Malignant Trophoblastic Disease Research Articles

Actinomycin-D vs Methotrexate in Low-Risk Gestational Tropoblastic Neoplasia: Which is the better option?

Background Low-Risk Gestational Trophoblastic Neoplasia (LRGTN) is a malignant trophoblastic disease that can be cured with the proper management. Actinomycin-D (ACT) and Methotrexate (MTX) have been used as a single drug regimen for LRGTN. Therefore, this study aims to compare the efficacy and safety of ACT-based regimen and MTX-based regimen for LRGTN treatment. Methods Electronic databases were systematically searched for Randomized Controlled Trials (RCTs) and High-Quality Non-Randomized Controlled Trials (Non-RCTs) comparing ACT with MTX for patients with LRGTN. Studies were fully screened, extracted, and assessed. Studies without Complete Remission (CR) were excluded. The meta-analysis was carried out to quantify the efficacy and safety of each ACT and MTX regimens based on odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: In total, 8 RCTs and 14 non-RCTs were included (2203 patients). Our study concludes that ACT has a higher CR than MTX (79.4% [716/902] vs 66.9%[871/1301]; OR 2.13; 95% CI 1.46-3.10, in the random-effects model). Furthermore, ACT is better in terms of efficacy compared to MTX in both the RCTs [81.2% (259/319) vs 66.1% (199/301); OR 2.17; 95% CI 1.49-3.16, in the fixed-effects model] and non-RCTs group [457/583 (78.4%) vs 672/1000(67.2%); OR 2.10; 95% CI 1.28-3.45, in the random-effects model]. Safety wise, the use of ACT has a higher incidence of alopecia (OR 3.52, 95% CI: 1.27-9.75, in the random-effects model) compared to MTX while MTX has a higher risk of developing liver toxicity (OR 0.54, 95% CI: 0.32-0.91, in the fixed-effects model) compared to ACT. Other side effects are not significantly different between the two groups. Conclusion: Our meta-analysis concluded that ACT has a better efficacy compared to MTX for LRGTN patients. In terms of safety, ACT-based regimens have a higher chance of suffering from alopecia and a lower chance of suffering from liver toxicity. Future clinical studies on single-drug regimens for LRGTN should be conducted in order to produce higher-quality data. Keywords: Methotrexate, MTX, Dactinomycin, Actinomycin-D, ACT, Low-Risk Gestational Trophoblastic Neoplasia, LRGTN

Malignant trophoblastic disease: a rare tumor requiring personalized treatment. Stateof-the-art

Gestational trophoblastic disease (GTD) is a rare tumor characterized by spectrum of trophoblastic proliferative disorders associated with pregnancy. These neoplasms occur in less than 1% of female genital malignancies. There is a high curability of the disease even in the presence of disseminated process with the ability to preserve reproductive function. However, this is possible if timely diagnosis and adequate treatment tactics were applied. The article presents a review of the literature and the summary of guidelines of treatment of this malignancy.

Non-gestational choriocarcinoma as a cause of heavy menstrual bleeding-potential: Primary care detection

Choriocarcinoma is a malignant trophoblastic disease. It can be divided into gestational and non-gestational type. Gestational choriocarcinoma consists of less than 1% of total endometrial malignancy, and usually is diagnosed via histopathological examination preceding a suspected molar pregnancy. In contrast to gestational choriocarcinoma, only a few cases of primary non-gestational choriocarcinoma were reported in literature reviews. The reported locations for primary non-gestational choriocarcinoma were ovarian and uterine cervix. Due to its low incidence, this disease is often overlooked leading, to delayed diagnosis. In primary care practice, heavy menstrual bleeding is a common presentation. Further evaluations, such as full blood count, ultrasound pelvis or hysteroscopy are usually required. We would like to report a case of potentially earlier detection of non-gestational choriocarcinoma in a 52 years old lady who was presented with heavy menstrual bleeding for a duration of one year. Her symptom persisted despite receiving medical treatment in a few local primary care clinics. She was admitted to a tertiary hospital for symptomatic anaemia which required blood transfusion. Further evaluations, (i.e., laboratory tests, ultrasound, Computed Topography (CT) scan, bone scan, hysteroscopy and laparotomy total abdominal hysterectomy and bilateral salphingo-oophorectomy (TAHBSO) and histological examination) concluded a diagnosis of primary non-gestational choriocarcinoma of fundal uterus with lung metastasis.
 Bangladesh Journal of Medical Science Vol.19(4) 2020 p.755-759

