Hydatidiform Mole Patients Research Articles

Pre-evacuation hCG glycoforms in uneventful complete hydatidiform mole and persistent trophoblastic disease

Objective To investigate whether the glycoform distribution patterns of human chorionic gonadotropin (hCG) obtained by chromatofocusing in pre-evacuation serum are different for patients who will eventually develop into persistent trophoblastic disease in case of complete hydatidiform mole pregnancy as compared to those patients for whom trophoblastic tissue will regress uneventfully. Methods Pre-evacuation blood samples were collected from women with complete hydatidiform mole with uneventful spontaneous regression after molar evacuation ( n = 32), from women with complete hydatidiform mole who developed persistent trophoblastic disease after evacuation of their mole ( n = 28) and, as a control group, from women during the first trimester of normal pregnancy ( n = 22). The serum specimens were subjected to chromatofocusing, and hCG was determined in the fractions collected in the pH range 7.0–3.0. Results Receiver operating characteristics (ROC) analysis revealed that 36% of complete hydatidiform mole patients with post-molar persistent trophoblastic disease development had different hCG glycoform profiles at 97% specificity (pH interval 6.3–5.1, hCG cutoff 9.9%). There was a significant difference between complete hydatidiform mole with and without persistent trophoblastic disease for the cumulative percent amounts of hCG in the pH interval 6.3–5.1 ( p < 0.0003). Conclusion In 36% of the patients with complete hydatidiform mole with subsequent development of persistent trophoblastic disease, typical glycoform profiles for hCG are observed in pre-evacuation serum samples. This result suggests that hCG glycoform profiles are of potential use in the prediction of persistent trophoblastic disease.

Low Molecular Mass Polypeptide-2 in Human Trophoblast: Over-Expression in Hydatidiform Moles and Possible Role in Trophoblast Cell Invasion

Embryo implantation involves invasion of placental extravillous trophoblast cell (EVTs) into the uterus. Hyperactive EVT invasion occurs in hydatidiform moles and choriocarcinomas. We have previously demonstrated that the 20S proteasome is involved in mouse embryo implantation and its action is mediated via regulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the EVTs. Our objective was to investigate whether low molecular mass polypeptide-2 (LMP2), a beta subunit of the 20S proteasome, is involved in the regulation of human trophoblast invasion. Normal human placentas or placentas from hydatidiform mole patients were collected and the expression of LMP2 in different cell types including trophoblastic column (TC), cytotrophoblast cells (CTB) and syncytiotrophoblast (STB) under different pathological states were studied by immunohistochemical analysis. Furthermore, the effect of LMP2 or proteasome on cell invasion was measured by using RNAi and inhibitors in a Matrigel invasion assay system in HTR-8/SVneo cells, a human invasive extravillous trophoblast cell line. Changes in the invasion-related molecules including MMP-2 and MMP-9 were also examined by using real time PCR and gelatin zymography. We demonstrated that the expression of LMP2 in TC of partial hydatidiform mole and complete hydatidiform mole, is higher than that in TC of normal human placentas. Besides, LMP2 knockdown significantly attenuated IL-1β-induced cell invasion in vitro, a response readily induced by proteasome inhibitors. In summary, over-expression of the 20S proteasome β-subunit LMP2 in trophoblast cells of hydatidiform moles may contribute to its highly invasive phenotype.

