Complementary role of p57kip2 immunostaining in diagnosing hydatidiform mole subtypes.

OBJECTIVES: Gestational trophoblastic disease comprises of a spectrum of pregnancy-related tumours which includes complete (CHM) and partial hydatidiform moles (PHM). Accurate diagnosis and subclassification of HM subtypes are crucial as prognosis differs. Histopathological examination using haemotoxylin and eosin (H&E) staining remains the basis for diagnosing HM, with only 80% accuracy. p57kip2 is a cyclin-dependent kinase inhibitor (CDKI) protein and is strongly paternally imprinted, being expressed from maternal allele. Therefore, complete mole (CHM) with only paternal genome has nearly absent expression of p57kip2 compared to partial mole (PHM) having both paternal and maternal genomes. This study is aimed to determine usefulness of p57kip2 immunohistochemistry (IHC) analysis in the diagnosis of HM subtypes. METHODS: A total of 82 archived paraffin embedded HM tissues with subtypes classified based on H&E staining - 39 (47.5%) CHM, 41 (50.0%) PHM and two (2.43%) unclassified molar pregnancy were retrieved. All tissue samples were subjected for p57kip2 IHC analysis and HM subtypes were then reclassified. RESULTS: A total of 66 cases (80.5%) were re-classified as CHM, 14 cases (17.1%) as PHM and two cases (2.4%) were decidual and cystic tissues. Analysis using p57kip2 immunostaining showed a diagnostic discrepancy of 33.0% from routine H&E staining and helps to improve the characterisation of the HM subtypes specifically at early gestations which have less distinctive morphologies. CONCLUSIONS: IHC using p57kip2 monoclonal antibody should be considered as a routine ancillary test to H&E in improving the diagnosis of HM subtypes particularly in developing countries with limited resources.

Spermatogonium-Derived Complete Hydatidiform Mole.

A complete hydatidiform mole (CHM) is a conceptus with only sperm-derived chromosomes. Here, we report on a CHM with genomic DNA identical to that of the paternal somatic cells. The CHM developed in a woman who had undergone intrauterine implantation of a blastocyst obtained through in vitro injection of a presumed round spermatid into one of her oocytes. The CHM was genetically identical to peripheral white cells of her husband and contained no maternally derived nuclear DNA. We hypothesize that a spermatogonium, rather than a round spermatid, was inadvertently selected for the procedure. The CHM developed into a gestational trophoblastic neoplasia, which resolved after chemotherapy. (Funded by the Japan Society for the Promotion of Science.).

Partial hydatidiform mole in a phenylketonuria patient treated with sapropterin dihydrochloride.

Strict control of hyperphenylalaninemia is necessary in pregnant women with phenylketonuria (PKU) in order to prevent phenylalanine embryopathy in the fetus, characterized by intrauterine growth restriction, dysmorphic facies, congenital heart disease, microcephaly and intellectual disability, collectively known as maternal PKU syndrome. Sapropterin dihydrochloride (SD), an alternative or adjunct to dietary therapy in patients with tetrahydrobiopterin (BH4)-responsive PKU, has recently been used in several cases to treat PKU during pregnancy with satisfactory results. Here, we report two pregnancies treated with SD and unrestricted diet in a patient with BH4-responsive mild PKU. The first pregnancy resulted in a partial hydatidiform mole and was terminated, whereas a healthy infant was born from the second pregnancy. Phenylalanine control was optimal in both pregnancies. To the best of our knowledge, this is the first report on the development of partial hydatidiform mole associated with SD treatment and the second report on molar pregnancy in PKU. While the relation between SD and molar pregnancy is unknown, further studies may be needed to investigate the possible effects of SD on fertilization.

Effect of race/ethnicity on risk of complete and partial molar pregnancy after adjustment for age.

OBJECTIVE: To quantify the effect of race/ethnicity on risk of complete and partial molar pregnancy. METHODS: We conducted a cross-sectional study including women who were followed for complete or partial mole and those who had a live singleton birth in a teaching hospital in the northeastern United States between 2000 and 2013. We calculated race/ethnicity-specific risk of complete and partial mole per 10,000 live births, and used logistic regression to estimate crude and age-adjusted relative risks (RR) of complete and partial mole. RESULTS: We identified 140 cases of complete mole, 115 cases of partial mole, and 105,942 live births. The risk of complete mole was 13 cases per 10,000 live births (95% confidence interval [CI] 11-16) and that of partial mole was 11 cases per 10,000 live births (95% CI 9-13). After age-adjustment, Asians were more likely to develop complete mole (RR 2.3 95% CI 1.4-3.8, p<0.001) but less likely to develop partial mole (RR 0.2; 95% CI 0.04-0.7, p=0.02) than whites. Blacks were significantly less likely than whites to develop partial mole (RR 0.4; 95% CI 0.2-0.8, p=0.01) but only marginally less likely to develop complete mole (RR 0.6; 95% CI 0.3-1.0, p=0.07). Hispanics were less likely than whites to develop complete mole (RR 0.4; 95% CI 0.2-0.7, p=0.002) and partial mole (RR 0.4; 95% CI 0.2-0.9, p=0.02). CONCLUSION: Race/ethnicity is a significant risk factor for both complete and partial molar pregnancy in the northeastern United States.

