PTEN与Ki-67在原发性输卵管恶性肿瘤中的表达与临床意义
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摘要
目的检测张力蛋白同源、在10号染色体缺失的磷酸酶基因(phosphatase and tensin homology deleted on chromosome ten，PTEN)及细胞核相关抗原(nuclear-associated antigen，Ki-67)在原发性输卵管恶性肿瘤中的表达，探讨其表达与原发性输卵管恶性肿瘤临床病理参数、预后风险的关系，及两者的相关性，以了解PTEN和Ki-67的表达在原发性输卵管恶性肿瘤的发生、发展及其预后中的意义。
方法收集我院和省肿瘤医院31例原发性输卵管恶性肿瘤患者的妇科手术石蜡标本，采用免疫组织化学的方法检测31例原发性输卵管恶性肿瘤组织、15例慢性输卵管炎和15例正常输卵管组织中PTEN和Ki-67的表达，用Fisher确切概率法分析PTEN和Ki-67的表达在各组织中的表达是否有差别，及PTEN与Ki-67的表达与原发性输卵管恶性肿瘤临床参数之间的关系；用Spearman秩相关分析两者的相关性；生存率统计采用寿命表法，并绘制Kaplan-Meier曲线。以原发性输卵管恶性肿瘤患者的预后为因变量，年龄、病理分级、临床分期、残余癌灶、Ki-67的表达和PTEN的表达为自变量，建立Cox比例风险模型，探讨影响原发性输卵管恶性肿瘤预后的相关危险因素。
结果(1) PTEN在原发性输卵管恶性肿瘤组织、慢性输卵管炎组织和正常输卵管组织中的表达率分别为51.61％、86.67％、93.33％；Ki-67在上述三组中的表达率依次为83.87％、6.67％、0.00％；经Fisher确切概率法检验，三组间PTEN和Ki-67的表达差异有统计学意义(P＜0.01)，原发性输卵管恶性肿瘤组中两者的表达和炎症组与正常组间有显著差异(P＜0.05)，而正常组与炎症组中两者的表达差异无显著性(P＞0.05)。
(2) PTEN的表达在低分化组明显低于高分化组；PTEN的表达在临床Ⅲ-Ⅳ期组明显低于临床Ⅰ-Ⅱ期组；Ki-67的表达在低分化组明显高于高分化组；Ki-67的表达在临床Ⅲ-Ⅳ期组明显高于临床Ⅰ-Ⅱ期组。
(3)对31例原发性输卵管恶性肿瘤中PTEN和Ki-67的表达率进行相关性分析，采用Spearman秩相关分析，结果显示：两者r=-0.453，P=0.001(P＜0.05)，具有显著性差异，表明PTEN的表达与Ki-67的表达呈负相关。
(4)用寿命表法得到PTEN阳性组的两年生存率为75.0％，五年生存率为37.50％；PTEN阴性组的两年生存率为53.33％，五年生存率为13.33％。两组生存率比较，用Kaplan-Meier法分别计算PTEN阳性和阴性组的生存率：FFEN阳性组16人，平均生存时间为66.3月，中位生存时间为75.0月；PTEN阴性组15人，平均生存时间为40.9月，中位生存时间为38.0月。两组的生存曲线的差异性用Log-rank法进行检验，x~2=4.568，P=0.032(P＜0.05)，具有显著性差异，表明两组的生存率存在显著差异；Cox比例风险模型研究显示，PTEN的表达、Ki-67的表达、残余癌灶与原发性输卵管恶性肿瘤患者的预后之间存在有显著相关性。
结论(1)PTEN与原发性输卵管恶性肿瘤组的发生与发展有关；PTEN和Ki-67的表达与原发性输卵管恶性肿瘤的病理分级、临床分期和生存时间有关；
(2)PTEN表达的缺失和减少，可能与原发性输卵管恶性肿瘤的不良预后有关。
Objective This study detected the expression of PTEN and Ki-67 inprimary malignant tumor of the fallopian tube and investigate theinfluence of their expression on the clinicopathological and prognosis inprimary malignant tumor of the fallopian tube, and their dependablity.Thepurpose is to explore their role in the tumorigenesis and developmet ofprimary malignant tumor of the fallopian tube and to identify itssignificance in evaluating the prognosis of primary malignant tumor ofthe fallopian tube.
