Clinical and genetic-epigenetic aspects of recurrent hydatidiform mole: A review of literature

Hydatidiform Mole (HM) is the most common form of Gestational Trophoblastic Disease (GTD), defined by hyper-proliferation of trophoblastic cells. HM is typified as abnormal proliferation of extraembryonic trophoblastic (placental) tissues and failure of embryonic tissues development and is the only GTD with Mendelian inheritance, which can reoccur in different pregnancies. Moles are categorized into Complete Hydatidiform Moles (CHM) or Partial Hydatidiform Moles (PHM) and a rare familial trait, which forms a CHM and despite having androgenetic pattern, shows normal biparental inheritance, conceived from one sperm and egg. Recessive maternal-effect mutations in NLRP7 (NACHT, leucine rich repeat and PYD containing 7) and KHDC3L (KH Domain Containing 3-Like) genes have been shown to be responsible for Recurrent Hydatidiform Moles (HYDM1 MIM# 231090 when is caused by mutation in the NLRP7 gene and HYDM2 MIM#614293 when is caused by mutation in the KHDC3L gene). Methylation aberration in multiple maternally imprinted genes is introduced as the cause of Recurrent HYDM pathology. The current article reviews the histopathology, risk factors, and genetic and epigenetic characteristics of Recurrent HYDMs.     

层粘蛋白及受体在正常妊娠及妊娠滋养细胞疾病中的表达

目的探讨层粘蛋白(LN)及其受体(LN-R)在正常妊娠及妊娠滋养细胞疾病中的表达及其与恶性滋养细胞肿瘤侵袭的关系。方法收集1991年1月至2003年12月温州医学院附属一院正常妊娠、葡萄胎、侵蚀性葡萄胎及绒毛膜癌(绒癌)石蜡包埋组织,应用免疫组织化学SP方法检测各组中LN、LN-R的表达情况。结果LN、LN-R在正常妊娠、葡萄胎、侵蚀性葡萄胎及绒癌中的表达差异有非常显著性意义(P<0·01)。LN、LN-R在侵蚀性葡萄胎及绒癌中的表达与正常妊娠、葡萄胎比较差异有非常显著性意义(P<0·01)。结论LN、LN-R在妊娠滋养细胞疾病中的表达异常与恶性滋养细胞的高侵袭力密切相关。     

MASPIN基因在妊娠滋养细胞肿瘤中的表达及意义

目的：探讨MASPIN基因在妊娠滋养细胞肿瘤中的表达,了解MASPIN基因在妊娠滋养细胞肿瘤发生、发展中的作用。方法：采用免疫组化链霉菌抗生物素蛋白－过氧化物酶连接（SP）法检测10例妊娠滋养细胞肿瘤、30例葡萄胎、20例正常妊娠早期绒毛（对照组）各标本中MASPIN的表达。结果：妊娠滋养细胞肿瘤中MASPIN阳性表达率（10%,1/10）明显低于对照组（95 %,19/20）（P ＜0.05）。葡萄胎组中MASPIN阳性表达率（60 %,18/30）明显低于对照组（95 %,19/20）（P ＜0.05）。妊娠滋养细胞肿瘤中MASPIN阳性表达率明显低于葡萄胎组（P ＜0.05）。结论：MASPIN的表达下调与妊娠滋养细胞疾病的发生、发展有关,可能是妊娠滋养细胞疾病发病的重要机制之一。     

Trophoblastic reminiscences

Development of the radioimmunoassay in the 1950s and early '60s largely eliminated early problems with human chorionic gonadotropin and permitted the U.K. to offer a national service for gestational trophoblastic disease (GTD) patients. In 1973 a voluntary registration scheme for patients with hydatidiform mole (HM) opened at 3 U.K. locations. The Charing Cross Centre has followed > 35,000 women with HM, and 2,500 have undergone treatment for various forms of GTD. All treated patients are followed indefinitely and the data computerized. Disasters have occurred in 1 country from misinterpretation of erroneous hCG assays. In terms of experience and data collection, the advantages of a specialized service are overwhelming. This society's main thrust should be to ensure that women with GTD in all countries benefit from specialized management.     