Live-born diploid fetus complicated with partial molar pregnancy presenting with pre-eclampsia, maternal anemia, and seemingly huge placenta: A rare case of confined placental mosaicism and literature review.

A partial molar pregnancy almost always ends in miscarriage due to a triploid fetus. We describe a rare case of a singleton, partial molar pregnancy with a seemingly huge placenta, which continued to delivery of a live-born diploid baby. A 27-year-old primigravida suffered from severe pre-eclampsia and progressive anemia. The uterus was enormously enlarged for the gestational age. A cesarean section was performed because of deterioration of maternal status at 25 weeks' gestation, when more than 3000 mL blood spouted concurrently with the delivery of the placenta. The histological examination showed congestion in the decidua, which indicated disturbance of maternal venous return from the intervillous space. The chromosome complement of the placenta and the neonate were 69,XXX and 46,XX, respectively. We also reviewed all published cases of a singleton, partial molar pregnancy. A literature search yielded 18 cases of a singleton, diploid fetus with partial molar pregnancy. The mean gestational age at delivery was 24.5 ± 6.2 weeks, and fetuses survived outside the uterus in only four cases (22.2%). Intriguingly, previous reports numbered 10 cases with diploid placenta as well as five cases with no karyotyping of the placenta, indicating that they may have included a complete mole in a twin pregnancy or placental mesenchymal dysplasia. In conclusion, this was the first case of placentomegaly that presented manifestations of excessive abdominal distension and maternal severe anemia, and the second case of a singleton, partial molar pregnancy confirmed by chromosome analysis resulting in a diploid living baby.

[Abnormal Early Pregnancy: What Matters for Practice]. / Gestörte Frühschwangerschaft: Relevantes für die Praxis.

The first trim ester is referred to as early pregnancy and comprehends the lapse of time between conception and the end of the 12th week of gestation with embryo nic implantation and organogenesis. A pathological early gestation takes place when the embryo does not correctly implant in the cavity of the uterus (extrauterine pregnancy), when th ere is no growth of the embryo (missed abortion) or the embryo is not developing at all (blighted ovum) and sooner or later there is a miscarriage. A special case of missed abortion is the so called vanishing twin, when during a twin gestation, one embryo stops to grow. Rarely gestational trophoblastic disorders as the complete mole (without fetal tissue) or incomplete mole (with fetal tissue) and the invasive mole as villous trophoblastic diseases as well as the non-villous trophoblastic diseases with the extremely rare chorioniccarcinoma are detected.

Postmolar gestational trophoblastic neoplasia: beyond the traditional risk factors.

OBJECTIVE: To investigate the slope of linear regression of postevacuation serum hCG as an independent risk factor for postmolar gestational trophoblastic neoplasia (GTN). DESIGN: Multicenter retrospective cohort study. SETTING: Academic referral health care centers. PATIENT(S): All subjects with confirmed hydatidiform mole and at least four measurements of ß-hCG titer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Type and magnitude of the relationship between the slope of linear regression of ß-hCG as a new risk factor and GTN using Bayesian logistic regression with penalized log-likelihood estimation. RESULT(S): Among the high-risk and low-risk molar pregnancy cases, 11 (18.6%) and 19 cases (13.3%) had GTN, respectively. No significant relationship was found between the components of a high-risk pregnancy and GTN. The ß-hCG return slope was higher in the spontaneous cure group. However, the initial level of this hormone in the first measurement was higher in the GTN group compared with in the spontaneous recovery group. The average time for diagnosing GTN in the high-risk molar pregnancy group was 2 weeks less than that of the low-risk molar pregnancy group. In addition to slope of linear regression of ß-hCG (odds ratio [OR], 12.74, confidence interval [CI], 5.42-29.2), abortion history (OR, 2.53; 95% CI, 1.27-5.04) and large uterine height for gestational age (OR, 1.26; CI, 1.04-1.54) had the maximum effects on GTN outcome, respectively. CONCLUSION(S): The slope of linear regression of ß-hCG was introduced as an independent risk factor, which could be used for clinical decision making based on records of ß-hCG titer and subsequent prevention program.