Methods Paraffin-embedded tissue specimens from 31 cases ofprimary malignant tumor of the fallopian tube,15 cases of chronicinflammation of the fallopian tube, 15 cases of the normal fallopian tubewere examinated by antibody of PTEN and Ki-67 withimmunhistochemical technique.Their differences of PTEN and Ki-67among the three groups were assessed by Fisher exact probabilitytest.The correlation among PTEN and Ki-67 and clinicopathologicalparameters were assessed by Fisher exact probability test.Theirdependablity is analyzed by Spearman rank correlation test;Theprobability of primary malignant tumor of the fallopian tube survival asfunction of time was determined by life-table and Kaplan-Meier.High riskfactors of primary malignant tumor of the fallopian tube patients'survival time were analysed by Cox's proportional hazard regression model.
Result (1) PTEN expression in primary malignant tumor of thefallopian tube, chronic inflammation of the fallopian tube and the normalfallopian tube was 51.61%, 86.67%, 93.33%, Ki-67 expression was83.87、6.67、0.00%. Expression of PTEN and Ki-67 was significantlydifferent between primary malignant tumor of the fallopian tube andchronic inflammation of the fallopian tube,as well as between the normalfallopian tube and primary malignant tumor of the fallopiantube(p＜0.01),but not between the normal fallopian tube and the chronicinflammation of the fallopian tube(p＞0.05).
(2) PTEN expression of poor differentiation of pathology is less than thatof well differentiation of pathology, PTEN expression of the group ofclinicⅢ-Ⅳstage is lower than that of clinicⅠ-Ⅱstage. Ki-67expression of poor differentiation of pathology is more than that of welldifferentiation of pathology, Ki-67 expression of the group of clinicⅢ-Ⅳstage is morn than that of clinicⅠ-Ⅱstage.
(3) The result of dependability analysis(Spearman rank correlation) ofPTEN and Ki-67 from 31 case in primary malignant tumor of thefallopian tube discovers that coefficient correlation is -0.435(P＜0.05), andindicates that the expression of PTEN and Ki-67 is negative correlation.
(4) Life-table survival analysis showed survival rates for two years were75.0%, survival rates for five years were 37.50% in patients with PTEN(+), but survival rates for two years were 53.33%,survival rates forfive years were 13.33% in patients with PTEN(-),u=65.0,P=0.03.Kaplan-Meier survical analysis showed patients with PTEN(+) hadlonger median survical time(75 months, n=16), compared with patientswith PTEN(-) (38 months, n=15)(log-rank test, x~2=4.568, P=0.032),Cox's proportional hazard regression model suggested PTEN expression,Ki-67 expression and residue cancer were hazard factors of patients'survival time.
Conclusion (1)The loss of PTEN expression is related with theoccurrence and development of the primary malignant tumor of thefallopian tube; PTEN and Ki-67 expression is related with pathologicalgrading, clinical stage、live time of the primary malignant tumor of thefallopian tube;
(2) The loss of PTEN expression may be related with the prognosis of theprimary malignant tumor of the fallopian tube.
