The hydatidiform mole

ABSTRACT

The hydatidiform mole (HM) is a placental pathology of androgenetic origin. Placental villi have an abnormal hyperproliferation event and hydropic degeneration. Three situations can be envisaged at its origin: 1. The destruction/expulsion of the female pronucleus at the time of fertilization by 1 or 2 spermatozoa with the former being followed by an endoreplication of the male pronucleus leading to a complete hydatidiform mole (CHM) 2. A triploid zygote (fertilization by 2 spermatozoa) leading to a partial hydatidiform mole (PHM) but can also lead to haploid and diploid clones. The diploid clone may produce a normal fetus while the haploid clone after endoreplication generates a CHM 3. A nutritional defect during the differentiation of the oocytes or the deterioration of the limited oxygen pressure during the first trimester of gestation may lead to the formation of a HM.

In countries with poor medical health care system, moles (mainly the CHM) can become invasive or, in rare cases, lead to gestational choriocarcinomas.     

A controlled trial of Bestatin in hydatidiform mole

Summary A prospective randomized controlled trial was conducted to study whether Bestatin, an immunomodifier, can reduce the incidence of persistent gestational trophoblastic disease in patients with hydatidiform mole. A group of 21 patients (Bestatin group) received 30 mg Bestatin daily after evacuation of the hydatidiform mole. A second group of 23 patients (control group) did not receive any drug. Blood was taken for white cell counts, differential counts, lymphocyte subset counts (CD2⁺, CD4⁺, CD8⁺ and B cells) and natural killer cell activity before evacuation of the hydatidiform moles. The tests were repeated every 4 weeks after evacuation until the serum subunit of human chorionic gonadotropin (hCG) had returned to normal or until the patient had to receive chemotherapy because of persistent gestational trophoblastic disease. There was no significant difference in the age of the patients, the pre-evacuation serum hCG, or the gestational age between the two groups. Chemotherapy was needed by 6 patients in the Bestatin group (28.6%) and 3 patients in the control group (13%) because of persistent gestational trophoblastic disease. There was no significant difference in any of the immunological parameters between the two groups before or after evacuation. We conclude that Bestatin at this dosage does not improve the immunological functions or clinical outcome in patients with hydatidiform mole.     

Increased DNA damage in patients with complete hydatidiform mole

The pathologic mechanisms underlying the gestational trophoblastic diseases are largely unexplored, but are thought to involve oxidative damage to the maternal vasculature and also to the placenta. In this study we have assessed the plasma levels of total antioxidant response (TAR) and the levels of endogenous DNA damage--determined by the comet assay--in peripheral blood lymphocytes from 13 women with complete hydatidiform mole (CHM) and compared these with those of 12 healthy pregnant controls and 10 healthy non-pregnant controls. Significantly lower mean levels of plasma TAR were found in patients with CHM compared with healthy pregnant controls (1.08+/-0.29 versus 1.17+/-0.14 mmol Trolox Eq/L, p<0.05) and with healthy non-pregnant controls (1.08+/-0.29 versus 1.38+/-0.12 mmol Trolox Eq/L, p<0.05). Significantly higher mean levels of endogenous DNA damage were observed in patients with CHM than in healthy pregnant controls (234.5+/-50.74 versus 125.7+/-45.4 AU, p<0.05) or in healthy non-pregnant controls (234.5+/-50.74 versus 104.0+/-49.6 AU, p<0.05). We observed an inverse correlation between the plasma TAR and the levels of endogenous DNA damage (r=-0.64, p<0.01), in that the levels of oxidative damage to the DNA were found to parallel the decrease in the plasma TAR in the CHM group. These results reveal a relationship between the extracellular and intracellular (as reflected by damage to the DNA) levels of oxidation. Our observations suggest that there is a link between the increased levels of oxidative stress and the increase in endogenous DNA damage seen in patients with CHM, as compared with those seen in normal pregnancy. However, the nature of this link, and whether it is direct or indirect, remains to be explored.     

DNA diagnosis of hydatidiform mole using the polymerase chain reaction

Summary We have used the polymerase chain reaction (PCR) technique for the diagnosis of hydatidiform mole, a trophoblastic disease. For this, we targeted the hypervariable 3 flanking region of the APOB gene (APOB/ VNTR) because of its high heterozygosity index (0.61) in the Japanese population. We examined seven clinical cases which were tentatively diagnosed as hydatidiform moles. Five of these revealed DNA segments unique to the paternal APOB allele, allowing us to diagnose a complete mole. The PCR technique for targeting the APOB/VNTR appears useful for early diagnosis of hydatidiform mole.     

