RET/PTC重排与甲状腺乳头状癌的关系研究

近30年来甲状腺癌的发病率逐年上升,最常见的病理亚型为甲状腺乳头状癌(papillary thyroid carcinoma,PTC),其发生发展过程涉及多种基因改变。RET/PTC重排参与了PTC和甲状腺髓样癌的发展,这是具有不同胚胎起源的不同肿瘤,因此RET/PTC重排对于PTC的发生发展具有重要的临床意义。近年来针对RET/PTC重排的RET抑制剂研究取得了显著进展,本文对RET/PTC重排在PTC发病机制中的作用,以及其对PTC的诊断、治疗和预后的影响做一综述。     

头颈外科学

预防性颈部II区淋巴结清扫术对淋巴结阳性甲状腺乳头状癌患者的影响目的：通过术前超声（PU）检查伴有临床颈部淋巴结转移（levelIII,IV和/或V）的甲状腺乳头状癌（PTC）患者,探讨其隐匿性levelII淋巴结转移与发生频率、类型及预测因素的联系。方法：回顾性分析52例伴有levelIII,     

甲状腺乳头状癌中PTEN基因启动子甲基化及其蛋白表达的相关性

目的 探讨甲状腺乳头状癌(papillary thyroid carcinoma,PTC)组织中PTEN基因启动子区域甲基化状态及其蛋白表达的相关性.方法 采用甲基化特异性聚合酶链反应及免疫组化SP技术,检测80例PTC及其相对应的癌旁组织中PTEN基因启动子甲基化状态及其蛋白表达.结果 在癌旁组织中,无一例出现PTEN基因启动子甲基化,而在PTC中,有25%(20/80)出现甲基化,且其甲基化状态与TNM分期、病理分级及淋巴转移有关(P值均<0.05);癌旁组织和PTC组织中,PTEN蛋白表达的阳性率分别为100.0%(80/80)和41.3%(33/80),P<0.01.在PTC组中,在病理分级Ⅰ级和Ⅱ级组,PTEN蛋白阳性率分别为54.0%(27/50)和20.0%(6/30),在淋巴转移阳性和阴性组分别为20.6%(7/34)和56.5%(26/46),以上两组比较差异有统计学意义(χ~2值分别为8.944和10.046,P值均<0.01);PTEN基因启动子甲基化与其蛋白表达有明显的相关性(χ~2=9.095,P<0.01).结论 PTEN基因启动子区域甲基化是该基因失活的重要机制之一,在PTC的发生、发展中起着重要的作用.     

甲状腺乳头状癌Ⅵ区淋巴结清扫非劣性研究

目的：了解未行含Ⅵ区的择区性淋巴结清扫术的分化良好的甲状腺乳头状癌患者的复发情况;探讨分化良好的甲状腺乳头状癌是否要常规行含Ⅵ区的择区性颈淋巴结清扫术。方法：不同时期处理的甲状腺乳头状癌患者267例,按时间分成2组：A组为近期行含Ⅵ区的择区性淋巴结清扫的甲状腺乳头状癌151例;B组为早期未行Ⅵ区择区性淋巴结清扫的甲状腺乳头状癌116例。原发灶处理2组均一致：肿瘤发生侧行甲状腺全切除,甲状腺峡部全切,健侧甲状腺次全切除;若肿瘤两侧同时发生,则行双侧甲状腺全切术。统计第1组中Ⅵ区淋巴结转移发生率;随访第2组患者,观察头颈部淋巴结复发情况以及生存情况。结果：A组151例患者中59例仅行Ⅵ区淋巴结清扫,其中发生转移者22例,其余92例同时行Ⅱ、Ⅲ、Ⅳ、Ⅵ区颈淋巴结清扫,其中各区都没有转移者31例,Ⅵ区和其他区均转移者33例（35．8％）,只有Ⅵ区颈淋巴结转移者17例（18．4％）,除Ⅵ区外其他区域淋巴结有转移者11例（11．9％）。即甲状腺乳头状癌病例中Ⅵ区淋巴结转移率为47．7％（72／151）。B组116例甲状腺乳头状癌伴有颈淋巴结转移者47例,占40．5％;5年生存率为99．3％;复发率为6．0％（7／116）。A组颈淋巴结转移率（54．9％）高于B组（40．5％）。结论：分化良好的甲状腺乳头状癌患者较多的转移到气管前和喉返神经周围淋巴结,Ⅵ区淋巴清扫可成为常规。     

