1-2012.12,收集关于评价甲状腺切除术前Galectin-3检测对鉴别细针穿刺提示甲状腺滤泡性肿瘤良恶性诊断价值的前瞻性研究文献,并进行质量评价,采用Meta-disc软件进行meta分析,并绘制ROC曲线。结果：共8篇文献纳入分析,1082例患者进入本部分Meta分析。Galectin-3对细针穿刺提示为甲状腺滤泡性肿瘤的甲状腺癌诊断合并敏感性为0.83[95%CI(0.78,0.86)],合并特异性为0.90[95%CI(0.88,0.92)],合并阳性似然比为7.46[95%CI(5.06,10.99)],合并阴性似然比为0.21[95%CI(0.15,0.29)],合并诊断比值比为38.41[95%CI(21.90,67.35)]。结论:Galectin-3检测对细针穿刺不能区分良恶性的甲状腺滤泡性肿瘤诊断甲状腺癌具有较高的敏感度和特异度,诊断准确性较好,可以作为重要的诊断指标。但仍需要更多高质量的研究来加以验证。更多还原

【Abstract】 BackgroundFollicular thyroid carcinoma (FTC) is one type of differentiated thyroid carcinoma (DTC), which staging and therapeutic strategy is similar to Papillary Thyroid Carcinoma (PTC). However, FTC is more aggressive than PTC and easier to spread hematogenously with distant metastases, due to its clinicopathologic feature and biological behavior which is different from PTC. Some experts adviced FTC should be treated aggressively, including total thyroidectomy (TT)/near total thyroidectomy (NTT) followed by thyroid stimulating hormone (TSH) suppression therapy and radioiodine ablation (RAI). Generally, this aggressive therapeutic strategy was only accepted to treat patients with widely invasive follicular thyroid carcinoma (WIFTC) or with distant metastases. But for minimally invasive FTC (MIFTC), on the other hand, there was still a matter of controversy. The outcome of MIFTC is pretty good which will turn to be poor if patients developed early distant metastases. Any development of guideline which can select high risk patient and provide them better treatment would represent a significant advance in the management of thyroid carcinoma. Moreover, the diagnosis of FTC is difficult, the predictive values of preoperative fine needle aspiration cytology (FNAC) and frozen section (FS) were low. Many patients received surgical procedure for diagnostic purpose, and some others have to receive completion thyroidectomy soon after first operation.Recent decade, many molecular markers had been evaluated to improve diagnostic accuracy for follicular lesions. Galectin-3(GAL-3),a β-galactoside-binding molecule in the lectin group, was one of most frequently investigated molecular markers, be it in tissues or in cytological material of FNA. Large prospective studies have carried out to confirm the ability of galectin-3improving preoperative diagnostic accuracy for patients with follicular lesions.To this end, we built the database of thyroid carcinoma (TC) patients who were treated in the first affiliated hospital of Zhejiang University from January1997to June2011and discussed the epidemiology of TC patients in our hospital. Then FTC and MIFTC patients were selected from the database and followed up. The factors affecting the prognosis of FTC and MIFTC patients were analyzed. At the end, a meta-analysis on evaluating the accuracy of galectin-3expression test for follicular lesions was performed by using a search of PubMed, Cochrane Library, Wanfang data resource system, Chinese science and Technology Periodical Database and Chinese Biomedical Literature Database to provide the information for clinical practice.Part I:Building the database of thyroid carcinoma patients who were treated in the first affiliated hospital of Zhejiang University from1997-2011and analysing the clinical data of FTC patients.Objective:To build the database of TC patients for providing resource for basic and clinical research and for further research in part Ⅱ. Method:The clinical data of TC patients who were treated in the first affiliated hospital of Zhejiang university from January1997to June2011was collected to build the database of TC patients. The clinical information of FTC patients in database was selected and analyzed for the further research in part Ⅱ.Result:(1) From January1997to June2011, there were2437TC patients were treated in the first affiliated hospital of Zhejiang University, including2244cases of PTC (92.08%),134cases of FTC (5.5%),28cases of Medullary Thyroid Carcinoma (MTC)(1.15%).20cases of Anaplastic Thyroid Carcinoma (ATC)(0.82%) and11cases of other rare subtype (0.45%).In the first five years, there were227cases of TC patients accounted for9.31%of total, including200cases of PTC (88.1%),19cases of FTC (8.4%) and8cases others(3.5%); in the second five years, there were578cases of TC patients account for23.71%of total, including510cases of PTC (88.2%).45cases of FTC (7.8%) and23cases others (4%) and in the third five years, there were1632cases of TC patients account for66.97%of total, including1534cases of PTC (94%),70cases of FTC (4.3%) and28cases others(1.7%).(2) There were134cases of FTC patients were treated in our hospital in the last fifteen years. The incidence of thyroid carcinoma was3.01times higher in female than in male.71patients were older than45years of age,63patients below45years old. There were35patients whose tumor size bigger than4.0cm,99were smaller.95patients were in their Ⅰ TNM stage,16were in Ⅱ stage,17were in Ⅲ stage and6were in IV stage.25patients received lymph node dissection and109patients didn’t.82patients received TT/NTT,52received lobectomy (LC).Conclusion:(1) The amount of TC patients treated in the first affiliated hospital of Zhejiang University increased rapidly. Most of them were PTC. The ratio of PTC increased from88.1%in1997-2001to94.0%in2007-2011. The second part of TC was FTC, of which the ratio decreased from8.4%in1997-2001to4.3%in2007-2011.