Homozygosity of a 6/18 translocation in a hydatidiform mole

In a complete mole the chromosome investigation revealed a reciprocal translocation 6/18 in a homozygous status. The chromosome polymorphisms of the conceptus could be derived from those of the father. The delineation of the karyotype of the conceptus is discussed. A previous pregnancy of the mother had also led to an abortion of a hydatidiform mole.     

Inhibin: a new circulating marker of hydatidiform mole?

OBJECTIVE--To define the concentrations of inhibin in serum and tissue of patients with hydatidiform mole and assess their value as a clinical marker of the condition. DESIGN--Prospective study of new patients with hydatidiform mole, comparison of paired observations, and case-control analysis. SETTING--A university hospital, two large public hospitals, and a private women''s clinic in Japan. PATIENTS--Seven consecutive referred patients seen over four months with newly diagnosed complete hydatidiform mole, including one in whom the mole was accompanied by viable twin fetuses (case excluded from statistical analysis because of unique clinical features). All patients followed up for six months after evacuation of molar tissue. END POINT--Correlation of serum inhibin concentrations with trophoblastic disease. MEASUREMENTS AND MAIN RESULTS--Serum concentrations of inhibin, human chorionic gonadotrophin, and follicle stimulating hormone were compared before and seven to 10 days after evacuation of the mole. Before evacuation the serum inhibin concentrations (median 8.3 U/ml; 95% confidence interval 2.4 to 34.5) were significantly greater than in 21 normal women at the same stage of pregnancy (2.8 U/ml; 2.1 to 3.6), and inhibin in molar tissue was also present in high concentrations (578 U/ml cytosol; 158 to 1162). Seven to 10 days after evacuation inhibin concentrations in serum samples from the same patients declined significantly to values (0.4 U/ml; 0.1 to 1.4) similar to those seen in the follicular phase of normal menstrual cycles. None of the four patients whose serum inhibin concentrations were 0.4 U/ml or less after evacuation developed persistent trophoblastic disease. Though serum human chorionic gonadotrophin concentrations declined after evacuation (6.6 x 10(3) IU/l; 0.8 x 10(3) to 32.6 x 10(3], they remained far higher than in non-pregnant women. Serum follicle stimulating hormone concentrations remained suppressed. CONCLUSIONS--In this small study serum inhibin concentrations higher than those found in the early follicular phase one to two weeks after evacuation of a hydatidiform mole seemed to be specific for persistent trophoblastic disease. Further data are needed to confirm these promising results.     

Partial hydatidiform mole in a pregnant chimpanzee (Pan troglodytes)

Until now, the occurrence of hydatidiform mole in non-human primates has not been documented. This report presents a case in which a stillborn fetus, associated with a partial hydatidiform mole, was found at necropsy in the uterus of a pregnant chimpanzee (Pan troglodytes) which had suddenly died. Hydropic swelling of the chorionic villi and proliferation of trophoblastic cells were present. The trophoblast was stained enzyme-immunohistochemically with human chorionic gonadotropin (hCG) and pregnancy-specific-β1-glycoprotein (SP1). The concentrations of hCG and SP1 in maternal serum were high, 1,350 mIU/ml and 1,000 ng/ml, respectively. The distribution of DNA content of the cytotrophoblast in the molar villi shifted from diploid to an aneuploid pattern. © 1993 Wiley-Liss, Inc.     

Expression of Fas/Fas ligand by decidual leukocytes in hydatidiform mole

Complete hydatidiform moles are entirely paternally derived and, therefore, represent a complete intrauterine allograft that might be expected to provoke an altered maternal immune response compared with that of normal pregnancy. Uterine decidua contains a large leukocyte population, of which 10%-20% are T lymphocytes. Fas ligand (FasL) expression by placental trophoblast may induce apoptosis of Fas+ lymphocytes, thereby facilitating immune tolerance and survival of the molar trophoblast. Our previous studies have shown an increase in activated CD4+ decidual T cells in molar pregnancy compared with normal pregnancy. This study was designed to characterize and quantitate Fas/FasL expression by decidual leukocytes in complete and partial hydatidiform mole compared with that in normal early pregnancy using single and double immunohistochemical labeling (i.e., avidin-biotin-peroxidase and avidin-biotin-alkaline phosphatase). A significant increase was found in Fas and FasL expression by decidual CD4+ T cells in complete (Fas+, P = 0.0106; FasL+, P = 0.0081) and partial (Fas+, P = 0.0131; FasL+, P = 0.0051) hydatidiform moles, as was a significant decrease in Fas expression by decidual CD8+ T cells in complete (P = 0.0137) and partial (P = 0.0202) hydatidiform mole compared with normal early pregnancy. The implications of altered Fas/FasL status of decidual T-cell subsets in hydatidiform mole are also discussed.     

