A Study On The Clinical Value Of Serum HCG In Predicting Post-molar Gestational Neoplasia And The Clinical Value Of Total Hysterectomy In Preventing Post-molar Gestational Neoplasia

Background:Complete hydatidiform mole(CHM),the most common form of gestational trophoblastic disease,consists of 80%of the disease spectrum.The incidence of CHM in Asian population is ten times more than that of European population.The association between CHM and pregnancy was first noted in the year 1895,and since then,the diagnosis and treatment strategies of CHM have not much improved although its physiopathology has been deeply studied.The diagnosis is mainly dependent on ultrasonography and as soon as the diagnosis is established,uterine evacuation must be performed.For those older patients with CHM,total hysterectomy and prophylactic chemotherapy are considered as one of the treatment option.However,in spite of these above-mentioned therapeutic strategies,there are still 10%-17%of patients with CHM who progress to gestational trophoblastic neoplasia and 3%advance to choriocarcinoma.The incidence of GTN after hydatidiform mole is 2000 times greater than that after abortion and term pregnancy.Therefore,the malignancy of CHM after uterine evacuation is a severe life-threatening condition to reproductive women.A prompt diagnosis and treatment is the key to cure post-molar gestational trophoblastic neoplasia.Almost 100%of patients who are diagnosed and treated at an early stage can be eventually cured,while for those patients who delay the diagnosis or treatment,there will be an increased chance for metastases and mortality.The golden standard for the diagnosis of GTN is based on FIGO protocol,which requires weekly serum hCG measurements.Based on FIGO criteria,the diagnosis of post-molar GTN is made as follows;1)an elevated hCG plateau(days 1,7,14 and 21);2)rising hCG titers(days 1,7,14);3)when the hCG level remains elevated for 6 months or more;4)a histologic diagnosis of choriocarcinoma.This follow-up regime demands patients’ fully compliance,which is to return for hCG monitoring every seven days for a minimum period of 2 years.This long-time-interval strategy is a huge burden and usually imposes a severe inconvenience as well as a potential waste of medical resources.Moreover,once the patients miss the appointment,the diagnosis of GTN will be delayed.According to relevant data,the compliance of patients with CHM was extremely poor:in low-income American people,the fully compliance rate was only 7%-36%.Furthermore,this phenomenon is believed to be even worse in developing countries and less-developed countries.To solve the problem,researchers have proposed several prediction models.The most popular method is the prediction model of hCG regression pattern.There are two promising prediction models:weekly hCG regression curve and weekly hCG regression rate curve,which are low-cost and convenient in clinical practice.However,these models still require weekly hCG monitoring thus cannot overcome the inherent disadvantage,that is,when the patient does not return for follow-up in the seven-day interval(for instance,less than seven days or more than seven days),the models will lose their ability to predict.Therefore,one of the objectives of the current study is to establish a novel daily-hCG-based prediction model which can be applied to patients with poor compliance.Comparisons were conducted to evaluate the clinical value of the newly established prediction models and the existing prediction models.The other objective of the current study is to evaluate the effectiveness of prophylactic hysterectomy and prophylactic chemotherapy in preventing post-molar GTN.Considering the age-incidence relationship involved,some researchers might choose to offer hysterectomy to reduce the risk of developing GTN in older patients who have completed their families.In addition,other researchers may recommend prophylactic chemotherapy as an alternative way to prevent post-molar GTN,as chemotherapeutic agents can prevent GTN via eliminating trophoblastic cells hidden in lympho-vascular space.However,these procedures are controversial.Some studies have found no significance in preventing post-molar GTN after undergoing prophylactic hysterectomy.Some author even argued that the manipulation in surgery could facilitate vascular metastasis of trophoblastic cells.A similar situation was noted concerning to prophylactic chemotherapy.It is reported that prophylactic chemotherapy exposed 80%of patients unnecessarily to toxic side effects which lead to incomplete protection against persistent tumor and lower the probability of full recovery.Taken all the above facts into consideration,we conducted the current study to1)establish a novel prediction model(daily hCG regression rate curve)that can be applied to poor-compliant patients and compare the new prediction model with existing models;2)compare the effectiveness of four prediction models in predicting post-molar GTN;3)compare the