Development Of Gestational Trophoblastic Neoplasia Research Articles

Outcomes of Metastatic Gestational Trophoblastic Neoplasia: Fourteen Year Experience from a Northern Thailand Tertiary Care Center.

Metastatic gestational trophoblastic neoplasia (GTN) is an uncommon cancer. The principal treatment consists of chemotherapy with or without surgery or radiotherapy. We here retrospectively reviewed the outcomes of metastatic GTN treated at our institute between January, 1999 and December, 2013. Sixty-three patients met the criteria. The median age was 30.0 years and almost 90% were referral cases. Nearly 40% of the studied patients presented with vaginal bleeding while 22.2% were asymptomatic. The most common antecedent pregnancy was hydatidiform mole (57.1%) followed by term pregnancy (20.6%). The median interval time from antecedent pregnancy to the development of GTN was three months and the median pretreatment B-hCG was 58,274 mIU/ ml. Stage III (74.6%) was the most common staging followed by stage IV (20.6%) and stage II (4.8%). The most frequent surgery was hysterectomy (31.7%). Thoracotomy and craniotomy were performed in three and two patients, respectively. The most common first line chemotherapy regimen was methotrexate and folinic acid (36.5%) followed by EMA (etoposide, methotrexate, actinomycin D) (34.9%), EMACO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) (17.5%) with the remission rate of 66.7%. Nearly one-third of the patients were given a subsequent chemotherapy regimen after failure with the first line therapy and showed a final response rate of 73.0%. However, in stage IV, the response to first line treatment was only 38.5%. In conclusion, the outcomes of metastatic GTN were poor especially with the higher stages.

Clinical Presentation of Complete Hydatidiform Mole and Partial Hydatidiform Mole at a Regional Trophoblastic Disease Center in the United States Over the Past 2 Decades.

The aim of this study was to compare the clinical presentation and incidence of postmolar gestational trophoblastic neoplasia (GTN) among cases of complete mole (CM) and partial mole (PM) from 1994 to 2013. This study included all cases of patients with CM and PM from our trophoblastic disease center between 1994 and 2013. Their clinical and pathologic reports were reviewed. Gestational age at evacuation, features of clinical presentation, human chorionic gonadotropin levels, and the rate of progression to GTN were compared. The median gestational age at evacuation was 9 weeks for CM and 12 weeks for PM (P < 0.001). Patients with PM had lower pre-evacuation serum human chorionic gonadotropin levels (P < 0.001), and they were also less likely to present with vaginal bleeding (P < 0.001), biochemical hyperthyroidism (P < 0.001), anemia (P < 0.001), uterine size greater than dates (P < 0.001), and hyperemesis (P = 0.002). Consequently, patients with PM were less likely to have been clinically diagnosed as moles compared with CM prior to uterine evacuation (P < 0.001). The development of GTN occurred in 17.7% (33/186) and 4.1% (7/169) of patients with CM and PM, respectively (P < 0.001). This study indicates that, at our center over the past 20 years, both CM and PM were usually evacuated in the first trimester of pregnancy. Because CM more commonly presents with the signs and symptoms of molar disease than PM, CM is more commonly diagnosed prior to evacuation.

Is Doppler ultrasound useful for evaluating gestational trophoblastic disease?

Doppler ultrasound is a non-invasive method for evaluating vascularization and is widely used in clinical practice. Gestational trophoblastic neoplasia includes a group of highly vascularized malignancies derived from placental cells. This review summarizes data found in the literature regarding the applications of Doppler ultrasound in managing patients with gestational trophoblastic neoplasia.The PubMed/Medline, Web of Science, Cochrane and LILACS databases were searched for articles published in English until 2014 using the following keywords: “Gestational trophoblastic disease AND Ultrasonography, Doppler.”Twenty-eight articles met the inclusion criteria and were separated into the 4 following groups according to the aim of the study. 1 Doppler ultrasound does not seem to be capable of differentiating partial from complete moles, but it might be useful when evaluating pregnancies in which a complete mole coexists with a normal fetus. 2 There is controversy in the role of uterine artery Doppler velocimetry in the prediction of development of gestational trophoblastic neoplasia. 3 Doppler ultrasound is a useful tool in the diagnosis of gestational trophoblastic neoplasia because abnormal myometrial vascularization and lower uterine artery Doppler indices seem to be correlated with invasive disease. 4 Lower uterine artery Doppler indices in the diagnosis of gestational trophoblastic neoplasia are associated with methotrexate resistance and might play a role in prognosis.CONCLUSION:Several studies support the importance of Doppler ultrasound in the management of patients with gestational trophoblastic neoplasia, particularly the role of Doppler velocimetry in the prediction of trophoblastic neoplasia and the chemoresistance of trophoblastic tumors. Doppler findings should be used as ancillary tools, along with human chorionic gonadotropin assessment, in the diagnosis of gestational trophoblastic neoplasia.