Induction of labour with sulprostone after foetal death and in hydatidiform mole

Induction of uterine contractions was carried out with an intravenous infusion of sulprostone, a 16-phenoxy derivate of methylsulphonylamid prostaglandin E₂ in 21 patients after intrauterine foetal death and in seven patients having hydatidiform mole. The mean total dose of sulprostone was estimated as 1100–1300 μg in different groups. The mean induction-delivery time was 7–13 hours. Expellation of the foetus occurred in 20 out of 21 cases during 24 hours after commencement of sulprostone infusion. In all patients having molar pregnancy uterine contractions induced with sulprostone opened the uterine cervix for evacuation. The drug was clinically well tolerated without any serious side-effects.     

Analysis of p53 expression in partial hydatidiform mole and hydropic abortion

Background

Gestational trophoblastic disease (GTD) is a heterogeneous group of disorders characterized by abnormal trophoblast tissue. Molar and non-molar hydropic placental changes are the most common forms of GTD. Differential diagnosis of GTD is sometimes problematic. Recently, p53 expression was identified as a good marker for distinguishing GTD types.

Aims

Comparison of p53 expression in partial hydatidiform mole (PHM) and hydropic abortion.

Methods

In this prospective cross-sectional study, molar and non-molar hydropic pregnancy specimens were collected. Immunohistochemical staining, based on the Labeled Streptavidin Biotin (LSAB) technique, was carried out on multiple 4 mm paraffin block sections prepared from formalin-fixed trophoblastic tissues. Polymer-based Envision was used to assess p53 tumor suppressor protein immunoreactivity. p53 expression was then compared between both groups.

Results

In the study, 40 patients were included: 20 with confirmed PHM and 20 with hydropic pregnancy. p53 protein was positive in 60% of patients with PHM and 25% of patients with hydropic pregnancy. The p53 positive rate was significantly higher in patients with PHM (p = 0.027). Moreover, patients with PHM had a significantly high grade of staining (p<0.001).

Conclusion

Our findings indicate that immunohistochemical analysis of p53 protein can be used to distinguish PHM and hydropic pregnancy.

     

Kinetic analysis of 3 beta-hydroxysteroid dehydrogenase activity in microsomes from complete hydatidiform mole

Microsomes isolated from complete hydatidiform moles (CHM) were able to convert [3H]pregnenolone to [3H]progesterone which indicates the presence of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD) activity. The kinetic parameters found (Km = 0.63 microM and Vmax = 1-3.05 nmol/min/mg of protein) were like those observed in microsomes from normal early placenta (NEP) of similar gestational age (herein) and term placenta suggesting that the enzymes from the three sources are kinetically similar. Testosterone, progesterone and estradiol in a dose range of 0.05-5 mumol/l inhibited differently the in vitro conversion of [3H]pregnenolone to [3H]progesterone in a dose-dependent manner. The steroid concentrations necessary to inhibit the conversion of pregnenolone to progesterone by 50% (ID50) in CHM were 0.1 microM for testosterone, 0.6 microM for progesterone and 3 microM for estradiol, whereas in NEP they were 2.5, 1 and 5 microM respectively. The Ki values calculated from these ID50 in CHM together with the reported levels of endogenous steroids indicate that the accumulation of testosterone and progesterone inside the molar vesicle could physiologically regulate the rate of further conversion of pregnenolone to progesterone. The present findings could provide an explanation for the low level of progesterone in patients with CHM in the second trimester of pregnancy which in turn may directly or indirectly affect the spontaneous expulsion of this aberrant tissue.     

Purification and characterization of urinary choriogonadotropin from patients with hydatidiform mole.

Human choriogonadotropin was isolated from urine of patients with hydatidiform mole by acid and salt precipitation, immunoaffinity, and DEAE-Sephadex chromatography. Polyacrylamide gel electrophoresis, immunodiffusion, immunoelectrophoresis, and NH2-terminal amino acid analysis showed that the product obtained is essentially homogeneous. This choriogonadotropin was found to resemble the choriogonadotropin from urine of normal pregnant women in amino acid composition but to differ from it in having a lower content of N-acetylglucosamine and mannose.     

Cyclopia associated with triploidy and hydatidiform mole: a case report.

A live 22-week-old cyclops fetus with a 69 XYY chromosome pattern and partial hydatidiform mole of the placenta is reported. Although cyclopia and chromosomal triploidy have certain features in common they appear to be two quite distinct entities. As no other 69 XYY fetus has survived to 22 weeks gestation and no other case of cyclopia has been reported with a triploid set of chromosomes, the assumption that the two conditions occurred coincidently in this fetus will have to await the accumulation of additional case reports.