effectiveness of different therapeutic strategies for CHM in women who were at least 40 years old based on the data of our hospital;4)conduct a systematic review and meta-analysis to further study the value of prophylactic hysterectomy in preventing post-molar GTN in patients with HM being at least 40 years old.Part ⅠA novel hCG-based prediction model for post-molar gestational trophoblastic neoplasia in women with complete hydatidiform mole and its clinical valueObjective:To establish a novel prediction model applicable to poor compliant patients and compare with existing models in the aspect of clinical value.Materials and Methods:We retrospectively reviewed the medical records of all patients who were treated and were confirmed with a diagnosis of complete hydatidiform moles during the period from January 2000 to December 2010.Inclusion criteria were:1)histologically confirmed diagnosis of complete hydatidiform mole,2)initial therapy was D&C;3)complete follow-up period for a minimum of two years.Exclusion criteria were:1)histologically confirmed diagnosis of partial mole,invasive mole,choriocarcinoma,placental site trophoblastic tumor or epithelial trophoblastic tumor;2)initial therapy was prophylactic chemotherapy or hysterectomy;3)a follow-up period of less than two years.The medical records were reviewed and the clinical data such as general characteristics,therapeutic strategies,hCG results were collected.Four prediction models were constructed based on the hCG data of the spontaneous regression group(a sample of 1383 hCG values).The hCG data from post-molar GTN group was used to evaluate the clinical performance of each prediction model in predicting GTN.The weekly hCG regression standard curve and weekly hCG regression rate standard curve were constructed according to previous studies;the daily hCG regression standard curve and daily hCG regression rate standard curve were plotted based on the theory pioneered by us.Comparisons were conducted between the novel models and the existing models to evaluate the clinical value.Results:From a total of 222 patients,a natural regression was noted in 195 patients(spontaneous regression group)while the remaining 27 patients entered post-molar GTN(post-molar GTN group).All the patients with post-molar GTN were pre-identified by daily hCG regression rate standard curve,with an average of 15.3 days gained compared to FIGO criteria(P=0.008).The daily hCG regression standard curve had a sensitivity of 92.6%,with an average of 10 days gained(P=0.030).The weekly hCG regression rate standard curve had a sensitivity of 85.2%,with an average of 14 days gained(P=0.006).No significant differences were found between the weekly hCG regression standard curve and FIGO criteria.Conclusion:In comparison with the other three prediction models,our data showed that the daily hCG regression rate standard curve gives the best prediction of post-molar GTN,and might potentially enhance the monitoring of patients with molar pregnancy,especially those who could not adhere to FIGO protocols.Part IIThe clinical value of four hCG models in predicting post-molar gestational trophoblastic neoplasia:A prospective studyObjective:To prospectively study the clinical value of four hCG prediction models in predicting post-molar GTN.Materials and Methods:From 2011 to June 2015,Patients who were treated in our hospital and met the following criteria were prospectively shortlisted in the study:1)histologically confirmed diagnosis of CHM,2)and initial therapy was D&C.All patients were then followed for a minimum of two years,after which only those patients who had an intact data of pre-evacuation hCG level and hCG levels during the period of follow-up were finally included in this study.Based on the four hCG prediction models of Part I,the sensitivity,specificity,positive predictive value,negative predictive value,accuracy,Youden index,odds ratio,positive likelihood ratio and negative likelihood ratio,all of which were calculated and compared.Results:A total of 117 patients were selected.Of whom 16 patients(13.7%)developed post-molar GTN while 101 patients(86.3%)regressed naturally after initial treatment.For weekly hCG regression standard curve,7 patients with GTN were failed to predict and 9 patients who regressed naturally were failed to predict,with a sensitivity of 56.3%and a specificity of 91.1%.For weekly hCG regression rate standard curve,3 patients with GTN was failed to predict and 6 patients who regressed naturally were failed to predict,with a sensitivity of 81.2%and a specificity of 94.1%.For daily hCG regression standard curve,2 patients with GTN was failed to predict and 20 patients who regressed naturally were failed to predict,with a sensitivity of 87.5%and a specificity of 80.2%.For daily hCG regression rate standard curve,no patients with GTN were failed to predict and 2 patients who regressed naturally was failed to predict,with a sensitivity of 100%and a specificity of 98.1%.In general,daily hCG regression rate