Hormonal contraceptive use before hCG remission does not increase the risk of gestational trophoblastic neoplasia following complete hydatidiform mole: a historical database review.

To re-evaluate the safety of hormonal contraceptives (HC) after uterine evacuation of complete hydatidiform mole (CHM). Historical database review. Charing Cross Hospital Gestational Trophoblastic Disease Centre, London, United Kingdom. Two thousand four hundred and twenty-three women with CHM of whom 154 commenced HC while their human chorionic gonadotropin (hCG) was still elevated, followed between 2003 and 2012. We compared time to hCG remission between HC users and nonusers. The relationship between HC use and gestational trophoblastic neoplasia (GTN) development was assessed. The relationship between HC use and a high International Federation of Gynecology and Obstetrics (FIGO) risk score was determined. Time to hCG remission, risk of developing postmolar GTN and proportion of women with high FIGO risk score. No relationship was observed between HC use with mean time to hCG remission (HC users versus non-users: 12weeks in both, P=0.19), GTN development (HC users versus non-users: 20.1 and 16.7%, P=0.26) or high-risk FIGO score (HC users versus nonusers: 0% and 8%, P=0.15). Moreover, no association between HC and GTN development was found, even when an age-adjusted model was used (OR = 1.37, 95% CI 0.91-2.08, P=0.13). The use of current HC is not associated with development of postmolar GTN or delayed time to hCG remission. Therefore, HC can be safely used to prevent a new conception following CHM regardless of hCG level. Non-concurrent cohort study to re-evaluate the safety of low dose HCs after uterine evacuation of CHM.

Use of hormonal contraception after hydatidiform mole.

Effective contraception is important during monitoring of human chorionic gonadotrophin (hCG) levels after uterine evacuation for hydatidiform mole (HM), to avoid confusion between a rising hCG associated with ongoing gestational trophoblastic disease (GTD) and that resulting from a new pregnancy. Contraception should be started as soon as possible: conception can occur before menses are re-established. But how do women achieve effective contraception in the immediate aftermath of molar pregnancy? Typically, condom use is associated with an 18% contraceptive failure rate over a year of use. Intrauterine contraception has been avoided in GTD because of concerns about possible increased risk of bleeding and uterine perforation. Hormonal contraception (HC) is effective: the progestogen-only implant has a typical use failure rate of only 0.05% over a year, oral contraception 9% and injectables 6%. On discontinuation of HC (except injectables), there is a rapid return to fertility – important to many women after an episode of GTD. However, guidelines regarding use of HC during follow up of HM have been inconsistent. Royal College of Obstericians and Gynaecologists guidance (Green Top Guideline 38, London: RCOG; March 2010) recommended that HC be avoided until hCG levels normalised because of concern that use of combined HC after molar pregnancy might increase the risk of gestational trophoblastic neoplasia. However, a systematic review by Gaffield et al. (Contraception 2009;80:363–71) found no evidence of an effect of combined HC on the course of GTD after HM. On this basis, the 2009 World Health Organization Medical Eligibility Criteria for Contraceptive Use recommended that there should be no restriction on use of HC while hCG levels are elevated in GTD. In line with this, the Faculty of Sexual and Reproductive Healthcare (UK Medical Eligibility Criteria for Contraceptive Use, London: FSRH; 2009) and Centers for Disease Control (US Medical Eligibility Criteria for Contraceptive Use, Atlanta: CDC; 2010) advise that HC can safely be used while hCG remains elevated. In the current retrospective database study, Braga et al. find no association between use of HC started while hCG levels are still raised after uterine evacuation for complete HM and time to hCG regression, development of gestational trophoblastic neoplasia or FIGO risk score. The study includes 2423 women with complete HM. However, only 154 used HC (100 combined oral contraception, 43 progestogen-only pill, 11 progestogen-only injectable). Because numbers of women using each contraceptive were small, methods are considered together as ‘hormonal contraception’. The study is not powered to detect different effects of individual HC methods on GTD outcomes. Progestogen-only implants and non-oral combined contraceptives are not considered. Contraceptive method was not randomised. Prescribing might have been influenced by plateaued or rising hCG levels or by bleeding problems in the weeks following uterine evacuation so there is a potential prescribing bias. Despite its limitations, this study adds to the weight of evidence that suggests HC can safely be used after molar pregnancy before hCG levels normalise. Clinicians caring for women with a diagnosis of molar pregnancy should not forget about contraception and can advise women that the limited evidence is that HC is safe to start. None declared. Completed disclosure of interests form available to view online as supporting information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Outcomes of Non-Metastatic Gestational Trophoblastic Neoplasia: Twelve Year Experience from a Northern Thailand Tertiary Care Center.