Gestational Trophoblastic Neoplasia: A Tunisian Multicenter Study

Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization. It includes benign trophoblastic disease (hydatidiform moles (HM) and the malignant trophoblastic diseases or gestational trophoblastic neoplasia (GTN). The frequency of the GTD in Tunisia is one per 918 deliveries. The aim of this study is to analyze the clinical characteristics, treatment and outcomes of GTD at Salah Azaiez Institute (ISA). Medical records of women diagnosed with GTD at ISA from January 1, 1981 to December 31, 2012 were retrospectively reviewed. FIGO (International Federation of Gynecology and Obstetrics) score was determined retrospectively for patients treated before 2002 One hundred and nine patients with GTN were included. Patients presented with metastases at 43% of cases. The most common metastatic sites was lung (30%) and vagina (13%). 56 (51%) patients had low-risk and 21 (19%) cases had high-risk, the FIGO score was not assessed in 32 cases. After a median follow-up of 46 months, 21 patients were lost to follow-up, 12 patients died, 19 progressed and 8 relapsed. At 10 years, the OS rate was 85% and the PFS rate 79%. OS was significantly influenced by the presence of metastases at presentation (M0 100 % vs. Metastatic 62 %; p < 0.0001), FIGO stage (I-II 100% VS 61% and 65% for stage III and IV; p < 0.001), FIGO score (low-risk 99 % vs. high-risk 78 %; p < 0.001). GTN is a significant source of maternal morbidity with increased risk of mortality from complications if not detected early and treated promptly.

Gestational trophoblastic neoplasia: experience at Salah Azaiez Institute.

Gestational trophoblastic disease (GTD) develops from abnormal cellular proliferation of trophoblasts following fertilization. It includes benign trophoblastic disease (hydatidiform moles (HM)) and the malignant trophoblastic diseases or gestational trophoblastic neoplasia (GTN). The frequency of the GTD in Tunisia is one per 918 deliveries. The aim of this study is to analyze the clinical characteristics, treatment and outcomes of GTD at Salah Azaiez Institute (ISA). Medical records of women diagnosed with GTD at ISA from January 1st, 1981 to December 31st, 2012 were retrospectively reviewed. FIGO score was determined retrospectively for patients treated before 2002. One hundred and nine patients with GTN were included. Patients presented with metastases at 43% of cases. The most common metastatic sites were lung (30%) and vagina (13%). Fifty six (56 (51%) patients had low-risk and 21 (19%) cases had high-risk, the FIGO score was not assessed in 32 cases. After a median follow-up of 46 months, 21 patients were lost to follow-up, 12 patients died, 19 progressed and 8 relapsed. At 10 years, the OS rate was 85% and the PFS rate 79%. OS was significantly influenced by the presence of metastases at presentation (M0 100 % vs. Metastatic 62 %; p < 0.0001), FIGO stage (I-II 100% VS 61% and 65% for stage III and IV; p < 0.001), FIGO score (low-risk 99 % vs. high-risk 78 %; p < 0.001). GTN is a significant source of maternal morbidity with increased risk of mortality from complications if not detected early and treated promptly.

Lumpers and Splitters: The Debate Continues

To the Editor: In a 2009 Q&A, Glenn Braunstein said that in the field of human chorionic gonadotropin (hCG), “… there are ‘lumpers’ and ‘splitters.’ Lumpers want a single test that measures all of the hCG-related molecular variants, ideally in equimolar quantities. This would be the only test they would use to diagnose and monitor pregnancy, gestational and nongestational trophoblastic disease, and hCG (or variant)-producing nontrophoblastic tumors. As the tumor grows, the markers rise, as it shrinks, the markers fall. The splitters want to have separate assays that are highly specific for the different variants because the type of variant or the ratios of some the variants to each other may provide some additional diagnostic information, such as the differentiation of benign or malignant trophoblastic disease” (1). I was reminded of this quote when I read …

