HBME-1、CK19、Galectin-3、34βE12及Ki67在甲状腺微小乳头状癌中的表达及其临床意义
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摘要
按照WHO的标准，甲状腺微小乳头状癌定义为原发于甲状腺内直径在10mm以下的癌肿。部分甲状腺微小乳头状癌没有明确的乳头状结构，存在一定的漏诊率，这就给甲状腺微小乳头状癌的病理诊断带来了困难。随着免疫组织化学技术的发展和应用，有必要寻找一种敏感性高、特异性强、能够鉴别甲状腺良、恶性并判定其预后的特异性肿瘤标记物来辅助临床病理诊断。目前研究显示：HBME-1、CK19、Galectin-3在甲状腺微小乳头状癌中高表达，推测其可作为诊断甲状腺微小乳头状癌的标志物。高分子量细胞角蛋白(High molecular cytokeratin，34βE12）在甲状腺乳头状癌中呈强阳性表达，Ki67核抗原（Ki67Nuclear Antigen，Ki67）是某些恶性肿瘤预后的一个重要标志，但目前为止有关HBME-1、CK19、Galectin-3在甲状腺微小乳头状癌中与临床指标的相关性及34βE12和Ki67在甲状腺微小乳头状癌发生、发展过程的作用均未见报道。
本实验应用免疫组织化学检测30例结节性甲状腺肿不伴乳头状增生、26例结节性甲状腺肿伴乳头状增生及58例甲状腺微小乳头状癌中HBME-1、CK19、Galectin-3、34βE12及Ki67的表达，并分析其与临床指标的相关性及其在甲状腺微小乳头状癌鉴别诊断中的敏感性、特异性。
结果显示：HBME-1、CK19、Galectin-3、34βE12及Ki67在甲状腺微小乳头状癌中表达明显高于结节性甲状腺肿伴或不伴乳头状增生；34βE12在甲状腺微小乳头状癌淋巴结转移组中的表达明显高于无淋巴结转移组；联合检测HBME-1、CK19、Galectin-3、34βE12及Ki67在甲状腺微小乳头状癌鉴别诊断中的敏感性为94.8%、特异性为96.4%。
结论： HBME-1、CK19、Galectin-3、34βE12及Ki67联合检测可以用于鉴别诊断甲状腺微小乳头状癌与良性病变，对诊断甲状腺微小乳头状癌有重要的临床应用价值。其中CK19、 Galectin-3和Ki67敏感性高而特异性相对低，HBME-1和34βE12特异性高而敏感性相对低；五种抗体联合应用的特异性比五种以下任意几种联合应用，对诊断甲状腺微小乳头状癌更具有价值；34βE12高表达可作为甲状腺微小乳头状癌淋巴结转移潜能的指标；HBME-1、CK19、Galectin-3、34βE12及Ki67高表达可能促进了甲状腺微小乳头状癌的发生、发展及浸润。
Background: The histological features of thyroid micro-papillary carcinoma areconsistent with the diagnostic criteria of thyroid papillary carcinoma,while its tissue imagesare different with papillary thyroid carcinoma,and microcarcinoma does not form papillarystructures, which makes it difficult to diagnose. There is a certain rate of disdiagnose.Withthe use and development of immunohistochemical techniques,it is necessary to find a tumormarker with high sensitivity, specificity, which is able to identify benign or malignant thyroiddisease and determine the prognosis,and it will be a aid in the diagnosis of clinical pathology.HBME-1is mainly distributed in the mesothelial cells, which is an antigen recently using inthyroid tumor pathology.CK19is mainly distributed in the simple epithelium cells and is a lowmolecular weight keratin which was earlier found using in the differential diagnosis ofthyroid disease. In papillary thyroid carcinoma,CK19is a better marker and auxiliary diagnosis.Galectin-3is generally distributed in the normal cells and tumor tissues. At home and abroad alarge number of studies have shown that Galectin-3involved in many physiological andpathological process, including the role of cell growth, adhesion, inflammation, tumormetastasis, and apoptosis,and so on. It was found that Galectin-3overexpressed in manymalignant tumors such as liver cancer, stomach cancer, prostate cancer, breast cancer, coloncancer,so we concluded that the high expression of Galectin-3indicated that the tumor wasstrongly invasive and was closely related to tumor metastasis, recurrence.34βE12which is aspecific antibody of prostate basal cell was strongly positively expressed in papillary thyroidcarcinoma, generally not in the normal thyroid tissue. Antigen immune response of Ki-67which is a better marker to reflect the activity of tumor cell proliferation,widely using indetection of a variety of tumor cell proliferation activity, becoming an important indicator ofclinical prediction of tumor outcome is closely related to cell cycle, and its half-life is short,cells from the proliferation cycle was quickly degraded,and Its abnormal expression isclosely related to the occurrence and development of the tumor [51]. With the constantresearch and development of molecular genetics we found that the occurrence, development,invasion and metastasis of many kinds of thyroid cancers was associated with nucleinic acidand proteinum molecule. Selecting the appropriate immune markers which contributed to benign and malignant thyroid disease of differential diagnosis had become a hot topic. Atpresent,there is related report about combined with HBME-1、CK19、Galectin-3in smallpapillary carcinoma,which maybe promote the occurrence and development of small papillarycarcinoma.However,there is no report about dependablity of clinic index. At home and abroadthere is no report about combined with34βE12and Ki67in small papillary carcinoma.Athome and abroad there is no report about HBME-1, CK19, Galectin-3,34βE12, and Ki67andexpression of the five kinds of antibodies using in small papillary carcinoma. Compared withsingle marker, the researchers found that the combination of multiple markers to improve thevalue of the differential diagnosis of papillary thyroid carcinoma. We will combine HBME-1and CK19, Galectin-3,34βE12with Ki67to explore whether they can be specific molecularmarkers of small thyroid papillary, and contribute to the differential diagnosis of benign andmalignant tumors. By studying their expression differences in the small thyroid papillarycarcinoma to investigate the impact of changes in these genes on tumor occurrence,development and transfer.