Gestational trophoblastic neoplasia (GTN) is the malignant form of gestational trophoblastic disease. In non-metastatic GTN, the outcomes of treatment are impressive with methotrexate (MTX) or actinomycin D. We retrospectively reviewed the outcomes of non-metastatic GTN treated at our center from January, 1999 to December, 2013. One hundred and nine patients were recruited to the study. The median age was 33.1 years and over 90% were referral cases. Abnormal vaginal symptoms developed in 37.6% while 56.4% were asymptomatic. The most common antecedent pregnancy was a complete mole (92.7%) with the median interval time from antecedent pregnancy to GTN development being 2.0 months. The median pretreatment B-hCG was 5,624 mIu/ ml. The most common first line treatment was methotrexate (MTX) and folinic acid (91.7%) followed by weekly MTX (4.6%), etoposide+ MTX+actinomycin D (EMA) (2.8%), and actinomycin D (0.9%), with the median number of cycles at 5.0. The positive response to first line chemotherapy was 73.8%. The patients were given subsequent chemotherapeutic regimens after resistance to the first line therapy and showed a final remission rate of 89.9%.The significant factor that was frequently found in patients who were non-responders to the first line treatment was a hysterectomy procedure. Two patients developed lung metastasis and brain metastasis at one and four years after the first treatment, respectively. In conclusion, the outcomes of non-metastatic GTN were excellent. However, the patients need long term follow up due to the possibility of developing multiple organ metastases.

Ultrasound imaging after evacuation as an adjunct to β-hCG monitoring in posthydatidiform molar gestational trophoblastic neoplasia

The purpose of this study was to identify prognostic factors associated with development of gestational trophoblastic neoplasia (GTN) after hydatidiform mole (HM). A retrospective analysis of 189 patients with HM was performed. We recorded features such as maternal age, HM history, blood group, gestational age, uterine volume at evacuation, presence of theca lutein cysts, vaginal bleeding, and transvaginal ultrasonography with color Doppler imaging. We considered risk predictors to be the presence of nodules and hypervascularization within the myometrium or endometrium (positive ultrasound imaging). An univariate and multivariate analysis, with the COX nominal logistic model, was performed. Fourteen patients experienced GTN (7.4%). After univariate analysis, uterine size (P = .0139) and positive ultrasound results (P < .0001) were associated significantly with GTN development. At multivariate analysis, only positive ultrasound results maintained significance (likelihood ratio test: chi(2) = 0.0000). The risk of GTN is increased in patients with uterine involvement that is assessed by ultrasound imaging. None of the other prognostic factors that were evaluated was predictive of GTN development.

Overexpression of prostate stem cell antigen is associated with gestational trophoblastic neoplasia

Hydatidiform mole (HM) is the most common type of gestational trophoblastic disease. A proportion of patients with HM develop gestational trophoblastic neoplasia (GTN) requiring chemotherapy. The aim was to identify differentially expressed genes that are associated with development of GTN. Using cDNA microarray, differential expression of prostate stem cell antigen (PSCA) was identified in HMs that developed GTN compared with those that spontaneously regressed. Significant overexpression of PSCA RNA (P = 0.037) and protein (P < 0.05) in aggressive HM was verified by real-time polymerase chain reaction (PCR) and immunohistochemical analysis in 10 first-trimester placentas, 36 HM that subsequently regressed and 11 HM that developed GTN. A high level of PSCA expression was also found in three choriocarcinomas and three placental site trophoblastic tumours. A positive correlation was observed between PSCA expression and proliferation and apoptotic indices as assessed by Ki67 (P = 0.01), mcm7 (P = 0.001) and M30 (P = 0.016), as well as p53 (P < 0.01), p21(WAF1/CIP1) (P < 0.01) and mdm2 (P = 0.002) expression. Overexpression of PSCA is associated with development of GTN in HM. PSCA probably plays a role in the regulation of cell growth through p53-related signaling pathways.