甲状腺乳头状癌cN0患者颈侧区淋巴结转移规律的探讨

目的 探讨甲状腺乳头状癌cNO患者颈侧区淋巴结转移状况及规律.方法 回顾性分析106例甲状腺乳头状癌cNO患者的临床及病理资料.所有患者均为首次手术,手术方式均为甲状腺全切除或近全切除+中央区淋巴清扫+颈侧区淋巴清扫.分析指标包括患者性别、年龄、原发灶大小、肿瘤是否多发、肿瘤T分级及中央区淋巴结转移状况,同时对肿瘤原发灶位置与颈侧区淋巴结转移区域的关系进行探讨.结果 cNO甲状腺乳头状癌颈侧区淋巴结转移与男性(P=0.007)、原发灶最大径＞1 cm(P =0.014)、肿瘤T分级为T3、T4 (P=0.006)及中央区淋巴结阳性数≥2枚(P＜0.001)有关,而与年龄(P =0.947)及肿瘤是否多发(P =0.710)无关.颈侧区淋巴转移以Ⅲ区(47/116,40.5％)、Ⅳ区(41/116,35.3％)最常见,其次是Ⅱ区(18/116,15.5％),而Ⅴ区转移少见(2/29,6.9％).其中89.8％(79/88)的Ⅲ、Ⅳ区淋巴转移发生于原发灶位于(或包含)甲状腺中下极的患者,77.8％ (14/18)的Ⅱ区淋巴转移发生于原发灶位于(或包含)甲状腺上极的患者,83.3％(15/18)的Ⅱ区转移同时伴随着Ⅲ区转移.2例Ⅴ区淋巴转移的患者都伴有Ⅱ、Ⅲ、Ⅳ区同时转移.结论 对于男性、肿瘤为T3、T4级及中央区淋巴结阳性数≥2枚的甲状腺乳头状癌患者建议术中常规清扫颈侧Ⅲ、Ⅳ区淋巴结,如肿瘤位于甲状腺上极或Ⅲ区淋巴结阳性者还应清扫Ⅱ区,只有当Ⅱ、Ⅲ、Ⅳ区同时有淋巴转移时才应考虑Ⅴ区淋巴清扫术.对于肿瘤最大径≤1 cm且局限于甲状腺内及无中央区淋巴转移的甲状腺乳头状癌患者不建议行预防性颈侧区淋巴清扫术.     

抑癌基因PTEN在喉癌中的表达及临床意义

目的：研究抑癌基因PTEN在喉癌组织中的表达及其临床意义。方法：应用免疫组织化学SP法,检测PTEN在68例喉鳞状细胞癌组织（喉癌组）及33例癌旁正常黏膜组织（对照组）中的表达。结果：①喉癌组PTEN蛋白阳性表达率为61．8％（42／68）,对照组为100．0％（33／33）,喉癌组PTEN蛋白阳性表达率显著低于对照组（P＜0．01）。②PTEN蛋白阳性表达与喉癌临床病理特征的关系：高、中分化组与低分化组之间PTEN蛋白阳性表达率比较（79．3％：48．7％）差异有统计学意义（P〈0．01）;淋巴结转移者PTEN蛋白阳性表达率（55．0％）显著低于无淋巴转移者（71．4％）（P＜0．05）;根据临床病理分期,Ⅰ加Ⅱ期与Ⅲ加Ⅳ期之间PTEN蛋白阳性表达率（76．0％：53．5％）差异有统计学意义（P＜0．05）;随临床分期增加、喉癌分化程度降低及淋巴结的转移,PTEN蛋白阳性表达率逐渐降低。另外,PTEN蛋白阳性表达与患者年龄、性别、肿瘤组织大小及部位无关（P〉0．05）。结论：抑癌基因PTEN在喉癌的发生及发展中起重要作用,对其蛋白的检测可作为判定喉癌发生及侵袭转移能力的一项客观指标。     