The involvement of the trans-generational effect in the high incidence of the hydatidiform mole in Africa.

INTRODUCTION: While the incidence of various chromosomal anomalies observed, including triploid partial moles is independent of the socio-economic level, higher incidences of complete hydatidiform mole "CHM" is generally associated with under developed areas. Moreover, studies have shown that some nutritional deficiencies are related to the abnormal development of oocytes and placenta. In Senegal and Morocco, the annual seasonal cycle contains one period with food shortages and the incidence of complete moles is significant. Accordingly, accurate statistical analyses have been performed in these two countries. METHODS: Each month during a one year period, we investigated the occurrence of normal conceptions, molar conceptions and the conception of the future patients in Senegal and Morocco. The comparisons of the conception dates for these three types of conception were analyzed using the Chi-squared test. RESULTS: 94% of the patients were conceived just prior to the period in the year with food shortages. Consequently, the development of the female embryos occurred under nutritional constraints, which negatively affect the recruitment of the vital factors required for the normal synthesis of DNA, proteins and placental differentiation. DISCUSSIONS: A nutritional deficiency in the mother at conception of their daughter (future patient) is implicated in the higher incidence of CHM in their daughters' filiation. These nutritional deficiencies during the first weeks of pregnancy will have repercussions on the normal development of the oocytes. Accordingly, these developmental impairments take place during the embryonic life of the future mothers of complete moles and not during the conception of the moles themselves.

Novel NLRP7 mutations in familial recurrent hydatidiform mole: are NLRP7 mutations a risk for recurrent reproductive wastage?

OBJECTIVE: Familial recurrent hydatidiform mole is an exceedingly rare clinical condition. Affected women are predisposed to molar pregnancies of diploid, biparental origin rather than androgenetic origin. At present, NLRP7 and KHDC3L (C6orf221) are the only genes known to be associated with familial recurrent hydatidiform mole. This study investigated the genetic dispositions in two large Turkish families with recurring molar conceptuses. STUDY DESIGN: Copy number variation analysis was performed followed by NLRP7 gene sequencing. The finding of a mono-allelic condition in one family led to investigation of the adjacent NLRP2 gene and recently associated KHDC3L gene. Sampled molar tissues were genotyped using microsatellite markers. RESULTS: In one family, a homozygous single nucleotide insertion that caused a frameshift leading to an early stop codon, c.2940_2941insC (p.Glu981ArgfsX13), was identified in the affected sisters. In the other family, a heterozygous 60-kb deletion eliminating substantial portions of the NLRP2 and NLRP7 genes on one allele was found. Screening of NLRP2 and KHDC3L genes revealed no alterations that were considered to be pathological. Genotyping of six independent molar conceptions revealed that five were of diploid, biparental origin and one was of diandric, triploid origin. CONCLUSIONS: Two novel protein-truncating mutations in the NLRP7 gene were found to be associated with familial recurrent hydatidiform mole. Mutations in the NLRP7 gene causing recurrent biparental hydatidiform mole may also be associated with other forms of recurrent reproductive wastage.

Preditores moleculares de evolução da mola hidatiforme no tecido trofoblástico / Molecular prognostic predictors in trophoblastic tissue of hydatidiform mole

A mola hidatiforme (MH) é a forma mais comum de doença trofoblástica gestacional e representa uma condição benigna que em alguns casos pode sofrer malignização. Todas as pacientes diagnosticadas com doenças molares são acompanhadas por pelo menos seis meses para detecção precoce da neoplasia trofoblástica gestacional. No momento, existem poucas ferramentas para avaliação prognóstica da mola hidatiforme. Foi descrita a expressão diferencial de diversos fatores em tecido molar em comparação ao trofoblasto não neoplásico. Essas moléculas podem estar relacionadas com o comportamento agressivo da MH e consequentemente poderiam servir para melhor entendimento do processo de malignização e como preditoras da evolução da doença trofoblástica gestacional.

The hydatidiform mole (HM) is the most common form of gestational trophoblastic disease and a benign condition that in some cases may undergo malignant transformation. All patients diagnosed with molar diseases are monitored for at least six months for early detection of gestational trophoblastic neoplasia. Currently, there are few prognostic tools for the prediction of hydatidiform mole evolution. Differential expression on molar tissue of different molecular factors have been described when compared to non-neoplastic trophoblast. These markers may be associated with aggressive behavior of HM and therefore could serve as predictors of the development of gestational trophoblastic disease and to better understand molar malignant transformation. This review article will summarize and evaluate prognostic molecular markers of HM.