Expression of CD44, E-cadherin, and antimetastatic protein nm23-H1 in complete hydatidiform moles

There is scant information about the expression of CD44 and E-cadherin, two cell adhesion molecules, and the antimetastatic protein nm23-H1, in complete hydatidiform moles. We measured the expression of these markers to determine their usefulness in predicting the development of invasive disease. We performed a retrospective study of 27 patients with complete hydatidiform moles, collecting clinical information including the patient's age, pre-evacuation hCG level, pathology, hCG monitoring, and the development of gestational trophoblastic neoplasia. Immunohistochemical staining for CD44, E-cadherin, and nm23-H1 was performed. CD44 expression was classified as positive or negative. For E-cadherin and nm23-H1, the intensity of expression was graded on a 0 to 3 scale. Chi-square or Fisher's exact testing was used to evaluate the relationship between these markers and the development of invasive disease. CD44 was expressed in 26% of cases. E-cadherin expression was 1+, 2+, and 3+in 8%, 33%, and 59% of cases, respectively. Nm23-H1 expression was 1+, 2+, and 3+in 4%, 11%, and 85% of cases. The risk of developing invasive disease did not correlate with the expression of CD44, E-cadherin, or nm23-H1. In this preliminary study, there is no relationship between CD44, E-cadherin, and nm23-H1 expression in complete hydatidiform moles and the risk of invasive disease. Other molecular markers predictive of invasive disease should be sought to limit hCG surveillance to those at risk.

Estrogen and progesterone receptors and telomerase enzyme immunohistochemical detection in gestational trophoblastic tumors

The purpose of this study is to evaluate the immunohistochemical detection of telomerase enzyme and estrogen receptor (ER) and progesterone receptor (PGR) in gestational trophoblastic neoplasia (GTN) and its clinical significance. Formalin-fixed paraffin blocks for 30 patients (24 with molar pregnancy, 3 with choriocarcinoma, and 3 with placental site trophoblastic tumor) as cases and six products of conception samples from patients with incomplete abortion as controls were included in the study. Immunohistochemical detection of the telomerase catalytic protein and ER and PGR was carried out using streptavidin-biotin-peroxidase method. All control tissues were negative for telomerase and ER expression, while five of six were PGR positive. Significant positive telomerase expression was detected in all gestational trophoblastic tumors (three of six partial moles, 12 of 18 complete moles, three of three choriocarcinomas, and two of three placental site trophoblastic tumors). Nine of 24 molar pregnancies were followed by GTN. Molar pregnancies followed by GTN were associated with higher serum beta-hCG (human chorionic gonadotrophic hormone), larger uterine size for gestational age, negative ER expression, negative PGR expression, and positive telomerase expression. All patients with molar pregnancy with negative telomerase expression (9 of 24) showed spontaneous regression after evacuation. Positive telomerase expression and its immunohistochemical detection are associated with the development of GTN. Negative telomerase expression is highly predictive of postmolar spontaneous regression. Patients with molar pregnancies with negative telomerase expression can be saved the long-term follow-up. ER and PGR expression do not show a significantly different pattern in molar tissues, while negative expression is associated with developing GTN. Cautions on the use of postmolar hormonal contraception may be unjustified.

Differential expression of insulin‐like growth factor binding protein 1 and ferritin light polypeptide in gestational trophoblastic neoplasia

Hydatidiform mole (HM), the most common type of gestational trophoblastic diseases, can be considered as placenta with abnormal chromosome composition with potential of malignant transformation. Few biologic markers can predict subsequent development of persistent gestational trophoblastic neoplasia (GTN) requiring chemotherapy. Suppression subtractive hybridization (SSH) combined with cDNA microarray was used to compare the differential expression pattern of HM that spontaneously regressed and that subsequently developed metastatic GTN. Tissue-specific chips were constructed from the subtracted cDNA libraries, followed by cDNA microarray analysis. Verification by quantitative RNA analysis by real-time polymerase chain reaction (PCR) and immunohistochemical analysis was performed in 23 genotyped complete HM. Sixteen differentially expressed transcripts were identified. Quantitative RNA analysis confirmed down-regulation of ferritin light polypeptide (FTL) (P = 0.037) and insulin-like growth factor binding protein 1 (IGFBP1) (P = 0.037) in HM that subsequently developed GTN when compared with those HM that regressed. Immunohistochemical analysis further confirmed reduced IGFBP1 protein (P = 0.03) expression in HM that developed GTN. Findings showed that reduced expression of genes related to cell invasion and immunosuppression, especially FTL and IGFBP1, were associated with development of GTN, and this finding may provide a better understanding of the pathogenesis of GTN. The potential application of FTL and IGFBP1 in management of patients with HM should be explored.