Objective: To investigate the significance of HBME-1、 CK19、Galectin-3、34βE12and Ki67in the occurrence and development of thyroid micro-papillary carcinoma,as well ascombined application of these antibody diagnose thyroid micro-papillary carcinoma.
Methods: To detect the expression of HBME-1,CK19, Galectin-3,34βE12and Ki67in30patients with nodular goiter without papillary hyperplasia,26patients with nodular goiterwith papillary hyperplasia and58patients with thyroid micro-papillary carcinoma byimmunohistochemistry (IHC).
Results:(1)The expression of HBME-1and CK19, Galectin-3,34βE12and Ki67inthyroid micro-papillary carcinoma was significantly higher than nodular goiter with orwithout papillary hyperplasia.(2) The expression of34βE12in small thyroid papillarycarcinoma with lymph node metastasis was significantly higher than without lymph nodemetastasis.(3)The sensitivity of five antibodies of HBME-1, CK19, Galectin-3,34βE12andKi67was98.2%,and their specificity was96.4%.
Conclusion: Thigh expression of HBME-1and CK19, Galectin-3,34βE12and Ki67may promote the occurrence of small thyroid papillary carcinoma; Thigh expression of34βE12may promote lymph node metastasis in thyroid micro-papillary carcinoma;Combination of five kinds of antibodies contributed to the diagnosis of small thyroid papillary carcinoma and differential diagnosis of small thyroid papillary carcinoma andnodular goiter with or no papillary thyroid hyperplasia.
本实验应用免疫组织化学检测30例结节性甲状腺肿不伴乳头状增生、26例结节性甲状腺肿伴乳头状增生及58例甲状腺微小乳头状癌中HBME-1、CK19、Galectin-3、34βE12及Ki67的表达，并分析其与临床指标的相关性及其在甲状腺微小乳头状癌鉴别诊断中的敏感性、特异性。
结果显示：HBME-1、CK19、Galectin-3、34βE12及Ki67在甲状腺微小乳头状癌中表达明显高于结节性甲状腺肿伴或不伴乳头状增生；34βE12在甲状腺微小乳头状癌淋巴结转移组中的表达明显高于无淋巴结转移组；联合检测HBME-1、CK19、Galectin-3、34βE12及Ki67在甲状腺微小乳头状癌鉴别诊断中的敏感性为94.8%、特异性为96.4%。
结论： HBME-1、CK19、Galectin-3、34βE12及Ki67联合检测可以用于鉴别诊断甲状腺微小乳头状癌与良性病变，对诊断甲状腺微小乳头状癌有重要的临床应用价值。其中CK19、 Galectin-3和Ki67敏感性高而特异性相对低，HBME-1和34βE12特异性高而敏感性相对低；五种抗体联合应用的特异性比五种以下任意几种联合应用，对诊断甲状腺微小乳头状癌更具有价值；34βE12高表达可作为甲状腺微小乳头状癌淋巴结转移潜能的指标；HBME-1、CK19、Galectin-3、34βE12及Ki67高表达可能促进了甲状腺微小乳头状癌的发生、发展及浸润。
Background: The histological features of thyroid micro-papillary carcinoma areconsistent with the diagnostic criteria of thyroid papillary carcinoma,while its tissue imagesare different with papillary thyroid carcinoma,and microcarcinoma does not form papillarystructures, which makes it difficult to diagnose. There is a certain rate of disdiagnose.Withthe use and development of immunohistochemical techniques,it is necessary to find a tumormarker with high sensitivity, specificity, which is able to identify benign or malignant thyroiddisease and determine the prognosis,and it will be a aid in the diagnosis of clinical pathology.HBME-1is mainly distributed in the mesothelial cells, which is an antigen recently using inthyroid tumor pathology.CK19is mainly distributed in the simple epithelium cells and is a lowmolecular weight keratin which was earlier found using in the differential diagnosis ofthyroid disease. In papillary thyroid carcinoma,CK19is a better marker and auxiliary diagnosis.Galectin-3is generally distributed in the normal cells and tumor tissues. At home and abroad alarge number of studies have shown that Galectin-3involved in many physiological andpathological process, including the role of cell growth, adhesion, inflammation, tumormetastasis, and apoptosis,and so on. It was found that Galectin-3overexpressed in manymalignant tumors such as liver cancer, stomach cancer, prostate cancer, breast cancer, coloncancer,so we concluded that the high expression of Galectin-3indicated that the tumor wasstrongly invasive and was closely related to tumor metastasis, recurrence.34βE12which is aspecific antibody of prostate basal cell was strongly positively expressed in papillary thyroidcarcinoma, generally not in the normal thyroid