| BackgroundHydatidiform mole is a common benign gestational trophoblastic disease,which has a tendency to be malignant for partial hydatidiform mole was 4%and complete hydatidiform mole was 15%.?-hCG level plays an important role for diagnosis of gestational trophoblastic neoplasia(GTN)without histopathological proofs while medical imaging examinations including pelvic ultrasound scanning,computed tomography(CT),X-ray chest film and MRI are non-required diagnosis proofs.The diagnosis of GTN needs time to observe human chorionic gonadotropin(hCG)level after emptied uterus,and so the patients of GTN are usually existing invaded uterine muscle and lungs metastasis.For this reason,high-risk factors have to be studied to diagnose GTN and forecast malignant changes earlier and to increase survival rates and well prognosis.High-risk factors that can be recognized so far are hCG level of more than 105U/L,excessive uterine enlargement,lutein cysts more than 6cm,age above 40 years old,repeated hydatidiform mole,with gestational hypertension or Hyperthyroidism.Prophylactic chemotherapy that has side effect is not a routine treatment for complete hydatidiform mole with high-risk factors which is lack of specificity and sensibility.So,how to diagnose and early predict malignant hydatidiform mole is an emergent problem needing to be resolved.ObjectivesTo explore clinical features and risk factors of malignant transformation of hydatidiform mole,and evaluate their predicting values.MethodsThis research is a retrospective study about hydatidiform mole.Total 148 cases with hydatidiform mole receiving treatment in Lin Yi People's Hospital from January of 2010 to June of 2014 were collected.The 148 cases were divided into two groups,one was malignant group with 71 cases of malignant hydatidiform mole and the other was benign group with 77 benign cases after 2 years follow-up.The indexes include age,gestational age,uterine size,volume of nidus in uterus,the mean radial line of uterine focus,?-hCG level,second surgical evacuation,trophoblastic cell hyperplasia,corpus luteum cyst,number of days from emptying to diagnosis of malignant transformation and clinical features of gestational trophoblastic neoplasia.SPSS 24.0 software(IBM,Chicago,USA)was used to analyze the data.The t test and x2 test,Mann-Whitney test,binary logistic regression,correlation analysis and receiver operating characteristic curve(ROC)were applied in the two groups.P-value<0.05 was considered statistically significant.ResultsAge:Age>40 years old in the malignant group(39.44%)was significantly higher than benign group(20.78%),(x2=6.155,P=0.013<0.05).Age ?35 years old in the malignant group(47.89%)was also significantly higher than benign group(24.68%),(x2=8.658,P=0.003<0.01).But in the malignant group,there were 37 cases with age<35 years old(52.11%).Gestational age:Gestational age ?12 weeks in the malignant group(29.58%)was more than benign group(20.78%),without significant difference(x2=1.525,P=0.217>0.05).Uterine size:Uterine size greater than the gestational age,benign group(45.45%)was more than malignant group(40.85%),without significant difference(x2=0.32,P=0.572>0.05).Volume of nidus in uterus:The mean volume of nidus in uterus of benign group was 307619.75±476989.456mm3 and the malignant group was 467764.25±929271.77 mm3.There was no significant difference between them by t test(t=-1.299,P=0.196>0.05).Mean radial line of uterine focus:Mean radial line of uterine focus?6cm,malignant group(69.01%)was more than benign group(37.66%)with significant difference(x2=14.566,P=0.000<0.01).There were 78 cases with mean radial line of uterine focus ? 6cm including 49 cases from malignant group(62.82%)and 29 cases from benign group(37.18%).Level of ?-hCG:?-hCG level>105 mIU/ml,malignant group(85.92%)was higher than benign group(76.62%),without significant difference(x2 = 2.079,P=0.49>0.05).Second surgical evacuation:Second surgical evacuation,benign group(63.64%)was higher than malignant group(56.34%)without significant difference(x2 =0.821,P=0.365>0.05).Trophoblastic cell hyperplasia:Histopathological grade I,there is no significant difference between the benign group(64.94%)and malignant group(73.24%),(x2= 1.189,P=0.272>0.05).There was no significant difference about Histopathological grade I,? and ? between the benign group and malignant group by Mann-Whitney test(Z=-1.065,P=0.2875>0.05).So,trophoblastic cell hyperplasia was irrelevant with malignant transformation of hydatidiform mole.Corpus luteum cyst:The benign group without corpus luteum cyst(89.61%)was significantly higher than the malignant group(74.65%),(x2 = 5.711,P=0.017<0.05).The result suggested that there was significant difference