方法收集我院和省肿瘤医院31例原发性输卵管恶性肿瘤患者的妇科手术石蜡标本，采用免疫组织化学的方法检测31例原发性输卵管恶性肿瘤组织、15例慢性输卵管炎和15例正常输卵管组织中PTEN和Ki-67的表达，用Fisher确切概率法分析PTEN和Ki-67的表达在各组织中的表达是否有差别，及PTEN与Ki-67的表达与原发性输卵管恶性肿瘤临床参数之间的关系；用Spearman秩相关分析两者的相关性；生存率统计采用寿命表法，并绘制Kaplan-Meier曲线。以原发性输卵管恶性肿瘤患者的预后为因变量，年龄、病理分级、临床分期、残余癌灶、Ki-67的表达和PTEN的表达为自变量，建立Cox比例风险模型，探讨影响原发性输卵管恶性肿瘤预后的相关危险因素。
结果(1) PTEN在原发性输卵管恶性肿瘤组织、慢性输卵管炎组织和正常输卵管组织中的表达率分别为51.61％、86.67％、93.33％；Ki-67在上述三组中的表达率依次为83.87％、6.67％、0.00％；经Fisher确切概率法检验，三组间PTEN和Ki-67的表达差异有统计学意义(P＜0.01)，原发性输卵管恶性肿瘤组中两者的表达和炎症组与正常组间有显著差异(P＜0.05)，而正常组与炎症组中两者的表达差异无显著性(P＞0.05)。
(2) PTEN的表达在低分化组明显低于高分化组；PTEN的表达在临床Ⅲ-Ⅳ期组明显低于临床Ⅰ-Ⅱ期组；Ki-67的表达在低分化组明显高于高分化组；Ki-67的表达在临床Ⅲ-Ⅳ期组明显高于临床Ⅰ-Ⅱ期组。
(3)对31例原发性输卵管恶性肿瘤中PTEN和Ki-67的表达率进行相关性分析，采用Spearman秩相关分析，结果显示：两者r=-0.453，P=0.001(P＜0.05)，具有显著性差异，表明PTEN的表达与Ki-67的表达呈负相关。
(4)用寿命表法得到PTEN阳性组的两年生存率为75.0％，五年生存率为37.50％；PTEN阴性组的两年生存率为53.33％，五年生存率为13.33％。两组生存率比较，用Kaplan-Meier法分别计算PTEN阳性和阴性组的生存率：FFEN阳性组16人，平均生存时间为66.3月，中位生存时间为75.0月；PTEN阴性组15人，平均生存时间为40.9月，中位生存时间为38.0月。两组的生存曲线的差异性用Log-rank法进行检验，x~2=4.568，P=0.032(P＜0.05)，具有显著性差异，表明两组的生存率存在显著差异；Cox比例风险模型研究显示，PTEN的表达、Ki-67的表达、残余癌灶与原发性输卵管恶性肿瘤患者的预后之间存在有显著相关性。
结论(1)PTEN与原发性输卵管恶性肿瘤组的发生与发展有关；PTEN和Ki-67的表达与原发性输卵管恶性肿瘤的病理分级、临床分期和生存时间有关；
(2)PTEN表达的缺失和减少，可能与原发性输卵管恶性肿瘤的不良预后有关。
Objective This study detected the expression of PTEN and Ki-67 inprimary malignant tumor of the fallopian tube and investigate theinfluence of their expression on the clinicopathological and prognosis inprimary malignant tumor of the fallopian tube, and their dependablity.Thepurpose is to explore their role in the tumorigenesis and developmet ofprimary malignant tumor of the fallopian tube and to identify itssignificance in evaluating the prognosis of primary malignant tumor ofthe fallopian tube.
Methods Paraffin-embedded tissue specimens from 31 cases ofprimary malignant tumor of the fallopian tube,15 cases of chronicinflammation of the fallopian tube, 15 cases of the normal fallopian tubewere examinated by antibody of PTEN and Ki-67 withimmunhistochemical technique.Their differences of PTEN and Ki-67among the three groups were assessed by Fisher exact probabilitytest.The correlation among PTEN and Ki-67 and clinicopathologicalparameters were assessed by Fisher exact probability test.Theirdependablity is analyzed by Spearman rank correlation test;Theprobability of primary malignant tumor of the fallopian tube survival asfunction of time was determined by life-table and Kaplan-Meier.High riskfactors of primary malignant tumor of the fallopian tube patients'survival time were analysed by Cox's proportional hazard regression model.