tissue. Antigen immune response of Ki-67which is a better marker to reflect the activity of tumor cell proliferation,widely using indetection of a variety of tumor cell proliferation activity, becoming an important indicator ofclinical prediction of tumor outcome is closely related to cell cycle, and its half-life is short,cells from the proliferation cycle was quickly degraded,and Its abnormal expression isclosely related to the occurrence and development of the tumor [51]. With the constantresearch and development of molecular genetics we found that the occurrence, development,invasion and metastasis of many kinds of thyroid cancers was associated with nucleinic acidand proteinum molecule. Selecting the appropriate immune markers which contributed to benign and malignant thyroid disease of differential diagnosis had become a hot topic. Atpresent,there is related report about combined with HBME-1、CK19、Galectin-3in smallpapillary carcinoma,which maybe promote the occurrence and development of small papillarycarcinoma.However,there is no report about dependablity of clinic index. At home and abroadthere is no report about combined with34βE12and Ki67in small papillary carcinoma.Athome and abroad there is no report about HBME-1, CK19, Galectin-3,34βE12, and Ki67andexpression of the five kinds of antibodies using in small papillary carcinoma. Compared withsingle marker, the researchers found that the combination of multiple markers to improve thevalue of the differential diagnosis of papillary thyroid carcinoma. We will combine HBME-1and CK19, Galectin-3,34βE12with Ki67to explore whether they can be specific molecularmarkers of small thyroid papillary, and contribute to the differential diagnosis of benign andmalignant tumors. By studying their expression differences in the small thyroid papillarycarcinoma to investigate the impact of changes in these genes on tumor occurrence,development and transfer.
Objective: To investigate the significance of HBME-1、 CK19、Galectin-3、34βE12and Ki67in the occurrence and development of thyroid micro-papillary carcinoma,as well ascombined application of these antibody diagnose thyroid micro-papillary carcinoma.
Methods: To detect the expression of HBME-1,CK19, Galectin-3,34βE12and Ki67in30patients with nodular goiter without papillary hyperplasia,26patients with nodular goiterwith papillary hyperplasia and58patients with thyroid micro-papillary carcinoma byimmunohistochemistry (IHC).
Results:(1)The expression of HBME-1and CK19, Galectin-3,34βE12and Ki67inthyroid micro-papillary carcinoma was significantly higher than nodular goiter with orwithout papillary hyperplasia.(2) The expression of34βE12in small thyroid papillarycarcinoma with lymph node metastasis was significantly higher than without lymph nodemetastasis.(3)The sensitivity of five antibodies of HBME-1, CK19, Galectin-3,34βE12andKi67was98.2%,and their specificity was96.4%.
Conclusion: Thigh expression of HBME-1and CK19, Galectin-3,34βE12and Ki67may promote the occurrence of small thyroid papillary carcinoma; Thigh expression of34βE12may promote lymph node metastasis in thyroid micro-papillary carcinoma;Combination of five kinds of antibodies contributed to the diagnosis of small thyroid papillary carcinoma and differential diagnosis of small thyroid papillary carcinoma andnodular goiter with or no papillary thyroid hyperplasia.
引文
[1]方海飞,沈美萍,徐银峰.甲状腺乳头状癌TGF-β1、CD31表达与肿瘤转移的关系[J].南京医科大学学报,2007,27(5):472-475
[2] KohLK,Sedrine WB,TorralbaTP,et al Asimple tool to identifyAsian Women atincreased risk of osteoporosis Osteoporos Int,2001,12(8):699
[3] Kubota K. The four-arm cooperative study (FACS) for advance non-small-cell lungcancer (NSCLC)[J]. Proc Am Soc Oncol,2004;23:7006
[4] PIERSANTI M,EZZAT S,ASA SL.Controversies inpapillary microcarci-nomathyroid[J]. EndocrPathol,2003,14:183.