Id helix‐loop‐helix proteins are differentially expressed in gestational trophoblastic disease

To assess the expression of Id proteins in trophoblastic tissues and to correlate this with clinical parameters, proliferative and apoptotic indices as well as to related oncogene expression. Immunohistochemistry for Id1, Id2, Id3 and Id4 was performed on 83 trophoblastic tissues including 17 normal first-trimester placentas, seven term placentas, 47 hydatidiform moles (HM), and 12 spontaneous miscarriages. The four Id proteins were predominantly expressed in the villous and implantation site intermediate trophoblast. Expression of Id1 in HM was significantly higher than that in normal placenta (P = 0.0006) and spontaneous miscarriage (P = 0.0001) but did not correlate with subsequent development of gestational trophoblastic neoplasia (GTN). Id1 expression correlated with the proliferation index as assessed by MCM7 (P = 0.003) and Ki67 (P = 0.017) and with the apoptotic activity assessed by TUNEL (P = 0.001) and M30 CytoDeath antibody (P = 0.013). Moreover, the expression of Id1 correlated with the expression of p53 (P = 0.004), p21(WAF1) (/CIP1) (P = 0.003) but not with p16 (P = 0.107). Id proteins may play a role in the regulation of proliferative and apoptotic activity in trophoblastic tissue and are potentially useful in differentiating molar and non-molar gestation, but are not helpful in predicting GTN.

Promoter Hypermethylation of Multiple Genes in Hydatidiform Mole and Choriocarcinoma

The methylation status of genes in hydatidiform mole and choriocarcinoma and its significance is relatively unexplored. We investigated the methylation status of the promoter regions of six genes, p16, HIC-1, TIMP3, GSTP1, death-associated protein kinase (DAPK), and E-cadherin in 54 hydatidiform moles, five choriocarcinomas, and 10 first trimester placenta by methylation-specific polymerase chain reaction (PCR). Immunohistochemical expression of p16, TIMP3, and E-cadherin, and quantitative real-time RT-PCR of p16 was also performed. Among the six genes examined, the promoter region of four genes (E-cadherin, HIC-1, p16, TIMP3) in choriocarcinoma and three genes (E-cadherin, HIC-1, p16) in hydatidiform mole exhibited aberrant methylation whereas none was hypermethylated in normal placenta. There was a significant correlation between methylation and reduced expression of p16, E-cadherin, and TIMP3 (P < 0.001). Fifteen of the 54 patients with hydatidiform mole developed gestational trophoblastic neoplasia requiring chemotherapy. Promoter hypermethylation of p16 alone, or combined with E-cadherin, was significantly correlated to such development (P = 0.001, 0.0005, respectively). Hypermethylation of multiple genes, especially p16, might be related to the subsequent development of gestational trophoblastic neoplasia.

Morphologic Characteristics of the Interaction Between Normal Cytotrophoblasts and Their Malignant Counterpart in the Development of Trophoblastic Neoplasia

To define the biology of the tumor-host cell interaction with regard to cellular kinetics and morphologic changes during cell-cell interaction in an in vitro model of trophoblastic neoplasia. Using a coculture in vitro system of cytotrophoblasts and choriocarcinoma cells, we investigated the cellular kinetics and the morphologic changes in these interacting cells. A fully automatic time-lapse image system was used to record phase contrast images of the cocultured cells in a tissue culture chamber. To examine cytoskeletal structure, immunofluorescent-labeled antibodies against intermediate filaments were used. Slides were examined with a confocal laser scanning microscope and subjected to computed analysis. The choriocarcinoma cells attract normal cytotrophoblasts using what resembles pseudopodia to engulf the latter cells and thus form slow-growing colonies. In this process, new hybrid cells are formed, which can be differentiated from their original contributors by morphologic characteristics. This phenomenon supports our previous biochemical and molecular data on the role of cell-cell interaction in the complex process of cytotrophoblast transformation and the development of gestational trophoblastic neoplasia.

Serum Progesterone Monitoring in Post-Molar Surveillance

Serial serum progesterone and β human chorionic gonadotropin (βhCG) levels were measured during surveillance of 24 women at risk for development of gestational trophoblastic neoplasia (GTN) following evacuation of complete molar gestations. Six of the 24 patients developed post-molar GTN. The initial median progesterone level of 76 ng/ml in these six patients drawn at evacuation was significantly higher than the median of 18 ng/ml in those not developing GTN ( P = 0.026). Additionally, the serum progesterone decreased to <5 ng/ml within a week of evacuation in 16/18 patients without GTN. In 5/6 GTN cases, levels of progesterone remained >5 ng/ml for ⩾3 weeks of the surveillance period ( P < 0.05). Serum βhCG levels required 4-11 weeks of surveillance to distinguish between nonpersistent cases and GTN. We conclude that serial serum progesterone levels measured during post-molar surveillance parallel βhCG regression.