curve had the highest sensitivity,specificity and accuracy.Moreover,daily hCG regression rate curve was the only prediction model which met the criteria that positive likelihood ratio was over 10 and negative likelihood was ratio less than 0.1.Conclusion:Our data showed that daily hCG regression rate curve had the best performance in predicting post-molar GTN,and might be applied to monitor poor-compliant patients with CHM.Part ⅢThe clinical value of prophylactic hysterectomy for preventing malignant transformation of complete hydatidiform mole in patients at least 40 years old:a retrospective cohort studyObjective:To evaluate the clinical value of prophylactic hysterectomy in preventing post-molar gestational trophoblastic neoplasia(GTN)pertaining to patients with complete hydatidiform mole(CHM)who were at least 40 years old.Materials and Methods:Patients from our hospital who had histologically been diagnosed of CHM and underwent treatment from January 2004 to December 2013 were included.Inclusion criteria were:1)histologically confirmed diagnosis of CHM,2)being at least 40 years old of age,3)initial therapy was D&C and no evidence of residual tissue in the uterus,4)no evidence of local invasion or metastasis before initial therapy,5)follow-up for a minimum of two years.Relevant clinical data,such as clinical characteristics,traditional high risk factors,therapeutic methods,outcome of treatment,malignant rate of GTN,chemotherapy resistance rate and the time interval to GTN diagnosis were extracted and analyzed.Results:A total of 171 patients were included.The age ranged from 40 to 56 with a mean of 46.9.The mean parity was 1.2(range:0-4).The mean of gestational age was 9.5 weeks.All patients were divided into three groups based on the therapeutic strategy they received.Group 1 consisted of 124 patients,treated by dilation and curettage only,and the incidence of post-molar GTN was 37.1%.Group 2 included 12 patients who received prophylactic chemotherapy,with an incidence of 41.7%.The remaining 35 patients,Group 3,underwent total hysterectomy,with the lowest incidence of 11.4%.A significantly lower incidence was noted in group 3 as compared to group 1(χ2=8.342,P=0.004).No significant differences were noted in group 2 compared to group 1(P=0.035,P<0.017(0.05/3)were considered significant,Bonferroni correction).Conclusion:Prophylactic hysterectomy was the most effective therapeutic strategy for preventing malignancy of CHM in women being at least 40 years old of age.Part ⅣManagement of hydatidiform mole with prophylactic hysterectomy in women who were at least 40 years old:a systematic reviewand meta-analysisObjective:To conduct a systematic review and meta-analysis to evaluate the clinical value of total hysterectomy in preventing post-molar gestational trophoblastic neoplasia(GTN)pertaining to patients with HM who were at least 40 years old.Materials and Methods:Five electronic databases,including PubMed,Embase,the Cochrane database of systematic review,China National Knowledge Infrastructure and ClinicalTrials.gov,were searched.Studies were included if they:1)were human studies,2)explicitly indicated exposure to hysterectomy,3)explicitly indicated control to uterine evacuation,4)explicitly indicated the participants were older patients with hydatidiform mole being at least 40 years in age,5)compared the outcome of interest as the incidence of post-molar GTN.Studies were excluded if they were1)review articles,2)case report or case series,3)studies with data that could not be extracted to calculate a risk ratio.Meta-analysis was conducted based on the incidence of post-molar GTN.Results:Five studies with a total of 291 participants were included in the current meta-analysis.Two studies were conducted in USA and three studies were conducted in Asia(one in Thailand and two in China).The age of participants was at least 40 years old in three studies,40 to 49 in one study and 50 or older in one study.The case group included the group of patients who received total hysterectomy.The control group comprised patients who received only uterine evacuation.The sample size ranged from 22 to 159.The follow-up time was 3-14 years in one study and 3-12 years in another study,while for the other three studies,such data were not reported.The outcome of each study was predominantly focused on incidence of post-molar GTN.The overall pooled effect size of hysterectomy group had a significant advantage over uterine evacuation group with an OR of 0.14(95%CI,0.06-0.34;P<0.0004)and a low heterogeneity(I2=21%,P=0.28).Similar results were noted in the subgroup analysis based on the age and locale.No publication bias was found(Egger’s test,P=0.149;Begg’s test,P=0.462).Conclusion:Hysterectomy,comparing to uterine evacuation,is a better therapeutic method for treating patients with HM who are at least 40 years old.Therefore,total hysterectomy can be recommended for this age-specific group of patients in preventing post-molar GTN unless fertility is still desired.