(2) The clinical features of TC patients were good. Patients were trend to be treated with total thyroidectomy and without lymph node dissection.Part II:The clinical study of outcome and prognostic factor of FTC and MIFTC patients.Objective:to investigate outcome and prognostic factors of FTC and MIFTC patients.Methods:The cumulative cause-specific survival (CSS) and disease-free survival (DFS) of FTC and MIFTC patients in our TC database were assessed and the prognosis factors were analyzed. The major variables including age at surgery (<45years vs.≥45years), sex, tumor size (<4.0cm vs.≥4.0cm), present of distant metastases or recurrence (DFS didn’t analyze by this variable), TNM classification staging, multiple lesions, operation procedure, lymph node dissection method. A univariate analysis was conducted in relation to CSS and DFS by the Kaplan-Meier method. Differences between groups were analyzed for significance by the log-rank test. Multivariate analysis was performed by using the Cox proportional regression model. P values<0.05were regarded as statistically significant.Result:(1) After excluding patients didn’t match the criterion,102cases of FTC patients were included and followed-up. Cause-specific death occurred in4patients. The overall5-years,10-year,15-year CSS rates were97%,91.6%,69%; The5-year and10-year CSS rates of patients older than45years of age were94.3%,82.5%; the5-year and10-year CSS rates of patients younger than45years of age were100%.12M0patients present distant metastases or recurrence in follow-up period,4patients presented distant metastases and8presented local recurrent or regional lymph node metastases. The overall5-year and10-year DFS rates were87.8%,75%; The5-year and10-year DFS rates of patients older than45years of age were83.1%,56.1%; the5-year and10-year DFS rates of patients younger than45year of age were92.9%,88%. Univariate analysis showed that CSS was affected by age, presentation of recurrence or metastasis, TNM stage. The prognosis was poorer in patients who were elder than45years old, presented recurrence or metastasis, with high TNM stage.(2)86cases of MIFTC patients were included in this study. Cause-specific death occurred in2patients. The overall5-years and10-year CSS rates were97.7%,89.6%; The5-year and10-year CSS rates of patients older than45years of age were97.1%,87.4%; the5-year and10-year CSS rates of patients younger than45year of age were100%.8MO patients presented distant metastases or recurrence in follow-up period,3patients presented distant metastases and5presented local recurrent or regional lymph node metastases. The overall5-year and10-year DFS rates were87.7%,83.3%; the5-year and10-year DFS rates of patients older than45years of age were81.8%,71.6%; the5-year and10-year DFS rates of patients younger than45year of age were94%. Univariate analysis showed that CSS was affected by presentation of recurrence or metastasis, TNM stage. The prognosis was poorer in patients who presented recurrence or metastases and in patients with high TNM stage. Multivariate Cox proportional hazards model analysis showed tumor size>4.0cm was independent factor that impact on DFS of MIFTC.Conclusion:The prognosis of FTC and MIFTC is good. Early treatment and close following-up are essential to improve the prognosis of patients with FTC.Part Ⅲ:A Meta-analysis on evaluating the diagnostic value of galectin-3expression test for follicular lesion with FNAC result of "follicular pattern" preoperatively.Objective:To evaluate the predictive value of galectin-3expression test to distinguish malignancy from thyroid lesions with FNAC result of "follicular pattern" preoperatively. Methods:A search of PUBMED, Cochrane library, Wanfang data resource system, Chinese science and Technology Periodical Database and Chinese Biomedical Literature Database was done from January1995to December2012. The prospective research on evaluating the predictive value of galectin-3expression test to distinguish malignancy from follicular lesions detected by FNAC preoperatively were collected and reviewed. The Summary Receiver Operating Characteristic (ROC) curve and meta-analysis were performed by meta-disc software version1.4.Result:8studies involving1082patients were included. The pooled sensitivity was0.83[95%CI (0.78to0.86)] and the pooled specificity was0.90[95%CI (0.88to0.92)]; the pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were7.46[95%CI (5.06to10.99)] and0.21[95%CI (0.15to0.29)]. The pooled diagnostic odds ratio (DOR) was38.41[95%CI (21.90to67.35)].Conclusion:The galectin-3may well prove to be a useful tool for distinguishing malignancy from thyroid lesions with FNAC result of "follicular pattern" because of high sensitivity and specificity, but more high quality trials are required.更多还原