Recurrent gestational trophoblastic disease after hCG normalization following hydatidiform mole in The Netherlands

Objectives To determine the risk for recurrent trophoblastic disease after spontaneous normalization of human chorionic gonadotropin (hCG) levels in patients with hydatidiform mole and to determine the risk for tumor relapse after apparent remission following chemotherapy in patients with low- and high-risk persistent trophoblastic disease. Methods From 1994 until 2004, 355 patients with hydatidiform mole were registered at the Dutch Central Registry of Hydatidiform Mole and were monitored by sequential hCG assays in serum at the department of Chemical Endocrinology of the Radboud University Nijmegen Medical Centre. HCG regression curves were analyzed together with clinical information collected from the Hydatidiform Mole Database. Results Among the 355 registered hydatidiform mole patients, 265 patients attained spontaneous normalization following evacuation. Of the 265 patients, one patient (0.38%) subsequently required chemotherapeutic treatment for recurrent trophoblastic disease (95% confidence interval 0.0% to 2.1%). HCG levels did not decline to normal (< 2.0 ng/ml) spontaneously in 90 patients; those patients were subsequently treated. Relapse rates were 8.1% (6/74) and 6.3% (1/16) for the low- and high-risk category respectively. Conclusion Our analysis indicates that relapse risk in hydatidiform mole patients with spontaneous normalization is extremely low (one in 265 patients) after two normal hCG levels (< 2.0 ng/ml) are achieved. Our results support the suggestion that two subsequent normal hCG levels may be sufficient to ensure sustained remission after hydatidiform mole evacuation. In contrary, in order to assure sustained remission, the relapse rates after chemotherapy in the current study emphasize the need for surveillance of trophoblastic tumor patients even after complete remission has apparently been achieved.

Serum levels of zinc and copper in hydatidiform mole.

The aim of this study was to identify any association between serum levels of trace elements zinc and copper and development of hydatidiform mole. Blood samples of 35 patients with complete hydatidiform mole and 34 pregnant women controls were evaluated for serum levels of zinc and copper. Student's t-test was used for comparison of mean values of serum zinc and copper and for demographic variables. p< or =0.05 was considered statistically significant. Levels of zinc in serum were found to be significantly higher in hydatidiform mole patients than controls (86.3 vs. 68.7 microg/l, p=0.027). Serum copper levels were significantly lower in hydatidiform mole patients than controls (123.8 vs. 147.8 microg/l, p=0.039; Table 2). This is the first study in the English scientific literature reporting higher serum levels of zinc and lower serum levels of copper associated with complete hydatidiform mole.

Proliferation and differentiation of human first trimester cytotrophoblast in vitro

Embryo implantation involves invasion of placental extravillous trophoblast cell (EVTs) into the uterus. Hyperactive EVT invasion occurs in hydatidiform moles and choriocarcinomas. We have previously demonstrated that the 20S proteasome is involved in mouse embryo implantation and its action is mediated via regulating the expression and activities of matrix metalloproteinase (MMP)-2 and MMP-9 in the EVTs. Our objective was to investigate whether low molecular mass polypeptide-2 (LMP2), a beta subunit of the 20S proteasome, is involved in the regulation of human trophoblast invasion. Normal human placentas or placentas from hydatidiform mole patients were collected and the expression of LMP2 in different cell types including trophoblastic column (TC), cytotrophoblast cells (CTB) and syncytiotrophoblast (STB) under different pathological states were studied by immunohistochemical analysis. Furthermore, the effect of LMP2 or proteasome on cell invasion was measured by using RNAi and inhibitors in a Matrigel invasion assay system in HTR-8/SVneo cells, a human invasive extravillous trophoblast cell line. Changes in the invasion-related molecules including MMP-2 and MMP-9 were also examined by using real time PCR and gelatin zymography. We demonstrated that the expression of LMP2 in TC of partial hydatidiform mole and complete hydatidiform mole, is higher than that in TC of normal human placentas. Besides, LMP2 knockdown significantly attenuated IL-1β-induced cell invasion in vitro, a response readily induced by proteasome inhibitors. In summary, over-expression of the 20S proteasome β-subunit LMP2 in trophoblast cells of hydatidiform moles may contribute to its highly invasive phenotype.