[5]韩晓晨、张凡等，HBME-1、CK19基因在甲状腺结节的表达状态及诊断价值[j]河北北方学院学报(医学版)，2006,8第23卷第4期
[6] Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroidtumors:a commentary on the second edition[J].Cancer,1989,63(3):908-911.
[7]滕晓东,王丽君,姚洪田,等.细胞角蛋白19、galectin-3、HBME-1在甲状腺病变上的表达及鉴别诊断意义[J].中华病理学杂志,2004,33(3):212-6
[8] Casey M B，Lohse C M，Lloyd R V．Distinction between papillary thyroid hyperplasiaand papillary thyroid carcinoma by immunohistochemical staining for cytokeratin19galectin-3，and HBME-1［J］．Endocr Pathol，2003，14(1):55－60．
[9] Barut F，kandemir N O，Bektas S，et al．Universal markers of thyroid malignancies:Galectin-3，HBME-1，and cytokeratin-19［J］．Endocr Pathol，2010，21(3):80－9．
[10]邓敏，叶顾萍，马建中，祝鋆,等.甲状腺乳头状癌中CK19、Galectin-3、HBME-1和TPO的表达及意义.[J].临床与实验病理志,2011,27(8):843-846
[11] Ordonez NG.Va1ue of thyroid transeriPtion faetor-1is a marker of lung and thyroidcareinomas.Adv Anat Pathol.2000;7:123-7.
[12] Afify AM，al-KhafajiBM.Diagnostic utility of thyroid transeription factor-1expressionin adenocareinomas Presenting in serous fluids.Acta Cytol2002;46(4):675-8.
[13] Mase T, Funahashi H, Koshikawa T, et al. HBME-1immunostaining in thyroid tumorsespecially in follicular neoplasm [J]. Endocrine Journal,2003,50(2):173-177.
[14] M iettinen M, Karkkainen P. Differen tial reactivity of HBME-1and CD15an tibodiesin benign and malignant thyroid tumours,preferential reactivity with malignant tumours
[J]. Virch ow sArch,1996,429(4-5):213-219
[15] Matos PS, FerreiraAP, deOliveira Facuri F, et a.l Usefulness of HBME-1, cytokeratin19and galectin-3immunostaining in the diag-nosis of thyroidmali〔J〕.Histopathology,2005,47(4):391-401.
[16] ItoY, YoshidaH, TomodaC,etal. HBME-1expression in follic-ular tumor of the thyroid:an investigation ofwhet her it can be used as amarker to diagnose follicularcarcinoma[J]. Anticancer Res,2005,25(1A):179-182.
[17]佟杰,罗杰,王跃,等.甲状腺乳头状增生活跃于微小乳头状癌的诊断与鉴别诊断〔J〕.诊断病理杂志,2011,6(18):173-1
[18] Cheung CC, Ezzat S, Freeman JL, et al. Immunohistoche-mical diagnosis of papillarythyroid carcinoma [J]. Mod Pathol,2001,14(4):338-342
[19] Prasad ML, Huang Y, Pellegata NS, et al. Hashimoto’s thyroiditis with papillarythyroid carcinoma (PTC)-like nuclear alterations express molecular markers ofPTC[J]. Histopathology,2004,45:39-46
[20] Mauro P, Jaime R, Pompa R D, et al. Galectin-3and HBME-1expression inwell-differentiated thyroid tumors with follicular architecture of uncertain malignantpotential[J]. Modern Pathology,2005,18:541-546.
[21]陈云新,沈丹华,孙昆昆,高松源,王颖,宋秋静,梁添等。甲状腺微小乳头状癌中Galectin-3、CK19、HBME-1和CD56的表达及意义，临床与实验病理学杂志[J]2010.26（4），425-428
[22] Bondenmuller H,Banauch D.Technical evaluation of a new automated tumor markerassay；the Enzymun-test CYFRA21-1.In：Klapdor R．Tu-mor associated antigensoncogenes receptors，cytokines in tumor diag-nosis and therapy at the beginning of the90th[J].Zuckschwerdt Verlag,1992:137-138.
[23] de Matos P S，Ferreira A P，de Oliverira Facuri F， et al． Usefulnessof HBME-1，cytokeratin19and galectin-3immunostaining in the diagnosis of thyroid malignancy［J］．Histopathology，2005，47(4):391－401．
[24] Nasser, SM, Pitman,MB, Pilch, BZ, et a.l Fine-needle aspiration biopsy ofpapillarythyroid carcinoma: diagnostic utility of cytokeratin19immunostaining[J].Cancer,2000,90(5):307-311.