between them and corpus luteum cyst was a risk factor of malignant hydatidiform mole.The diameter of corpus luteum cyst>6cm,the malignant group(11.27%)was significantly higher than benign group(2.6%),(x2 = 4.407,P=0.036<0.05).From this result,we could know the diameter of corpus luteum cyst>6cm was a high risk factor;but there were about 122 cases(82.43%)of hydatidiform mole(including of benign and malignant groups)without cyst,and the number of cases with corpus luteum cyst>6cm was so small.Therefore,corpus luteum cyst>6cm could not well predict malignant transformation of hydatidiform mole because of lacking sensitivity.Binary logistic regression:Binary logistic regression was used to analyze the data,and three factors significantly increased the risk of malignancy,namely age?35 years old(OR:3.06,95%CI:1427?6.561),mean radial line of uterine focus?6cm(OR:4.514,95%CI:1.909?10.67)and the diameter of corpus luteum cyst>6cm(OR:2.188,95%CI:1.038?4.611).Number of days and clinical features:In the malignant group,there were about 65 cases(84.42%)diagnosed in 60 days after first surgical evacuation,and about 1/3 cases with myometrial invasion by ultrasound,and 1/4 cases with lung metastases by CT or X-ray chest examination,and ?-hCG level of all cases increased abnormally.Therefore,the diagnosis of gestational trophoblastic neoplasia was too late.Correlation analysis and ROC curve:Mean radial line of uterine focus was negative correlation with number of the days and index was-0.333(P<0.01).The areas under ROC curve of age and mean radial line of uterine focus were in 0.5?0.7 with lower accuracy in predicting malignant mole,and corpus luteum cyst is of little value in predicting malignant transformation of hydatidiform mole.Conclusions1.Age?35 years old,mean radial line of uterine focus?6cm and corpus luteum cyst>6cm were high risk factosr of malignant transformation of hydatidiform mole.2.Factors such as ?-hCG level>105 mIU/ml,gestational age?12 weeks,uterine size greater than the gestational age,second surgical evacuation,trophoblastic cell hyperplasia and so on were irrelevant with malignant transformation of hydatidiform mole.3.After first surgical evacuation,about 65 cases(84.42%)was diagnosed as GTN in 60 days,and the diagnosis was too late because of about 64.79%of them with myometrial invasion and lung metastases.BackgroundAs we all know,hydatidiform mole(HM)from placental villus belongs to gestational trophoblastic disease,and its main manifestation is vesicular mole because of degeneration of trophoblastic cells and edema of villus.HM is seen as a benign disease and can be cured by surgical evacuation,which has a tendency to be malignant is 10%?20%.HM and gestational trophoblastic neoplasia(GTN)are considered as different stages of the same disease,and the reason and molecular mechanism of malignant transformation are also unclear and need to be further discovered.HM is an androgenesis disease without maternal genes,which maybe a reason of malignancy.In normal pregnancy,trophoblastic cells can invade endometrium but be limited by maternal tissue,while the invasion of cells in HM with malignant tendency is too powerful to be restricted.Invasive mole is a common GTN from malignant transformation of hydatidiform mole,and its pathological diagnosis depends on finding villus invasion in blood vessel and myometrium of uterine specimen.Therefore,pathologists have difficulty in diagnosis of invasive mole without uterus,and hysterectomy is not a routine treatment for HM and GTN.At present,the diagnosis of malignancy of HM is too late because ? human chorionic gonadotropin(?-hCG)level plays an important role and needs time to diagnose GTN without histopathological proof.While GTN has powerful damage and can distant metastasis in early stage,the prognosis of malignancy of HM may be better,and drug resistance of signal agent and the probability of drug combination may be decreased if malignancy of HM could be diagnosed earlier.So,researchers have looked for methods to predict malignancy of HM.Gene p57 is a paternal imprinted gene and can be expressed in parent body.In complete hydatidiform mole(CHM),p57 is negative expression and positive expression in partial hydatidiform mole(PHM);therefore,p57 can distinguish CHM from PHM but it can not predict malignancy of HM,while malignancy for CHM was 20%.How to diagnose and early predict malignant hydatidiform mole earlier is an emergency problem needed to be resolved,which can provide evidences for preventive chemotherapy.ObjectivesThis study is to detect value of p21-activated protein kinase 1(PAK1),epithelial cadherin(E-CD),p53,eukaryotic initiation factor 3a(eIF3a)and matrix metalloproteinas-9(MMP-9)in