NLRP7基因在葡萄胎发生中的作用

葡萄胎（HM）是异常人类妊娠,以绒毛滋养细胞增生、间质水肿,同时缺乏胚胎发育或者异常的胚胎发育为特征,是一种滋养细胞疾病（GTD）。超声的广泛使用使早期诊断和处理葡萄胎成为可能,但其确诊依据仍是组织学诊断;葡萄胎治疗有一定难度,且葡萄胎特别是复发性葡萄胎的预后不理想。葡萄胎的发生机制尚不明确,细胞遗传学研究发现葡萄胎组织染色体核型异常和基因印迹错误。最近对葡萄胎患者基因方面的研究发现,NLRP7基因与复发性葡萄胎存在相关性。就葡萄胎及其与NLRP7基因的研究进展综述。     

Increase in the incidence of gestational trophoblastic disease in The Netherlands

Objective

The objective of this study is to determine the incidence and time trends of gestational trophoblastic disease (GTD) in The Netherlands using population-based data.

Methods

Data on patients with a pathologically confirmed diagnosis of GTD from 1995 to 2008 were obtained from PALGA, a national archive containing all histopathology reports in The Netherlands. Data on number of deliveries were obtained from the Database of Statistics Netherlands.

Results

During the study period, 4249 GTD patients were registered. Overall incidence rates of hydatidiform mole (HM), choriocarcinoma and placental site trophoblastic tumor (PSTT) were 1.34 per 1000 deliveries, 3.1 per 100,000 deliveries, and 1.0 per 100,000 deliveries, respectively. Incidence rates of HM increased from 1.02 per 1000 deliveries in 1995 to 1.56 per 1000 in 2001, an increase of 0.091 per year (95% CI 0.081-0.101). After 2001 incidence rates remained constant (increase per year −0.010, 95% CI −0.045-0.024). Maternal age and ethnicity are known to influence the risk of HM. Highest incidences were observed in women under 20 and over 40 years of age. The proportion of deliveries accounted for by women over 40 years of age increased from 1.5% to 2.9%, whereas women under 20 accounted for 1.5% of deliveries. The proportion of live births of Asian descent increased from 2.6% to 3.7%.

Conclusion

The incidence of GTD in The Netherlands increased significantly from 1995 to 2008. This can partially be explained by increased maternal age and increased proportion of live births of Asian descent. Part of the increase might result from improved diagnostic techniques. However, these factors do not seem to account for the total observed increase and part of the increase therefore remains unexplained.     

MASPIN基因在妊娠滋养细胞肿瘤中的表达及意义

目的：探讨MASPJN基因在妊娠滋养细胞肿瘤中的表达,了解MASP,N基因在妊娠滋养细胞肿瘤发生、发展中的作用。方法：采用免疫组化链霉菌抗生物素蛋白-过氧化物酶连接（SP）法检测10例妊娠滋养细胞肿瘤、30例葡萄胎、20例正常妊娠早期绒毛（对照组）各标本中MASPIN的表达。结果：妊娠滋养细胞肿瘤中MASPIN阳性表达率（10％,1／10）明显低于对照组（95％,19,20）（P〈0．05）。葡萄胎组中MASPIN阳性表达率（60％,18／30）明显低于对照组（95％。19／20）（P〈0．05）。妊娠滋养细胞肿瘤中MASPIN阳性表达率明显低于葡萄胎组（P〈0．05）。结论：MASPIN的表达下调与妊娠滋养细胞疾病的发生、发展有关,可能是妊娠滋养细胞疾病发病的重要机制之一。     

Gestational trophoblastic disease of the fallopian tube.

Tubal gestational trophoblastic disease (GTD) was diagnosed in 16 (0.8%) of 2,100 women with GTD managed at the New England Trophoblastic Disease Center. Tubal partial mole, complete mole and choriocarcinoma were present in 5, 5 and 6 patients, respectively. Patients with tubal GTD were not clinically distinguishable from those with traditional tubal pregnancies. While only one patient with tubal mole developed metastases, four patients with tubal choriocarcinoma presented with metastases. All the patients achieved complete, sustained remission.     