Gestational trophoblastic disease in Abuth Zaria, Nigeria: A 5-year review

Gestational trophoblastic diseases (GTD) includes a spectrum of diseases (tumor or tumor-like conditions) characterised by aberrant growth and development of the trophoblasts that may continue even beyond the end of pregnancy. It encompasses the benign trophoblastic disease (complete and partial moles), and the malignant trophoblastic diseases including the invasive mole (chorioadenoma destruens), choriocarcinoma, and Placental Site Trophoblastic Tumor (PSTT). This study was to determine the prevalence, risk factors, clinical presentation, diagnosis, treatment options and outcomes of GTD in Ahmadu Bello University Teaching Hospital (ABUTH) Zaria. A five-year retrospective study of patients with GTD managed at ABUTH, North-west Nigeria, from 1 st January 2008 to 31 st December, 2012 was undertaken. Data of all cases of GTD in the hospital over the 5 year period were obtained. The gynaecology ward and labour ward registers also provided information on the total number of gynaecological admissions and deliveries respectively. The data processing and analysis were carried out using the SPSS software version 16. The data obtained were expressed in percentages, means, and standard deviations. During the period of study there were 8,138 deliveries and 2,453 gynaecological admissions. There were 59 cases of GTD with 41 having choriocarcinoma, 18 molar pregnancies and no case of invasive mole or PSTT. Out of the 41 case folders retrieved, 23 were choriocarcinoma and 18 of molar pregnancies. The prevalence of GTD was 7.2 per 1000 deliveries (0.72% or 1 in 138 deliveries) and constituted 2.4% of gynaecological admissions. Hydatidiform mole (HM) occurred in 1 in 452 deliveries and choriocarcinoma occurred in 1 in 198 deliveries. Ages ranged from 19-49 years with mean of 32.5+ 5.0 years. Most (66.7%) cases of HM were 19-29years while 60.9% of choriocarcinoma cases were 30-39years. Majority of cases were multiparous. The antecedent events predating choriocarcinoma were Hydatidiform mole (31.7%), abortions (29.3%) and 2.4% followed term pregnancy. History of amenorrhea was present in all cases while vaginal bleeding occurred in 97.6%, pallor (87.8%), hyperemesis gravidarum (48.8%) and 4.9% came in shock. Consequently, common complications reported were haemorrhage (90.2%), anemia (87.8%) and shock (12.2%). Pregnancy test was positive in 90.2% of cases and serum beta hCG was done in 24.4% with more than half having a level >12,000miu/ml. All patients had pelvic ultrasound scan and snowstorm appearance occurred in 41% of benign GTD cases. Histology was used to confirm 56.1% cases of choriocarcinoma and 43.9% of molar gestation. Most (94.4%) of HM had suction evacuation while 95.6% of choriocarcinoma cases had chemotherapy, one case (2.4%) had Total Abdominal Hysterectomy. Contraception was used in 78% and common methods were male condom (41.5%) and 36.6% used combined oral contraceptive pills. Less than half (43.9%) had follow up for 6 months and 9.8% were seen for more than a year. Eight patients had subsequent pregnancies and there was one death in the series giving a case fatality of 2.4%. Gestational trophoblastic disease is a significant source of maternal morbidity with increased risk of mortality from complications if not detected early and treated promptly.

Antibody Recognition of a Human Chorionic Gonadotropin Epitope (hCGβ66–80) Depends on Local Structure Retained in the Free Peptide

Human chorionic gonadotropin (hCG) is an important biomarker in pregnancy and oncology, where it is routinely detected and quantified by specific immunoassays. Intelligent epitope selection is essential to achieving the required assay performance. We present binding affinity measurements demonstrating that a typical β3-loop-specific monoclonal antibody (8G5) is highly selective in competitive immunoassays and distinguishes between hCGβ(66-80) and the closely related luteinizing hormone (LH) fragment LHβ(86-100), which differ only by a single amino acid residue. A combination of optical spectroscopic measurements and atomistic computer simulations on these free peptides reveals differences in turn type stabilized by specific hydrogen bonding motifs. We propose that these structural differences are the basis for the observed selectivity in the full protein.

Elimination of Complement Interference in Immunoassay of Hyperglycosylated Human Chorionic Gonadotropin

To the Editor: Hyperglycosylated human chorionic gonadotropin (hCG-h)1 is the major form of hCG occurring in early pregnancy and trophoblastic disease, whereas the glycans are smaller in hCG produced later in pregnancy (1, 2). hCG-h can be measured by immunoassays based on monoclonal antibody B152, which reacts with a type 2 core O-glycan attached to Ser132 and surrounding peptide structures but not with hCG lacking this glycan or having a type 1 core O-glycan in this position (3). In early pregnancy, reduced hCG-h concentrations in urine have been associated with early pregnancy loss (2), whereas increased concentrations at 9 to 12 weeks have been associated with Down syndrome (1). A high proportion of hCG as hCG-h is useful in diagnosing malignant trophoblastic disease (4). These results need to be confirmed, but an earlier-version assay for hCG-h is not presently available (5). We developed a time-resolved immunofluorometric assay that uses B152 and found that serum contains factors that interfere with the assay to cause falsely low results. We demonstrated B152 to be an IgG2a antibody (Mouse Monoclonal Isotype Kit; Serotec, http://www.abdserotec.com), which interacts with complement to decrease its binding …