埃兹蛋白和膜突蛋白及上皮型钙黏蛋白与甲状腺乳头状癌侵袭性的相关性研究

目的 探讨埃兹蛋白(Ezrin)、膜突蛋白(Moesin)和上皮型钙黏蛋白(E-Cadherin)在甲状腺乳头状癌侵袭和转移中的作用。方法 选取2005-2008年手术切除的81例甲状腺乳头状癌石蜡包埋标本,以癌旁组织为对照,采用免疫组织化学SP法,检测Ezrin、Moesin和E-Cadherin在甲状腺乳头状癌中的表达,并结合患者的临床资料进行分析。结果 甲状腺乳头状癌中的Ezrin、Moesin的阳性表达率均高于癌旁组织（x2值分别为61.691、57.949,P值均＜0.01）。甲状腺乳头状癌中E-Cadherin的阳性表达率低于癌旁组织(x2 =64.241,P＜0.01)。患者年龄≥45岁、肿瘤侵犯甲状腺被膜外、有颈淋巴转移、Ⅲ～Ⅳ期甲状腺乳头状癌,Ezrin、Moesin的阳性表达率增高,差异有统计学意义（P值均＜0.01）;而E-Cadherin的阳性表达率降低,差异有统计学意义（P值均＜0.01）。结论 甲状腺乳头状癌中Ezrin、Moesin的高表达和E-Cadherin的低表达与肿瘤的侵袭和转移有关,三者之间可能具有协同作用,联合检测Ezrin、Moesin和E-Cadherin可作为判断甲状腺乳头状癌侵袭、转移和预后的指标。     

微小RNA-489调控脑源性神经营养因子在甲状腺乳头状癌中的作用机制研究

目的　分析微小RNA（microRNA，miR）-489在甲状腺乳头状癌（papillary thyroid carcinoma，PTC）发生发展过程的影响，并探讨其在甲状腺乳头状癌临床诊断的价值。方法　采用实时荧光定量PCR（qRT-PCR）检测甲状腺乳头状癌组织中脑源性神经营养因子（brain derived neurotrophic factor，BDNF）及miR-489的表达变化；TargetScan和双荧光素酶报告基因实验预测并验证miR-489可靶调控BDNF；CCK-8、Transwell迁移侵袭实验等探究miR-489和BDNF对甲状腺乳头状癌细胞TPC-1的影响；构建裸鼠植瘤模型探究miR-489在体内实验中对甲状腺乳头状癌的影响。结果　miR-489在甲状腺乳头状癌组织及转移的肿瘤组织中的表达降低（P＜0.01）；BDNF是miR-489的靶基因；过表达BDNF能逆转miR-489对TPC-1细胞增殖、迁移、侵袭的抑制作用（P＜0.05)；miR-489可抑制裸鼠肿瘤的生长（P＜0.01）。结论　miR-489通过抑制靶基因BDNF的表达在甲状腺乳头状癌中扮演抑癌基因的角色。     

甲状腺乳头状癌术式探讨

目的：回顾分析甲状腺乳头状癌治疗效果，探讨外科治疗最佳方案。方法：对我院1984－1996年收治的228例甲状腺乳头状癌患者手术治疗结果进行分析。228例患者中肿瘤位于单侧叶者162例，狭部18例，双叶34例，侵犯甲状软骨及气管14例。颈淋巴cN0148例，cN^ 80例，术后均随访5年以上。结果：cN^ 者行功能性（41例）和根治性颈清扫（39例）的5年生存率分别为87．8％（36／41）和87．2％（34／39）。。腺内型cN0伴被膜侵犯者行选择性颈清扫21例，随诊观察20例，其5年生存率分别为90．5％（19／21）和90．0％（18／20），腺内型cN0不伴被膜侵犯者均未行颈清扫，其5年生存率为99．0％（99／100），5年内发生颈淋巴结转移率为1．0％（1／100）；腺外型cN0行颈清扫4例，5年内发生对侧转移为1／4，3例未行颈清扫者5年内发生颈淋巴转移为2／3。腺叶切除术后对侧复发率为2．47％（4／162）。行全甲状腺切除的5年生存率为85．7％（12／14），被膜内全甲状腺切除的5年生存率为85．0％（17／20）。侵犯甲状软骨板及气管者，行喉全切除，其5年生存率为3／5，保留喉功能的5年生存为6／9。结论：对甲状腺乳头状癌提倡功能性颈清扫；腺内型cN0者主张随访观察，发现淋巴转移再生颈清扫；腺外型cN0病人主张同期颈清扫。原发灶位于单侧行腺叶及峡部切除，位于峡部及左，右叶各1／3切除，位于双侧行被膜内全甲状腺切除，侵犯甲状软骨板及气管者尽可能保留喉功能。     