Ancillary Techniques to Refine Diagnosis of GTD

Gestational trophoblastic disease (GTD) consists of hyperplastic and neoplastic disorders of placental trophoblast; i.e., hydatidiform moles and gestational trophoblastic tumors, respectively. While the histological diagnosis of well-developed complete hydatidiform mole and gestational choriocarcinoma is generally accurate, significant diagnostic challenges persist in the routine evaluation of early complete hydatidiform mole, partial hydatidiform mole, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. Recently, the applications of new immunohistochemical markers and molecular techniques have significantly enhanced the diagnostic accuracy of various GTDs. P57 immunohistochemistry is a highly useful marker in confirming complete hydatidiform mole, including its early forms. PCR-based short tandem repeat DNA genotyping has emerged as a powerful diagnostic measure to precisely classify both complete and partial hydatidiform moles. With highly desired sensitivity and specificity, these powerful ancillary studies should be advocated and integrated into the routine diagnostic algorithm of GTD.     

Cytokeratin 20 as a biomarker of gestational trophoblastic disease: diagnostic and prognostic significance

OBJECTIVES: This study was designed to examine whether cytokeratin 20 (CK20) is expressed in molar pregnancies and may therefore be used in the diagnosis of gestational trophoblastic disease (GTD). The potential of CK20 expression in predicting the evolution and the prognosis of the different subtypes of GTD was also assessed. METHODS: A total of 48 samples were studied for CK20 expression by RT-PCR methodology. Among these, 24 samples were obtained by curettage of the uterine cavity of patients diagnosed with hydatidiform mole (14 complete moles and 10 partial moles), 4 samples were obtained from choriocarcinoma cell lines (2 JAR and 2 JEG), and 20 samples were of normal trophoblast (control group) obtained from patients that underwent elective termination of pregnancy. RESULTS: Expression of CK20 was identified in all the samples of complete mole (CM), all choriocarcinoma cell lines, and 50% of the patients with partial mole (PM). None of the preparations of normal trophoblastic tissue from the control group expressed the CK20. A significant difference (P < 0.00001) was found in CK20 expression between samples of patients with GTD and control samples. Comparison between CK20 expression in CMs and PMs revealed a significantly more frequent expression of CK20 in CMs (P = 0.006). More than 50% of the patients with PMs that were positive for CK20 had an invasive evolution. CONCLUSIONS: In our opinion, CK20 may assist in distinguishing between molar and normal trophoblastic tissue and may be considered a marker of GTD. In cases in which pathological classification of different subtypes of GTD is in doubt, CK20-positive expression is suggestive for a CM whereas CK20-negative is more indicative for PM.     

360余万次妊娠中妊娠滋养细胞疾病发生情况调查

目的 调查我国妊娠滋养细胞疾病(gestational tropphoblastic disease,GTD)的发生情况,为防治本病提供依据。方法 联合我国浙江、江苏、福建、安徽、江西、山西和河南7省143所医院,对1991-2000年间GTD的发生情况进行调查。结果 删除因填表有缺项的单位,实际统计了7省118所医院的资料,妊娠总数为3674654例,GTD为14222例,占3．87％。GTD中,葡萄胎9194例,占64．6％;侵蚀性葡萄胎3452例,占24．3％;绒毛膜癌1521例,占10．7％;胎盘部位滋养细胞肿瘤55例,占0．4％。葡萄胎中完全性葡萄胎7079例,占77．0％,部分性葡萄胎2115例,占23．0％。GTD发病年龄多在20～34岁,占85．5％。结论 本调查以医院为调查单位,葡萄胎的发生率较20世纪50年代有明显下降趋势。临床上需重视GTD的病理诊断,及完全性葡萄胎和部分性葡萄胎的诊断。     

Gestational trophoblastic disease among Hispanic women: a 21-year hospital-based study

OBJECTIVE: Hispanics are the fastest growing minority group in the United States. Few reports have described gestational trophoblastic disease (GTD) in this population. The purpose of this study was to determine the incidence of GTD at our public hospital which primarily serves the Hispanic population. METHODS: All women diagnosed with GTD (partial and complete hydatidiform mole, choriocarcinoma) between 1983 and 2004 were identified from the institutional tumor registry, surgical pathology reports and hospital ICD-9 codes. Clinical data were retrospectively extracted from medical records. The live birth denominator was tabulated over the same interval of time by retrieving labor and delivery statistics and sorting by race. RESULTS: GTD was diagnosed in 596 patients over a 21-year study interval encompassing 289,897 live births. The overall incidence of GTD was 2.06/1000 live births. Hispanic women had a higher incidence compared to Blacks (2.38 vs. 1.34; P < 0.001), but not Whites (2.00; P = 0.17). The 416 Hispanic women were diagnosed with GTD at an earlier gestational age in the latter part of this study (12.3 vs. 16.2 weeks; P < 0.001). Hispanics were more likely to have a partial hydatidiform mole compared to Blacks (29% vs. 13%; P < 0.001) and Whites (18%; P = 0.04). Choriocarcinomas occurred least commonly in Hispanic patients (1 per 35,000 live births). Teenage Hispanic women were the only ethnic age group with a higher risk of developing GTD (odds ratio = 1.6, 95% confidence interval: 1.1, 2.2). CONCLUSION: Hispanic women had the highest incidence of GTD in this hospital-based study, were diagnosed at an earlier gestational age in the last decade and more frequently were diagnosed with partial moles.     

Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia

OBJECTIVES: To determine whether circulating hyperglycosylated human chorionic gonadotropin (hCG-H), a promoter of choriocarcinoma growth and tumorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia. METHODS: Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)). RESULTS: We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinoma/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hCG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor. DISCUSSION AND CONCLUSION: hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings.     

Genetics and molecular markers in gestational trophoblastic disease with special reference to their clinical application

Gestational trophoblastic disease (GTD) encompasses a diverse group of lesions with specific cytogenetic and molecular pathogenesis. Although cytogenetic studies have been extensively reported, the molecular pathogenesis is poorly understood. We will summarize some of the recent molecular observations and correlate them with the pathology of GTD. Complete mole is androgenetic in origin. Thus, if a monoallelic contribution can be shown in complete mole, this would render the gene susceptible to functional inactivation by 'one-hit' kinetics. Alternatively, uniparental transmission of genes that are subject to parental imprinting in humans would impair their regulation. Loss of NECC1 expression, biallelic deletions at the critical (7p12-7q11.23) region and enhanced H19 expression in choriocarcinoma would reflect the genetic features exhibited by the putative forerunner, complete mole. In addition to the unique genetic features shown in GTD, alterations in gene expression profiles accompanied by malignant conversion of trophoblasts would facilitate the development of choriocarcinogenesis from complete mole. With recent advances in molecular techniques, further work is still necessary to provide a better understanding and useful markers for persistent trophoblastic disease. These may provide useful prognostic indications that may guide the different diagnosis of GTD.     

妊娠滋养细胞疾病Cyclin B1、PCNA表达的研究

目的 :检测CyclinB1和增殖细胞核抗原 (PCNA)蛋白在妊娠滋养细胞疾病(GTD)中的表达 ,探讨二者的相关性及与GTD的关系。方法 :采用免疫组化S P法检测 1 5例正常绒毛、38例葡萄胎 (HM)、42例侵蚀性葡萄胎 (IM)和 1 8例绒毛膜癌 (CC)组织中Cy clinB1和PCNA蛋白表达情况。结果 :葡萄胎、IM、CC组织中的CyclinB1和PCNA蛋白表达水平显著高于正常绒毛。术前未化疗的IM和CC组织中CyclinB1的表达水平明显高于葡萄胎。CC组织PCNA的表达水平高于葡萄胎 (P =0 .0 0 5)。葡萄胎恶变者CyclinB1和PCNA的表达显著高于未恶变者。术前未化疗的滋养细胞肿瘤患者 (包括IM和CC)Cy clinB1表达显著高于术前化疗≥3疗程者 (P =0 .0 0 2 )。WHO预后评分为高危者及中危者的CyclinB1表达显著高于低危者 (P =0 .0 0 5)。PCNA的表达与滋养细胞肿瘤是否化疗、WHO分期、WHO评分无关。PCNA与CyclinB1的表达呈正相关 (P =0 .0 0 0 )。结论 :GTD中存在CyclinB1的调节紊乱 ,CyclinB1异常表达可能与葡萄胎滋养细胞的增生、恶变及滋养细胞肿瘤的恶性生物学行为有关     