Non-Metastatic Malignant Trophoblastic Disease (NMTD) Treated by Combination of Surgery and Chemotherapy (1964-1970)

The result of treatment of choriocarcinoma by surgery plus cytostatics was compared with that by chemotherapy alone. Though the combined therapy was superior to chemotherapy alone, it however deprived the patient the chance for further pregnancy. Twenty six out of 57 cases responded well to cytostatics and had delivered full term normal, healthy babies. The response to MIX alone before and after hysterectomy was the same.

Prophylactic Use of Methotrexate and 6-Mercaptopurine for Prevention of Choriocarcinoma Following Molar Pregnancy

Prophylactic methotrexate therapy given to 33 cases of hydatidiform mole reduced the incidence of malignant trophoblastic disease from 17.3 per cent to 6.1 per cent and prevented the development of choriocarcinoma without producing any mortality. Toxic effects were more common with oral as compared with intramuscular administration. Two cases of hyperpyrexia are described, and one was further complicated by endotoxin shock. The number of courses of methotrexate given varied from one to five courses, depending on the pattern of H.C.G. excretion. Chemotherapy was discontinued when urinary gonadotrophin fell below 100 m.u.u. per 24 hours.

Influence of different distinct differentiation of trophoblastic cells on binding characteristics of targeted microbubble contrast agents in vitro

Objective In this study, we investigated the in vitro binding capacity of β-HCG antibody targeted SonoVue® microbubbles to trophoblasts with distinct differentiation in order to explore the possibility of utility of targeted SonoVue® microbubbles imaging for early locating diagnosis of malignant trophoblastic cell disease.

Hyperglycosylated hCG in the Management of Quiescent and Chemorefractory Gestational Trophoblastic Diseases

Abstract Introduction The literature shows that hyperglycosylated hCG is the invasion stimulus in malignant gestational trophoblastic diseases. The USA hCG Reference Service has characterized 2 gestational trophoblastic disease conditions marked by low proportion of hyperglycosylated hCG. These are quiescent gestational trophoblastic disease, defined as inactive or benign invasive disease, and minimally invasive gestational trophoblastic disease, defined as slow growing or chemorefractory disease with hCG increasing very slowly (doubling rate 2–6 weeks). Here we examine the USA hCG Reference Service experience with both diseases. Methods Patient were referred to the USA hCG Reference Service, 133 cases shown to have quiescent gestational trophoblastic disease, 35 cases with aggressive and 30 with minimally invasive gestational trophoblastic disease. Results Quiescent or inactive gestational trophoblastic disease was demonstrated in 133 women. In 127 of these cases, no hyperglycosylated hCG was detected, and in 6 cases 4–27% hyperglycosylated hCG was detected. This is quiescent or inactive disease. Only 1 of 35 cases with aggressive gestational trophoblastic disease (>40% hyperglycosylated hCG) was chemorefractory. In contrast, 30 of 30 minimally invasive cases ( 3000 IU/L before commencing chemotherapy. This was successful in 10 of 10 minimally invasive cases. Discussion Measurement of hyperglycosylated hCG or invasiveness is a critical step in management of invasive gestational trophoblastic disease. Quiescent of inactive gestational trophoblastic disease requires no therapy. Minimally invasive disease in chemorefractory. The USA hCG Reference Service experience suggests waiting until hCG exceeds 3000 IU/L before commencing any chemotherapy.

Gestational choriocarcinoma arising from a cornual ectopic pregnancy: a case report and review of the literature

Gestational choriocarcinoma associated with ectopic pregnancy is an extremely rare event. We report a case of a choriocarcinoma arising from a cornual pregnancy. The patient is a 35-year-old G8 P2052 who was referred to our department due to failure of treatment for a suspected ectopic pregnancy. The patient had initially been treated with methotrexate injection but her beta-hCG levels reached a plateau 3 weeks later and, despite another two methotrexate injections, started to rise. The patient underwent dilation and curettage that did not reveal any trophoblastic tissue. A diagnostic hysteroscopy that followed demonstrated occluded ostia of the left tube. The patient subsequently underwent diagnostic laparoscopy that revealed a mass in the left cornua, which was removed with wedge-wide resection. Histologic evaluation revealed choriocaricnoma. Appropriate monitoring of beta-hCG titers following conservative management of suspected ectopic pregnancy is important, not only to diagnose persistent ectopic gestation, but also to rule out the presence of malignant trophoblastic disease, albeit the latter is a rare diagnosis.