Mosaic moles and non-familial biparental moles are not caused by mutations in NLRP7, NLRP2 or C6orf221.

Hydatidiform moles (HMs) most often occur sporadically and are either diploid androgenetic or triploid. The very rare familial recurrent HMs (FRHMs) have been related to NLRP7 and C6orf221 mutations in the mother. FRHMs are most often diploid with both maternal and paternal origin of the molar genome. We have screened a cohort of 11 women with diploid HMs with biparental contributions to the molar genome with regard to mutations in NLRP7, NLRP2, the NLRP gene most homologous to NLRP7, and C6orf221. This was done in order to reveal if mutations in the mentioned genes play a major role in development of non-recurrent biparental moles. Recently, we have shown that eight of these diploid moles consist of two different cell lines. Only one woman had a mutation in the coding DNA sequence of NLRP7, which most likely contributed to HM development. This woman had non-mosaic repeated moles, and she was the only woman in our cohort with FRHM. We found no unequivocal pathogenic mutations in NLRP2 or C6orf221. Our observations suggest that although NLRP7 and C6orf221 mutations are related to diploid biparental FRHMs, neither of these genes, nor NLRP2, are related to diploid HMs with biparental contributions to the molar genome, in general.

Temporal trends in the frequency of hydatidiform mole in lombardy, northern Italy, 1996-2008.

OBJECTIVE: To analyze temporal trends of hospital admissions due to molar pregnancies in Italian and non-Italian women in Lombardy during the 1996-2008 period. METHODS: A standard form is used to register all discharges from public or private hospitals in Lombardy. Hydatidiform mole (HM) cases were identified when searching the database for code 630 of the International Classification of Diseases, Ninth Revision (ICD-9). Ratios of HM per 100,000 pregnancies in strata of age and nationality were computed. RESULTS: The estimated frequency of HM in Lombardy over the period 1996-2008 was 104.4 per 100,000 pregnancies (SE, 2.8) or 1 case in 935 pregnancies. The frequency of HM tended to decrease in the late 1990s, the crude ratio per 100,000 pregnancies being 127.3 in 1996, 89.3 in 2000, and 113.1 in 2008. The temporal trend analysis, adjusted for age class and geographical origin, showed a significant decrease (P = 0.025). The frequency of HM was 99.8/100,000 pregnancies among Italian women, 112.1/100,000 pregnancies among women from other European countries, 85.1/100,000 pregnancies among women from Africa, 176.9/100,000 pregnancies from South America, and 163.0/100,000 pregnancies among Asian women. Considering the periods 1996-2001 and 2002-2008 separately, the frequency of HMs was largely similar for all groups, except in Asian women: in this group, the frequency of HMs was 242.7/100,000 pregnancies and 120.1/100,000 pregnancies in 1996-2001 and 2002-2008, respectively. CONCLUSION: Between 1996 and 2008, the HM incidence in Lombardy showed a slight but significant decrease, mostly owing to the decrease of HM incidence among Asian women.

Cesarean scar molar pregnancy.

BACKGROUND: Molar pregnancy found in a cesarean scar is exceedingly rare. It can be challenging to manage and can have potentially catastrophic consequences. CASE: A 34-year-old multigravid woman presented with persistent symptoms of pregnancy after a surgical termination of pregnancy. Cesarean scar molar pregnancy was suspected on ultrasonography, and suction evacuation was performed under ultrasound guidance. This was followed by bimanual compression, oxytocin, and uterine artery embolization to reduce bleeding. CONCLUSION: A high index of suspicion is needed for early diagnosis and management of cesarean scar molar pregnancy.

Cervical hydatidiform mole pregnancy after missed abortion presenting with severe vaginal bleeding: case report and review of the literature.