乳头状甲状腺癌胸锁乳突肌与胸骨舌骨肌之间淋巴结转移的临床特征分析

目的探讨乳头状甲状腺癌（papillary thyroid carcinoma,PTC）颈前下部胸锁乳突肌与胸骨舌骨肌之间淋巴结（lymph node between sternocleidomastoid and sternohyoid muscle,LNSS）转移的临床特点及相关影响因素。方法回顾性分析126例PTC患者进行手术治疗的临床资料,计数LNSS数目,计算该组淋巴转移率,测定转移淋巴结最长径。对性别、年龄、甲状腺肿瘤最长径、原发灶侧别、肿瘤部位、多发癌灶、颈前带状肌侵犯、颈部多发淋巴结转移等7个因素与颈前下部LNSS转移的相互关系进行分析。结果 18例患者出现该组淋巴结转移,转移率14.3%;转移淋巴结共29个,平均最长径（0.5±0.12）cm。与未发生转移的患者比较,LNSS转移的患者同时发生颈中央区及颈侧区多发淋巴结转移的比例高（P﹤0.05）,肿瘤侵犯颈前带状肌较常见（P﹤0.05）。两组患者年龄、性别、肿瘤最长径大小、原发灶侧别、肿瘤发生部位、多发癌灶比例经比较差异无统计学意义（P﹥0.05）。结论颈部多发淋巴结转移和带状肌侵犯的PTC患者易同时发生LNSS转移。     

RET/PTC fusion gene rearrangements in Japanese thyroid carcinomas

The activation of RET proto-oncogene through chromosomal translocation is reported as being unique to papillary thyroid carcinomas. However, the reported prevalence of RET/PTC activation in papillary carcinoma was variable, and the clinical relevance of RET/PTC rearrangements in papillary carcinomas is still controversial. To investigate the roles of RET rearrangement in the carcinogenesis of papillary thyroid carcinoma, we have studied RET activation and p53 overexpression in various thyroid lesions of the Japanese population by immunohistochemical technique. RET activation and p53 overexpression were studied in 40 papillary carcinomas, 6 poorly differentiated carcinomas, 4 undifferentiated carcinomas, 2 medullary carcinomas, 2 follicular carcinomas and 19 follicular adenomas. RET activation was observed in 12 out of 40 papillary carcinomas, while no immunoreactivity of RET was detected in other lesions. P53 overexpression was observed in only 1 of 40 papillary carcinomas, but in 2 poorly differentiated carcinomas and 4 undifferentiated carcinomas. The prevalence of RET/PTC activation in papillary carcinoma among the Japanese population was higher than in previous reports. Immunohistochemical technique is proved to be a useful tool to detect RFT/PTC activation in thyroid tumors. RET rearrangements are restricted to a well-differentiated papillary carcinoma, suggesting that RET/PTC positive papillary carcinomas do not progress to undifferentiated carcinoma.This work was presented at the 6th Research Workshop on Head and Neck Cancer, 11 October 2002, McLean, VA.     

The sentinel node procedure with Patent Blue V dye in the surgical treatment of papillary thyroid carcinoma.