Result (1) PTEN expression in primary malignant tumor of thefallopian tube, chronic inflammation of the fallopian tube and the normalfallopian tube was 51.61%, 86.67%, 93.33%, Ki-67 expression was83.87、6.67、0.00%. Expression of PTEN and Ki-67 was significantlydifferent between primary malignant tumor of the fallopian tube andchronic inflammation of the fallopian tube,as well as between the normalfallopian tube and primary malignant tumor of the fallopiantube(p＜0.01),but not between the normal fallopian tube and the chronicinflammation of the fallopian tube(p＞0.05).
(2) PTEN expression of poor differentiation of pathology is less than thatof well differentiation of pathology, PTEN expression of the group ofclinicⅢ-Ⅳstage is lower than that of clinicⅠ-Ⅱstage. Ki-67expression of poor differentiation of pathology is more than that of welldifferentiation of pathology, Ki-67 expression of the group of clinicⅢ-Ⅳstage is morn than that of clinicⅠ-Ⅱstage.
(3) The result of dependability analysis(Spearman rank correlation) ofPTEN and Ki-67 from 31 case in primary malignant tumor of thefallopian tube discovers that coefficient correlation is -0.435(P＜0.05), andindicates that the expression of PTEN and Ki-67 is negative correlation.
(4) Life-table survival analysis showed survival rates for two years were75.0%, survival rates for five years were 37.50% in patients with PTEN(+), but survival rates for two years were 53.33%,survival rates forfive years were 13.33% in patients with PTEN(-),u=65.0,P=0.03.Kaplan-Meier survical analysis showed patients with PTEN(+) hadlonger median survical time(75 months, n=16), compared with patientswith PTEN(-) (38 months, n=15)(log-rank test, x~2=4.568, P=0.032),Cox's proportional hazard regression model suggested PTEN expression,Ki-67 expression and residue cancer were hazard factors of patients'survival time.
Conclusion (1)The loss of PTEN expression is related with theoccurrence and development of the primary malignant tumor of thefallopian tube; PTEN and Ki-67 expression is related with pathologicalgrading, clinical stage、live time of the primary malignant tumor of thefallopian tube;
(2) The loss of PTEN expression may be related with the prognosis of theprimary malignant tumor of the fallopian tube.
引文
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[2] Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumor suppressor gene, MMACI, at chromosome I0g23.3 that is mutated in multiple advanced cancers[J]. Nat Genet, 1997,15(4): 356-362.
[3] Tashiro H, Blazes MS, Wu R, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies[J]. Cancer Res, 1997,57(18):3935-3940.
[4] Gerdes J, Schwab U, Lemke H, et al. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation[J].Int J Cancer, 1983,31:13-20.
[5] David Seligson, Yunda Huang, Jian Yu Rao, et al. Ki67, gelsolin and PTEN expression in sarcomatoid renal tumors[J]. Urol Res, 2003, 30:387-389.
[6] Ajithkumar TV, Minimole AL, John MM, et al. Primary fallopian tube carcinoma[J]. Obstet Gynecol Surv, 2005,60(4):247-252.
[7] Halon A, Rabczynski J. PCNA and laminin as prognostic factors in primary Fallopian tube carcinoma[J]. Folia Morphol. 2003, 62(4): 475-478.
[8] Wu GS, Wang JH, Liu ZY, et al. Expression of cyclooxygenase land 2 in extra hepaticcholangiocarcinoma[J]. HBPD INT, 2002,1:429.
[9] Di Cristofano A, Pesce B, Codon-Cardo C, et al. Pten is essential for embryonic development and tumor suppression[J].Nat Genet, 1998,19: 348-355.
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