predicting malignant transformation of hydatidiform mole by immunohistochemistry(IHC).MethodsParaffin-embedded tissue samples were from cases in the first part of this paper,90 cases with HM receiving treatment in Lin Yi People's Hospital from January of 2010 to June of 2014 were collected.The 90 cases were divided into two groups,one was malignant group with 50 cases of malignant HM except diagnosed as malignancy within 1 week and the other was benign group with 40 benign cases during in 2 years follow-up.All cases which had complete clinical material were diagnosed as HM by pathology,and sections of all cases were reviewed and paraffin embedded blocks with rich trophoblastic cells were chosen.All paraffin embedded tissue samples were from the first surgical evacuation without chemotherapy.The expressions of PAK1,E-CD,p53,eIF3a and MMP-9 in HM tissue were performed by two-step IHC.With double blind,five perspectives of the sections were chosen with the high power microscope.Brown granules lay in cytoplasm of trophoblastic cells for expressions of PAK1,eIF3a and MMP-9,and lay in cell nucleus for expression of p53,lay in cytoplasm or cytomembrane for expression of E-CD.The expressions of PAK1,E-CD,p53,eIF3a and MMP-9 were judged according to the proportion of positive cells and staining intensity to develop IHC semiquantitative scoring standards.Staining intensity score:0 point:negative;1 point:weak;2 points:medium;3 points:strong;positive cells score:0 point:<25%;1 point:26%to 50%;2 points:51%to 75%;3 points:76%to100%.The above two scores were multiplied to make the final judgement result.Positive grades of expressions of PAK1,MMP-9 and p53:negative(-):0 point;weakly positive(+):1 to 3points;medium positive(++):4 to 5 points;strong positive(+++):?6 points.Normal expression of PAK1:? 3 points;excessive expression:>3point.Positive grades of expressions of E-ED and eIF3a:negative(-):0 point;weakly positive(+):1 to 3 points;medium positive(++):4 to 6 points;strong positive(+ ++)?>6 points.Normal expression of E-CD>6 points;abnormal expression:?6 points.SPSS 24.0 software(IBM,Chicago,USA)was used to analyze the data.The x2 test was applied in the two groups;correlation analysis was used to know the relationship of the five markers;receiver operating characteristic(ROC)curve was used to analyze sensitivity and specificity;P-value<0.05 was considered statistically significant.ResultsPAK1:Excessive expression of PAK1,malignant group(62%)was significantly higher than benign group(17.5%),(x2 =18.039,P=0.000<0.01).There were 38 cases existing excessive expression of PAK1,and 31 cases(81.58%)were from malignant group and 7 cases(18.42%)were from benign group.From the results,we could know that about 81.58%of HM would be malignant if PAK1 expressed excessively.E-CD:Positive expression of E-CD,malignant group(98%)was significantly higher than benign group(85%),(x2 =5.236,P=0.022<0.05).Medium and strong positive expression of E-CD,malignant group(90%)was significantly higher than benign group(62.5%),(x2 = 9.723,P=0.002<0.01).Abnormal expression of E-CD,malignant group(82%)was lower than benign group(82.5%),but without significant difference(x2 0.004,P=0.951>0.05).p53:Positive expression of p53,malignant group(90%)was significantly higher than benign group(67.5%),(x2-7.031,P=0.008<0.01).Medium and strong positive expression of p53,malignant group(28%)was higher than benign group(15%),(x2 =2.173,P=0.14>0.05),without significant difference.eIF3a:Positive expression of eIF3a,malignant group(92%)was lower than benign group(92.5%),(x2=0.008,P=0.93>0.05);Medium and strong positive expression of p53,malignant group(28%)was higher than benign group(15%),(x2 =2.173,P=0.14>0.05).Both without significant difference.MMP-9:Positive expression of MMP-9,malignant group(58%)was higher than benign group(42.5%),(x2 =2.137,P=0.144>0.05),without significant difference.Correlation analysis and ROC curve:The expressions of p53 and eIF3a were positive correlated with PAK1,E-CD and MMP-9(P<0.05,P<0.01).And the expression of p53 were positive correlated with eIF3a(P<0.01).The areas under ROC curve(AUC)of E-CD,p53,MMP-9 and eIF3a were in 0.5?0.7 with lower accuracy in predicting malignant mole,and PAK1 could predict accurately malignant transformation of mole with AUC in 0.7-0.9.Conclusions1.PAK1 could predict malignant transformation of hydatidiform mole with positive predictive value 81.85%,negative predictive value 63.46%,sensitivity 62%and specificity 82.5%.2.E-CD,p53,eIF3a and MMP-9 were connected with malignant transformation of hydatidiform mole,but they could not predict malignancy because of lacking of accuracy. |
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