[25] GuyetantS，MichalakS，Valol,et al.Diagnosis of the follicular variant of PapillaryThyroid carcinoma.Signifieance of immounohistochemistry [J].Ann Pathol，2003，23(1):11-20
[26]周炜洵,肖雨,刘彤华,等.细胞角蛋白和Ret蛋白在甲状腺乳头状癌中的表达[J].中华病理学杂志,2003,32(6):530-533.
[27]陈晓东,周本成,赖日权,等.细胞角蛋白表达在甲状腺乳头状癌诊断中的应用[J].诊断病理学杂志,2003,10(1):25-26.
[28] Erkilic S,Aydin A,KocerN E,etal.Diagnostic utility of cytokera-tin19expression inmultinodular goiter with papillary areas and papillary carcinoma of thyroid[J].Endocr Patho,l2002,13(3):207-11.
[29] Baloch ZW，Abraham S，RobertsS，et al.Differential,expres-Sion of cytokeratins infollicular variant of PaPillary carcinoma:an immunohistochemical study andn itsdiag-Nostic utility[j].Hum Pathol，1999，30(10):1166.
[30] Gal-Gombos EC, Esserman LE, Recine MA,et al. Large–needle core biopsy inatypical intraductal epithelial hyperplasia including immunohistochemical expression ofhigh molecular weight cytoker-atin analysis of results of a single institution[J].Breast，2002,8:269-274.
[31] Rossi ED, Raffaelli M, Mule`A, et al. Simultaneous immunohistochemical expressionof HBME-1and galectin-3differentiates papillary carcinomas from hyperfunctioninglesions of the thyroid[J]. Histopathology,2006,48(7):795-800
[32] Beesley MF, Mclaren KM. Cytokeratin19and galectin-3immunohistochemistry in thedifferential diagnosis of solitary thyroid nodules[J]. Histopathology,2002,41(3):236-243
[33] KawachiK, Matsushita Y, Yonezawa S,et al. Galectin-3expression in various thyroidneoplasms and its possible role inmetastasis formation[J]. Hum Patho,l2000,31:428-433.
[34] Orlandi F,Saggiorato E,Pivano G,et al.Galcetin-3is a presurgical maker ofhumanthyroid carcinoma[J].Cancer Res.1998,58(14):3015-3020.
[35] Xu XC,El-Nagger AK,lotan R.differential expression of galectin-1and galectin-3inthyroid tumors:potential diagnostic implications[J].Am J Puthol,1995,147(3):815-822.
[36] Kovacs RB,Foldes J,Winkler G,et al.The investigation of galectin-3in diseases of thethyroid gland J Eur[J].Endocrinol.2003,149(5):499-453
[37] Bartolazzi A,Gasbarri A,Papotti M,et al.Application of an Imuuodiag-nostic method forimproving preoperative diagnosis of nodular thyriod le-sion[J].Lancer,2001,357(9269):1664-l650.
[38] Coli A,Bigotti G,Zucchetti F,et al.Galectin-3,a marker of well differentiated thyroidcarcinoma is expressed in thyroid nodules with cytological atypia.Histopathology,2002,40(1):80-8
[39] Dowsett M,Smith IE,Ebbs SR,et al,proliferation and apoptosis as markers of benefit inneoodjuvant endocrine thrapy of breast Cancer.Clin Canccer Kes.2006,12:1024-1030
[40] Takayama S, Reed Jc, Homma S. Heat shock protein as regulators ofapoptosis[J].Oncogene,2003,22:9041-9047.
[41] Gal-Gombos EC, Esserman LE, Recine MA,et al. Large-needlecore biopsy in atypicalintraductal epithelial hyperplasia includingimmunohistochemical expression of highmolecular weight cytoker-atin analysis of results of a single institution[J].Breast，2002,8:269-274.
[42] Liberman E,Weidner N. Papillary and follicular neoplasms of thethyroid gland:Differential immunohistochemical staining with high-molecular-weightkeratin andinvolucrin[J].Appl ImmunoshitochemMolMorpho,l2000,8(1):42-48.
[43]莫祥兰,周祥祯,丁志敏等.高分子量角蛋白在甲状腺乳头状癌诊断中的作用[J].四川大学学报(医学版)2003,34(4):748-749.
[44]王新杰,李建团,李建华,王洪等，高分子量细胞角蛋白与上皮钙粘蛋白在甲状腺乳头状癌组织中的表达及意义，中国临床医学2008年12月第15卷第6期886-888
[45]张景丽，张红英，魏兵，等.细胞角蛋白在乳腺导管内增生性病变鉴别诊断中的应用[J].中华病理学杂志，2004,33(4)：316-319.