How far to extend the surgical treatment of papillary thyroid carcinoma (PTC) is still an open question. A contribution may come from intra-operative lymphatic mapping because, in other malignancies, the procedure has become an important aid in defining lymph node status. To assess the feasibility of using the sentinel lymph node (SLN) technique with the intratumoral injection of Patent Blue V dye to guide nodal dissection in PTC, 29 patients with a preoperative diagnosis of PTC and no clinical or ultrasonographic evidence of nodal involvement underwent cervicotomy and exposure of the thyroid gland, followed by Patent Blue V dye injection into the thyroid nodule. Total thyroidectomy was subsequently performed, resecting the lymph nodes at levels III, IV, VI and VII. The thyroid, SLN and the other lymph nodes were snap-frozen and submitted for both intra-operative and subsequent definitive pathological evaluation. Intra-operative lymphatic mapping located the SLN in 22/29 patients (75.9%) and the SLN revealed neoplastic involvement in 4/22 (18.2%); other lymph nodes were also positive in 2 cases. In the 18 patients whose SLNs were not metastatic, the other nodes were also disease-free. The SLN technique thus seems helpful in avoiding unnecessary lymph node dissection in PTC without spread to the SLN.     

The Sentinel Node Procedure with Patent Blue V Dye in the Surgical Treatment of Papillary Thyroid Carcinoma

How far to extend the surgical treatment of papillary thyroid carcinoma (PTC) is still an open question. A contribution may come from intra-operative lymphatic mapping because, in other malignancies, the procedure has become an important aid in defining lymph node status. To assess the feasibility of using the sentinel lymph node (SLN) technique with the intratumoral injection of Patent Blue V dye to guide nodal dissection in PTC, 29 patients with a preoperative diagnosis of PTC and no clinical or ultrasonographic evidence of nodal involvement underwent cervicotomy and exposure of the thyroid gland, followed by Patent Blue V dye injection into the thyroid nodule. Total thyroidectomy was subsequently performed, resecting the lymph nodes at levels III, IV, VI and VII. The thyroid, SLN and the other lymph nodes were snap-frozen and submitted for both intra-operative and subsequent definitive pathological evaluation. Intra-operative lymphatic mapping located the SLN in 22/29 patients (75.9%) and the SLN revealed neoplastic involvement in 4/22 (18.2%); other lymph nodes were also positive in 2 cases. In the 18 patients whose SLNs were not metastatic, the other nodes were also disease-free. The SLN technique thus seems helpful in avoiding unnecessary lymph node dissection in PTC without spread to the SLN.     

蛋白酪氨酸磷酸酶基因启动子过甲基化与喉癌的关系

目的：探讨蛋白酪氨酸磷酸酶（PTEN）基因启动子过甲基化与喉癌的关系。方法：采用过甲基化特异性PCR和RT-PCR法分析喉癌（喉癌组）及正常喉组织（对照组）PTEN基因启动子过甲基化及其mRNA表达情况。结果：喉癌组有16例（40．0％）PTEN基因启动子过甲基化;对照组未发现过甲基化。对照组PTEN基因mRNA的高、中、低表达率及阴性率分别为77．8％（7／9）、22．2％（2／9）、0和0,淋巴结转移组分别为26．7％（4／15）、33．3％（5／15）、26．7％（4／15）和13．3％（2／15）,两组比较,PTEN mRNA表达差异有统计学意义（P〈0．05）。病理高分化PTEN基因mRNA高、中、低表达率及阴性率分别为60．0％（6／10）、30．0％（3／10）、10．0％（1／10）和0,病理低分化mRNA分别为16．7％（2／12）、25．0％（3／12）、41．7％（5／12）和16．7％（2／12）,两者比较,其mRNA表达差异有统计学意义（P〈O．05）。PTEN基因在喉癌组织中,mRNA呈现低表达的10例中有7例（70．0％）出现启动子过甲基化,mRNA呈现高表达的17例中仅有4例（23．5％）出现启动子过甲基化;PTEN基因mRNA高表达与低表达在启动子过甲基化率的差异有统计学意义（P〈O．05）。结论：PTEN基因启动子过甲基化是该基因在喉癌中失活的原因之一,PTEN基因表达下降与喉癌淋巴结转移及病理低分化有关。     