Practical management of gestational trophoblastic disease

Gestational trophoblastic disease (GTD) represents a spectrum of tumors that arise from the fetal chorion during pregnancy, including benign partial and complete hydatidiform moles, persistent invasive or metastatic moles, placental-site trophoblastic tumors, and gestational choriocarcinomas. Gestational trophoblastic diseases all exhibit proliferation of both cytotrophoblast and syncytiotrophoblast cells, with the exception of placental-site tumor, which is derived from the intermediate trophoblast cells. Practical management of these tumors begins with preoperative evaluation and screening for metastatic disease followed by uterine evacuation or hysterectomy. Postmolar GTD includes local noninvasive proliferation of molar tissue, invasive mole, or gestational choriocarcinoma. The management of malignant GTD may be directed from three classification systems developed to predict patient prognosis and guide the decision for either single or multiagent chemotherapy. These systems assess clinical risk factors in addition to sites of metastatic disease. Treatment with aggressive multiagent chemotherapy and individualized multimodality therapy is warranted in these extremely high-risk patients. After remission, patients should be followed closely for 1 year and periodically thereafter. Pregnancy is deferred and contraception instituted for 1 year to prevent disruption of serum human chorionic gonadotropin surveillance.     

Regional perspectives on gestational trophoblastic disease in Turkey

Studies in Turkey are hospital based, and there is a wide variation in reported incidences that necessitate population based-studies to determine the real incidence of gestational trophoblastic diseases (GTDs). According to hospital-based studies, the frequency of GTD is generally very high and there are also regional differences. Epidemiologic study was performed to determine the frequency of hydatidiform mole (HM) in a rural part of Turkey. According to this study, the frequency of HM was lower than the frequencies reported by most of the hospital-based studies. In a national study, an inquiry form related to the approach to GTD was sent to obstetrics and gynecology departments. According to this study, a clinical classification system was used for gestational trophoblastic neoplasia by 60% of the hospitals. Methotrexate was the single-agent chemotherapy used most frequently. With regard to first-line combined chemotherapy, MAC (methotrexate, actinomycin, chlorambucil) was the preferred combination. EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, Oncovin) was the most commonly used second-line chemotherapeutic regimen. From more recent studies, EMA-CO is the first-line combination chemotherapy. There is no national registry system for GTD in Turkey. There appears to be a need to conduct properly designed community-based studies with well-established case registry system in Turkey.     

A case of a hydatidiform mole in a 56-year-old woman

A case of a 56-year-old woman with a mole pregnancy and a human chorionic gonadotropin (HCG)-induced thyreotoxicosis is presented. A proper diagnosis was only made after a period of patient and doctor's delay. After performing a hysterectomy, the HCG quickly normalized. Thyroid function normalized with thiamazol treatment. It is well known that older women have a higher risk to develop gestational trophoblastic disease (GTD). Furthermore, the chance of persistent trophoblastic disease is increased in this population. The literature on risk factors for developing persistent GTD and the possibilities for treatment in older patients is reviewed.     

妊娠滋养细胞疾病中EMT相关蛋白CK19和N-cad表达的研究

目的:探讨上皮细胞向间质转化(EMT)相关蛋白细胞角蛋白19(CK19)和神经钙黏蛋白(N-cad)在妊娠滋养细胞疾病发生、发展中的作用。方法:采用免疫组化SP法检测了41例正常早孕绒毛(NP)、31例葡萄胎(HM)、32例妊娠滋养细胞肿瘤(GTN)[26例侵蚀性葡萄胎(IM)+6例绒癌(CCA)]中CK19和N-cad的定位及表达情况。结果:NP组中CK19和N-cad蛋白相对表达均显著高于HM、GTN组(P0.05),HM组显著高于GTN组(P0.05)。CK19与N-cad的表达无相关性(r=0.202,P=0.268)。结论:伴随着滋养细胞恶性程度的升高,CK19和N-cad表达逐渐降低,提示EMT可能与滋养细胞的恶性转化有关。     

A familial case of recurrent hydatidiform mole with p.Asp108Ilefs130 causing mutation in KHDC3L: A genetic and clinical report

ObjectiveHydatidiform mole (HM) is defined by trophoblastic proliferation and vesicular enlargement of placental villi in which, KHDC3L gene plays a causal role.Case reportThis report presents a clinical review and genetic screening for p.Asp108Ilefs130 mutation in KHDC3L gene in an affected woman with a previous history of HM and three siblings with a history of HM. Pathological examination of molar pregnancy in proband confirmed a typical complete HM (CHM). Also, DNA extraction was done, polymerase chain reaction was carried out and then sequencing was performed by the Sanger sequencing method. The screened mutation was found in all three sisters in a homozygous state.ConclusionEgg donation is suggested for having viable children in these patients with the lowest risk of inadvertent damage.