[46]詹启敏.分子肿瘤学[M].第1版.北京:人民卫生出版社,2005:25-39
[47] Sherr CJ, Roberts JM.Inhibitors of mammalian G1cyclin-dependent Kinase[J].GenesDevelop,1995,9(3):1149-1163
[48] Saski K， Murakami Y，Kawasaki M，et a1．The Cell Cycle Associated Change of theKi一67Reactive Nucleay Antigen Expression[J]．J Cell Physiol，1987，133：579-584．
[49]黄凯，李晓飞，吴荣佩，等．Ki67和cyclinDl在肾癌组织中的表达及其临床意义[J]．临床泌尿外科杂志，2008，23(3)：219．221．
[50] Duchrow M，Schluter C，Wohlenberg C，et a1．Molecular Characterization of the GeneLocus of the Human Cell Proliferation Associated Nuclear Protein Defined byMonoclonal Antibody KJ67[J]．Cell Prolif,1996，29(1)：112．
[51]成继民,贺占国,刘艳丽,等. Ki-67与P-GP170在甲状腺乳头状癌中的表达及临床意义[J].华北国防医药,2004,16(2):83-84
[52]聂明豪，杜明，李秀荣．细胞角蛋白19及Ki67在甲状腺乳头状癌中的表达．黑龙江医学，2005，29(3)：168．169．
[53]伍石华, NF κB和Ki-67在甲状腺肿瘤中的表达及其意义[J].临床肿瘤学杂志,2007,12(11):825-829
[54]王翠芳，孙洁，滕猛，宦大为等RET、HBME-1和Ki67在甲状腺良、恶性肿瘤中的表达[J]实用肿瘤学杂志2007年第21卷第5期总第91期:427-429
[55] Kerkhof M，Steyerberg EW，Kusters JG，et a1．Aneuploidy and High Expression ofp53and Ki67is Associated with Neoplastic Progression in Barrett Esophagus[J]．Cancer Biomark，2008，4(1)：1．10．
[56] Chen L，Li X，Wang GL，Wang Y，et a1．Clinicopathological Significance ofOverexpression ofTSPANl，Ki67and CD34in Gastric Carcinoma[J]．Tumofi，2008，94(4)：531．S3R．
[57] Rammeh-Rommani S， Zermani R， Sfaxi M， et a1． Prognostic Value ofthelmmunohistochemical Expression of Ki67，p53，PCNA and Bcl2in the SuperficialTumors of the Bladder[J]．Tunis Med，2007，85(6)：509-512．
[2] KohLK,Sedrine WB,TorralbaTP,et al Asimple tool to identifyAsian Women atincreased risk of osteoporosis Osteoporos Int,2001,12(8):699
[3] Kubota K. The four-arm cooperative study (FACS) for advance non-small-cell lungcancer (NSCLC)[J]. Proc Am Soc Oncol,2004;23:7006
[4] PIERSANTI M,EZZAT S,ASA SL.Controversies inpapillary microcarci-nomathyroid[J]. EndocrPathol,2003,14:183.
[5]韩晓晨、张凡等，HBME-1、CK19基因在甲状腺结节的表达状态及诊断价值[j]河北北方学院学报(医学版)，2006,8第23卷第4期
[6] Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroidtumors:a commentary on the second edition[J].Cancer,1989,63(3):908-911.
[7]滕晓东,王丽君,姚洪田,等.细胞角蛋白19、galectin-3、HBME-1在甲状腺病变上的表达及鉴别诊断意义[J].中华病理学杂志,2004,33(3):212-6
[8] Casey M B，Lohse C M，Lloyd R V．Distinction between papillary thyroid hyperplasiaand papillary thyroid carcinoma by immunohistochemical staining for cytokeratin19galectin-3，and HBME-1［J］．Endocr Pathol，2003，14(1):55－60．
[9] Barut F，kandemir N O，Bektas S，et al．Universal markers of thyroid malignancies:Galectin-3，HBME-1，and cytokeratin-19［J］．Endocr Pathol，2010，21(3):80－9．
[10]邓敏，叶顾萍，马建中，祝鋆,等.甲状腺乳头状癌中CK19、Galectin-3、HBME-1和TPO的表达及意义.[J].临床与实验病理志,2011,27(8):843-846
[11] Ordonez NG.Va1ue of thyroid transeriPtion faetor-1is a marker of lung and thyroidcareinomas.Adv Anat Pathol.2000;7:123-7.
[12] Afify AM，al-KhafajiBM.Diagnostic utility of thyroid transeription factor-1expressionin adenocareinomas Presenting in serous fluids.Acta Cytol2002;46(4):675-8.
[13] Mase T, Funahashi H, Koshikawa T, et al. HBME-1immunostaining in thyroid tumorsespecially in follicular neoplasm [J]. Endocrine Journal,2003,50(2):173-177.
[14] M iettinen M, Karkkainen P. Differen tial reactivity of HBME-1and CD15an tibodiesin benign and malignant thyroid tumours,preferential reactivity with malignant tumours
[J]. Virch ow sArch,1996,429(4-5):213-219
[15] Matos PS, FerreiraAP, deOliveira Facuri F, et a.l Usefulness of HBME-1, cytokeratin19and galectin-3immunostaining in the diag-nosis of thyroidmali〔J〕.Histopathology,2005,47(4):391-401.