甲状腺乳头状癌Ⅱ区淋巴结隐匿性转移的临床分析

目的 分析甲状腺乳头状癌Ⅱ区淋巴结隐匿性转移的相关因素。方法 回顾分析天津医科大学附属肿瘤医院头颈外科2003年1月至2009年12月收治的213例术前Ⅱ区淋巴结临床阴性,颈侧其他区阳性的初治甲状腺乳头状癌患者的临床资料。淋巴清扫标本经病理证实颈侧区（Ⅱ～Ⅴ）有淋巴转移。单因素和多因素分析分别采用卡方检验和二分类Logistic回归分析。结果 颈部Ⅵ区淋巴结转移率79.3％( 169/213),Ⅲ、Ⅳ、Ⅴ区淋巴结转移率分别为83.6％( 178/213)、75.1％ (160/213)、13.1％ (28/213),Ⅱ区隐匿性淋巴结转移率为16.0％(34/213)。单因素分析显示：术前颈侧区Ⅲ、Ⅳ区淋巴结同时阳性或者术前Ⅲ区淋巴结阳性,与Ⅱ区淋巴结隐匿性转移密切相关（x2值分别为11.120和5.614,P值均＜0.05）;多因素分析显示术前颈侧区Ⅲ、Ⅳ区淋巴结同时阳性是隐匿性Ⅱ区淋巴转移的独立危险因素(P=0.033,OR =3.846)。结论 甲状腺乳头状癌患者术前未发现Ⅱ区和Ⅲ区淋巴结阳性时,可以考虑暂时不进行预防性Ⅱ区颈淋巴清扫术。     

Clinical study on papillary thyroid carcinoma presenting with lymph node metastasi

Papillary thyroid carcinoma (PTC) may metastasize to cervical lymph nodes. It is, however, uncommon for a palpable neck node alone to lead to the diagnosis of this disease when it is not apparent at presentation. Standard treatment for such cases has not yet been established. We retrospectively analyzed clinical courses in 8 patients with thyroid papillary carcinoma presenting with palpable lymph node metastasis at Hokkaido University Hospital between 1990 and 2003. Three had high thyrogloblin in cervical cystic lesions, leading to the diagnosis of PTC with lymph node metastasis. In 4, PTC was diagnosed by pathological examination of cervical lymph nodes initially diagnosed as lateral cervical cysts. Preoperative examination did not indicate PTC within the gland in any case. All 8 were alive at the last visit after follow-up from 23 to 150 months (mean: 78 months). Total thyroidectomy was done on 4 and thyroid lobectomy on 3. Pathological examination of resected thyroid glands confirmed multifocal papillary carcinoma from 4 mm to 15 mm in diameter. Six underwent unilateral neck dissection and 1 chose bilateral dissection. The other patient received no additional surgery on either the thyroid or neck after the single enlarged lymph node initially diagnosed as a lateral cervical cyst was resected. Postoperative radioiodine treatment was done in 2 undergoing total thyroidectomy. Recurrence in the cervical area were observed in 1 whose neck dissection was insufficient. Based on these observations, we concluded that patients who undergo thyroid lobectomy and adequate neck dissection may enjoy longer survival than those treated with total thyroidectomy without sacrificing thyroid and parathyroid function. We therefore propose a prospective study on the effectiveness of thyroid lobectomy with neck dissection including positive nodes in patients with occult PTC presenting with lymph node metastasis.     

甲状腺乳头状癌颈部淋巴结转移规律及影响因素分析

目的：探讨甲状腺乳头状癌颈部淋巴结转移规律及其相关影响因素,为甲状腺乳头状癌颈部淋巴结清扫术提供一定的临床依据。方法：回顾性分析314例甲状腺乳头状癌患者的临床资料。314例患者中,行甲状腺腺叶峡部切除、中央区淋巴结清扫术79例,甲状腺全切、中央区淋巴结清扫术173例,甲状腺全切、中央区淋巴结清扫术、侧颈部改良根治性颈部淋巴结清扫术62例。手术中清扫出淋巴结1～55个,其中阳性淋巴结0～14个。结果：314例患者中经病理证实共有168例（53．50％）患者有淋巴结转移,其中中央区淋巴结转移159例（50．64％）,中央区＋侧颈转移淋巴结55例（17．52％）,单纯侧颈淋巴结转移9例（2．87％）。患者年龄、肿瘤直径、甲状腺被膜受侵犯、临床分期是甲状腺乳头状癌颈部淋巴结转移的影响因素（P〈0．05）。结论：甲状腺乳头状癌患者最常发生中央区淋巴结转移,应常规进行中央区淋巴结清扫术。