We report a 28-year-old woman presenting with a complete hyaditiform mole localized to the cervix. She had undergone curettage of missed abortion two months previously and the aborted material showed normal placental tissue on histopathologic examination. Two months after curettage she presented with sudden severe vaginal bleeding. Clinical examination revealed a lesion of the epithelial outer surface of the cervix. Due to the bleeding, immediate surgical intervention was necessary. Histological examination revealed a complete hydatidiform mole. Currently, only three cases of this exceedingly rare diagnosis have been published: two reported a partial mole and one a complete hydatidiform mole. In our case, we hypothesize that the pathogenesis took place in two steps. Initially the curettage of the missed abortion damaged the endometrial lining. During a new rapid re-fertilization after the missed abortion, a hydatidiform molar pregnancy developed. Normally this abnormal trophoblast tissue would adhere to the endometrium but in this case we assume that intrauterine implantation was not possible because of endometrial damage at the prior curettage, allowing the abnormal trophoblast tissue to pass the endocervix and emerge into the vaginal vault. Presumably, during the curettage an epithelial defect was produced on the outer surface of the cervix, due to clamping the cervix during dilatation. We speculate that this weak spot on the epithelial surface was responsible for the adherence to the cervix and subsequent bleeding was caused by injury of maternal blood vessels. We propose that careful holding of the cervix with atraumatic clamps during curettage is important to avoid subsequent complications.

What do women with gestational trophoblastic disease understand about the condition?

INTRODUCTION: Little is known about patients' understanding of the causes, treatments, and implications of gestational trophoblastic disease (GTD). Clinical observation suggests that such health literacy is limited. We report on the perceptions of causes and treatment of GTD and its impact on fertility and reproductive outcomes. METHODS: Cross-sectional analysis of 176 Australian women previously diagnosed with GTD (no longer receiving follow-up/treatment) recruited from a state-wide registry. Participants comprised 149 (85%) women with GTD who did not require chemotherapy and 27 (15%) women who required chemotherapy for malignancy or persistent molar disease. Data were collected from medical records and via self-report questionnaire. RESULTS: Participants were 94 women (53%) with partial mole, 75 (43%) with complete mole, 4 (2%) with choriocarcinoma, and 3 (2%) with hydatidiform mole not otherwise specified. Mean (SD) age at diagnosis and time since diagnosis were 32.1 (6.3) and 4.7 (3.3) years, respectively. Chance/bad luck was the most endorsed cause (n = 146, 83%); 23 (13%) thought GTD was hereditary and 10 (6%) identified a chromosomal etiology. Between 24% and 32% were unsure of the role of alcohol/drugs, venereal diseases, smoking, pollution, contraceptives, and lowered immunity. Surgical/medical procedure (n = 127, 72%) and healthy diet (n = 53, 30%) were the most endorsed treatments. Between 18% and 23% were unsure of the treatment effectiveness of diet, vitamins, exercise, complementary therapy, and contraception. All women treated with chemotherapy understood the rationale thereof; 23 (85%) perceived chemotherapy to be successful, and 19 (70%) could name the agent. Few women perceived a negative impact on their fertility (n = 28, 16%); 52 (30%) were reluctant to conceive again and 100 (57%) questioned their ability to have healthy children. After diagnosis, 111 (63%) had at least 1 live birth. CONCLUSIONS: Notwithstanding limitations, this study is the largest of its type to date. These descriptive data enhance our understanding of patients' experience on GTD, highlight the scope of GTD health literacy, and may be useful for clinicians to adjust the content of their patient education.

Management of a partial molar pregnancy: a case study report.

Partial molar pregnancy with coexisting fetus is a rare complication of pregnancy and carries significant risks to both the mother and the fetus. Maternal risks include abnormal bleeding and the development of preeclampsia. The fetus frequently develops abnormally, often due to abnormal karyotype. This case presents a woman with a partial molar pregnancy with coexisting fetus, including diagnosis, plan of care, and delivery information.

Analysis of risk factors for persistent gestational trophoblastic disease.

SETTING: Persistent disease is a serious consequence of molar pregnancies. Its early detection is critical to effective chemotherapy. Therefore, determination of risk becomes an important clinical decision. OBJECTIVES: To determine the relative risk of persistent disease in a cohort of patients with partial and complete molar pregnancies by analysis of five factors derived from a database using multivariate analysis. RESULTS: Of 686 patients, 78 developed persistent disease which required treatment (rate of 11.3%). Risk was markedly increased when serum human chorionic gonadotrophin (HCG) failed to reach negative by 12 weeks after evacuation [hazard ratio (HR) = 120.78, P < 0.001]. Risk was markedly decreased when the interval from last pregnancy exceeded 12 months (HR = 0.24, P = 0.005). Other factors such as patient's age, stage of gestation and serum HCG level at presentation were not found to be strongly associated with risk of persistent disease. CONCLUSION: These findings support the application of the following two factors in risk prediction for molar pregnancies: > 12 weeks to become HCG negative and interval from last pregnancy < 12 months. They will contribute to a greater awareness of persistent disease and assist in early detection and effective chemotherapy.