[16] ItoY, YoshidaH, TomodaC,etal. HBME-1expression in follic-ular tumor of the thyroid:an investigation ofwhet her it can be used as amarker to diagnose follicularcarcinoma[J]. Anticancer Res,2005,25(1A):179-182.
[17]佟杰,罗杰,王跃,等.甲状腺乳头状增生活跃于微小乳头状癌的诊断与鉴别诊断〔J〕.诊断病理杂志,2011,6(18):173-1
[18] Cheung CC, Ezzat S, Freeman JL, et al. Immunohistoche-mical diagnosis of papillarythyroid carcinoma [J]. Mod Pathol,2001,14(4):338-342
[19] Prasad ML, Huang Y, Pellegata NS, et al. Hashimoto’s thyroiditis with papillarythyroid carcinoma (PTC)-like nuclear alterations express molecular markers ofPTC[J]. Histopathology,2004,45:39-46
[20] Mauro P, Jaime R, Pompa R D, et al. Galectin-3and HBME-1expression inwell-differentiated thyroid tumors with follicular architecture of uncertain malignantpotential[J]. Modern Pathology,2005,18:541-546.
[21]陈云新,沈丹华,孙昆昆,高松源,王颖,宋秋静,梁添等。甲状腺微小乳头状癌中Galectin-3、CK19、HBME-1和CD56的表达及意义，临床与实验病理学杂志[J]2010.26（4），425-428
[22] Bondenmuller H,Banauch D.Technical evaluation of a new automated tumor markerassay；the Enzymun-test CYFRA21-1.In：Klapdor R．Tu-mor associated antigensoncogenes receptors，cytokines in tumor diag-nosis and therapy at the beginning of the90th[J].Zuckschwerdt Verlag,1992:137-138.
[23] de Matos P S，Ferreira A P，de Oliverira Facuri F， et al． Usefulnessof HBME-1，cytokeratin19and galectin-3immunostaining in the diagnosis of thyroid malignancy［J］．Histopathology，2005，47(4):391－401．
[24] Nasser, SM, Pitman,MB, Pilch, BZ, et a.l Fine-needle aspiration biopsy ofpapillarythyroid carcinoma: diagnostic utility of cytokeratin19immunostaining[J].Cancer,2000,90(5):307-311.
[25] GuyetantS，MichalakS，Valol,et al.Diagnosis of the follicular variant of PapillaryThyroid carcinoma.Signifieance of immounohistochemistry [J].Ann Pathol，2003，23(1):11-20
[26]周炜洵,肖雨,刘彤华,等.细胞角蛋白和Ret蛋白在甲状腺乳头状癌中的表达[J].中华病理学杂志,2003,32(6):530-533.
[27]陈晓东,周本成,赖日权,等.细胞角蛋白表达在甲状腺乳头状癌诊断中的应用[J].诊断病理学杂志,2003,10(1):25-26.
[28] Erkilic S,Aydin A,KocerN E,etal.Diagnostic utility of cytokera-tin19expression inmultinodular goiter with papillary areas and papillary carcinoma of thyroid[J].Endocr Patho,l2002,13(3):207-11.
[29] Baloch ZW，Abraham S，RobertsS，et al.Differential,expres-Sion of cytokeratins infollicular variant of PaPillary carcinoma:an immunohistochemical study andn itsdiag-Nostic utility[j].Hum Pathol，1999，30(10):1166.
[30] Gal-Gombos EC, Esserman LE, Recine MA,et al. Large–needle core biopsy inatypical intraductal epithelial hyperplasia including immunohistochemical expression ofhigh molecular weight cytoker-atin analysis of results of a single institution[J].Breast，2002,8:269-274.
[31] Rossi ED, Raffaelli M, Mule`A, et al. Simultaneous immunohistochemical expressionof HBME-1and galectin-3differentiates papillary carcinomas from hyperfunctioninglesions of the thyroid[J]. Histopathology,2006,48(7):795-800
[32] Beesley MF, Mclaren KM. Cytokeratin19and galectin-3immunohistochemistry in thedifferential diagnosis of solitary thyroid nodules[J]. Histopathology,2002,41(3):236-243
[33] KawachiK, Matsushita Y, Yonezawa S,et al. Galectin-3expression in various thyroidneoplasms and its possible role inmetastasis formation[J]. Hum Patho,l2000,31:428-433.
[34] Orlandi F,Saggiorato E,Pivano G,et al.Galcetin-3is a presurgical maker ofhumanthyroid carcinoma[J].Cancer Res.1998,58(14):3015-3020.