Pregnancy zone protein: a re-evaluation of serum levels in healthy women and in women suffering from breast cancer or trophoblastic disease

Pregnancy zone protein (PZP) and alpha 2-macroglobulin (alpha 2M) serum concentrations were studied in healthy female donors, in women suffering from benign and malignant breast tumours, and in relation to normal and abnormal pregnancies. PZP was found to be useless as a tumour marker. Thus, PZP levels in breast cancer patients did not differ from those of fibroadenoma patients or healthy women. There was no correlation between PZP (or alpha 2M) concentrations and the pTNM-classification or metastatic burden of the breast cancer patients. Moreover, PZP levels were unaffected by cancer treatment and the course of disease. Neither patients nor control donors showed any age-dependent increase in circulating PZP and the mean serum value (8.38 +/- 4.83 mg/l, mean +/- SD) determined in a population of 154 non-pregnant women was considerably lower than that of most previous reports. Serum concentrations were unchanged during the normal menstrual cycle, but increased during pregnancy. However, late pregnancy sera (35th gestational week) contained significantly less PZP than previously reported by others, and non-pregnancy levels were observed in one out of 22 cases. Results obtained in hydatidiform mole patients were similar to findings in normal pregnancy. Neither serum 17 beta-oestradiol nor morphological differentiation between complete and partial mole showed any correlation with circulting PZP levels. Apart from a moderate increase during gestation, alpha 2M concentrations showed little variation between the populations examined.

Specific Inhibitory Substance to the Husband's HLA Allotype in Sera From Patients With Gestational Trophoblastic Disease Detected by Lymphocytotoxicity Testing

The sera of nine patients with gestational trophoblastic disease were investigated for the inhibitory substance specific to the HLA allotypes of the patients' husbands by microcytotoxicity inhibition testing using monoclonal antibodies (anti-A2, A9, A10) and HLA-typing serum to Bw52. The specific inhibitory substance was present in three of three choriocarcinoma patients, in three of four invasive mole patients, and in one of two hydatidiform mole patients and seemed to change in titer parallel with tumor growth. These facts suggest that the inhibitory substance could have some relation to the patient's immunological response against the tumor; that is, this inhibitory substance could be the reason why patients could not induce graft rejection response to trophoblastic tumor cells.

Plasma 19‐Hydroxyandrostenedione and Androstenedione Levels in Hydatidiform Moles and Early Pregnancies With and Without Hypertensive Diseases

Because of the association of preeclampsia with hydatidiform mole, and since levels of 19-hydroxyandrostenedione (19-OH-A) and androstenedione (A) are raised in hypertensive diseases of pregnancy, we compared plasma 19-OH-A and A in hydatidiform mole patients with control early pregnant women. Both steroids were significantly elevated in 27 patients with partial or complete hydatidiform moles, as compared with the levels in 36 control pregnancies at similar stages of gestation.

Placental protein 21. Localization in human placenta and concentrations in the body fluids of men and nonpregnant and pregnant women.

The immunohistochemical localization of placental protein 21 (PP21) was marked in the syncytial brush border and basal membrane during the 1st and 2nd trimesters of pregnancy and also in the chorionic epithelial brush border and basement membrane at term. A weaker stain was found in the cell membranes of amniotic epithelial and chorionic trophoblast cells. Neither heparin nor changes in temperature significantly influenced PP21 concentration. Relatively high serum PP21 concentrations were measured during the follicular and luteal phases in healthy nonpregnant women and in healthy men whose seminal plasma also showed a high PP21 concentration. Serum PP21 levels in normal pregnancy rose from a median of 29.1 ng/ml at 6-7 weeks of gestation to 82.0 ng/ml at 36-37 weeks of gestation. Although maternal urine showed low PP21 levels during pregnancy, amniotic fluid PP21 levels were higher at 7-21 weeks of gestation than at term. Cord blood sera showed almost the same PP21 concentration as maternal sera, but retroplacental blood showed much higher levels. Maternal serum PP21 levels in hydatidiform mole patients did not differ from the normal pregnancy range, although their molar vesicular fluids contained higher PP21 concentrations. These results suggest an extraplacental source for PP21.