Malignant gestational trophoblastic disease: a review of seventeen cases

Malignant gestational trophoblastic disease: a review of seventeen cases

Choriocarcinoma – postdisease ultrasonographic findings

This is a case report of consequences that malignant gestational trophoblastic disease (GTD) can cause on reproductive health protruding into uterine wall and damaging uterine tissue. Transvaginal Doppler ultrasound examination can be of great value in detecting molar tissue, protrusion of malignant trophoblast in uterine wall, and neovasularization in malignant tissue. It is expected to measure a low resistance index in a field of neovascularization, because neovascularization in malignancy is not rare and those vessels do not have muscular stratum. This case is an example of possible irreversible serious and large damages that can be seen after successful treatment of GTD. They are warning on possible high degree of malignancy in GTD as well as on possible serious impact on reproductive health.

Malignant gestational trophoblastic disease presenting as extradural mass

Malignant gestational trophoblastic disease presenting as extradural mass

Unusual presentation of choriocarcinoma

BackgroundChoriocarcinoma is an aggressive neoplasm arising in the body of the uterus. The disease normally spreads to lung and brain.Case ReportA case of malignant trophoblastic disease with brain metastasis, raised intra cranial pressure and small bowel metastasis presenting with acute abdomen is reported.ConclusionsMalignant transformation in a hydatidiform mole is rare event. Involvement of gastrointestinal tract is rarer even in presence of disseminated disease. Surgery is the treatment of choice for gastrointestinal complications.

Altered Mitochondrial Gene Expression in Human Gestational Trophoblastic Diseases

To assess the molecular basis of phenotypic alterations present in the gestational trophoblastic diseases (GTDs) and to identify genes whose expression is specifically associated with these placental proliferative disorders we performed differential display (DD) techniques. This strategy resulted in the isolation of four mitochondrial transcripts downregulated in benign, as well as in malignant, trophoblastic diseases encoding the cytochrome oxidase subunit I (COX I), the ATPase subunit 6, the 12S ribosomal RNA (12S rRNA) and the transfer RNA for phenylalanine (tRNAPhe).This expression pattern was confirmed by Northern blot in normal early placenta (NEP), complete hydatidiform mole (CHM), persistent gestational trophoblastic disease (PGTD) and the human choriocarcinoma derived cell line JEG-3. Quantification of mitochondrial DNA by dot blot indicated that these changes in expression were not associated with a significant alteration in the number of mitochondrial genome. In addition, a reduction in the mitochondrial transcription factor A (mtTFA) mRNA level was observed in benign as well as in malignant trophoblastic diseases in correlation with the decrease in the mitochondrial transcript levels. Furthermore, Western blot analysis for COX-I showed a close parallelism with the expression level of the cognate RNA. Taken together, these data demonstrate that a significant change in mitochondrial transcription is associated with the phenotypic alteration present in GTDs.

Choriocarcinoma developing after prolonged molar surveillance.

EDITORIAL COMMENT: This case, as the authors point out, illustrates yet again the unpredictability of the development of malignant trophoblastic disease especially after a hydatidiform mole. The editor is not an oncologist but has been interested in hydatidiform moles and their sequelae for more than 40 years. It would seem that the method of treatment of an evacuated or unevacuated hydatidiform mole in a multipara aged 44 years should consider ‘primary prophylactic hysterectomy’ as advocated by Professor Tow as a result of his analysis of a large series of patients in Singapore and analyzed in detail in his MD thesis. Had hysterectomy been performed in this patient following the diagnosis of a hydatidiform mole she would almost certainly have avoided the need for chemotherapy and the risks of metastatic choriocarcinoma. Readers are referred to the fourth paragraph of the summary of a study of 328 consecutive molar pregnancies in the State of Victoria during the 30 years 1940 to 1970, that ‘it is concluded that Tow's recommendation for primary prophylactic hysterectomy in patients over 40 is valid for this community’ (A). N.B.(A) Beischer NA, Bettinger HF, Fortune DW, Pepperell R. Hydatidiform mole and its complications in the State of Victoria. J Obstet Gynaecol Br Commonw 1970; 77: 263–276