[35] Xu XC,El-Nagger AK,lotan R.differential expression of galectin-1and galectin-3inthyroid tumors:potential diagnostic implications[J].Am J Puthol,1995,147(3):815-822.
[36] Kovacs RB,Foldes J,Winkler G,et al.The investigation of galectin-3in diseases of thethyroid gland J Eur[J].Endocrinol.2003,149(5):499-453
[37] Bartolazzi A,Gasbarri A,Papotti M,et al.Application of an Imuuodiag-nostic method forimproving preoperative diagnosis of nodular thyriod le-sion[J].Lancer,2001,357(9269):1664-l650.
[38] Coli A,Bigotti G,Zucchetti F,et al.Galectin-3,a marker of well differentiated thyroidcarcinoma is expressed in thyroid nodules with cytological atypia.Histopathology,2002,40(1):80-8
[39] Dowsett M,Smith IE,Ebbs SR,et al,proliferation and apoptosis as markers of benefit inneoodjuvant endocrine thrapy of breast Cancer.Clin Canccer Kes.2006,12:1024-1030
[40] Takayama S, Reed Jc, Homma S. Heat shock protein as regulators ofapoptosis[J].Oncogene,2003,22:9041-9047.
[41] Gal-Gombos EC, Esserman LE, Recine MA,et al. Large-needlecore biopsy in atypicalintraductal epithelial hyperplasia includingimmunohistochemical expression of highmolecular weight cytoker-atin analysis of results of a single institution[J].Breast，2002,8:269-274.
[42] Liberman E,Weidner N. Papillary and follicular neoplasms of thethyroid gland:Differential immunohistochemical staining with high-molecular-weightkeratin andinvolucrin[J].Appl ImmunoshitochemMolMorpho,l2000,8(1):42-48.
[43]莫祥兰,周祥祯,丁志敏等.高分子量角蛋白在甲状腺乳头状癌诊断中的作用[J].四川大学学报(医学版)2003,34(4):748-749.
[44]王新杰,李建团,李建华,王洪等，高分子量细胞角蛋白与上皮钙粘蛋白在甲状腺乳头状癌组织中的表达及意义，中国临床医学2008年12月第15卷第6期886-888
[45]张景丽，张红英，魏兵，等.细胞角蛋白在乳腺导管内增生性病变鉴别诊断中的应用[J].中华病理学杂志，2004,33(4)：316-319.
[46]詹启敏.分子肿瘤学[M].第1版.北京:人民卫生出版社,2005:25-39
[47] Sherr CJ, Roberts JM.Inhibitors of mammalian G1cyclin-dependent Kinase[J].GenesDevelop,1995,9(3):1149-1163
[48] Saski K， Murakami Y，Kawasaki M，et a1．The Cell Cycle Associated Change of theKi一67Reactive Nucleay Antigen Expression[J]．J Cell Physiol，1987，133：579-584．
[49]黄凯，李晓飞，吴荣佩，等．Ki67和cyclinDl在肾癌组织中的表达及其临床意义[J]．临床泌尿外科杂志，2008，23(3)：219．221．
[50] Duchrow M，Schluter C，Wohlenberg C，et a1．Molecular Characterization of the GeneLocus of the Human Cell Proliferation Associated Nuclear Protein Defined byMonoclonal Antibody KJ67[J]．Cell Prolif,1996，29(1)：112．
[51]成继民,贺占国,刘艳丽,等. Ki-67与P-GP170在甲状腺乳头状癌中的表达及临床意义[J].华北国防医药,2004,16(2):83-84
[52]聂明豪，杜明，李秀荣．细胞角蛋白19及Ki67在甲状腺乳头状癌中的表达．黑龙江医学，2005，29(3)：168．169．
[53]伍石华, NF κB和Ki-67在甲状腺肿瘤中的表达及其意义[J].临床肿瘤学杂志,2007,12(11):825-829
[54]王翠芳，孙洁，滕猛，宦大为等RET、HBME-1和Ki67在甲状腺良、恶性肿瘤中的表达[J]实用肿瘤学杂志2007年第21卷第5期总第91期:427-429
[55] Kerkhof M，Steyerberg EW，Kusters JG，et a1．Aneuploidy and High Expression ofp53and Ki67is Associated with Neoplastic Progression in Barrett Esophagus[J]．Cancer Biomark，2008，4(1)：1．10．
[56] Chen L，Li X，Wang GL，Wang Y，et a1．Clinicopathological Significance ofOverexpression ofTSPANl，Ki67and CD34in Gastric Carcinoma[J]．Tumofi，2008，94(4)：531．S3R．
[57] Rammeh-Rommani S， Zermani R， Sfaxi M， et a1． Prognostic Value ofthelmmunohistochemical Expression of Ki67，p53，PCNA and Bcl2in the SuperficialTumors of the Bladder[J]．Tunis Med，2007，85(6)：509-512．