Choriocarcinoma following a partial hydatidiform mole: a case report.

Hydatidiform moles are classified as partial or complete by histologic criteria (Am J Obstet Gynecol 131:665-671, 1978 and Am J Obstet Gynecol 132:20-27, 1978). While persistent gestational trophoblastic tumors follow both types, there remains controversy as to whether the malignant extreme of gestational trophoblastic tumors, choriocarcinoma, can follow a partial hydatidiform mole (Am J Obstet Gynecol 127:167-170, 1977 and Arch Gynecol 234:161-166, 1984). In this instance, a 37-year-old woman presented with a partial hydatidiform mole that persisted and was treated with one course of chemotherapy. She attained a remission for 10 months, when a routine follow-up examination revealed an asymptomatic rise in serum beta-human chorionic gonadotropin from baseline to 14,600 mIU/mL. Dilatation and curettage revealed abundant avillous cytotrophoblast and syncytiotrophoblast with marked atypia, diagnostic of choriocarcinoma. Flow cytometry of paraffin blocks of both specimens showed the partial hydatidiform mole to be triploid and the choriocarcinoma diploid. The patient had no evidence of metastatic disease and was successfully treated with multiple-agent chemotherapy.     

Complete hydatidiform mole and normal live birth: a novel case of confined placental mosaicism: case report

Hydatidiform molar change, characterized by abnormal fetoplacental development and placental villous trophoblast hyperplasia, results from genetically abnormal conception, in which there is an excess of paternally derived genetic material. The majority of pregnancies in which molar change has been reported in association with a live fetus represent dizygotic twin pregnancies in which one fertilization results in a complete hydatidiform mole (CM) and the other a normal co-twin. In such cases, there is usually a clear distinction, both sonographically and pathologically, between the molar and non-molar regions of the placenta. We present a singleton pregnancy, with diffuse placental molar change detected prenatally, which resulted in a chromosomally and phenotypically normal female infant at term. Pathological examination revealed the presence of intermixed populations of morphologically normal chorionic villi and villi with the characteristics of CM. Studies of genetic polymorphisms demonstrated that the CM, normal villi and fetus were all derived from the same sperm; the fetus was diploid and biparental whereas the areas of pathological CM were androgenetic and monospermic. We believe this represents the first well-documented case of apparent confined placental mosaicism involving CM and a coexisting normal fetus, which has presumably arisen following mitotic abnormalities in the early post-fertilization period.     

中期妊娠完全性葡萄胎与正常胎儿共存一例

患者女,32岁.孕1产0,孕14周6 d,因产前检查发现宫内异常回声16 d,于2009年7月30日收入院.患者婚后5年一直未孕,1年前于本院诊断为多囊卵巢综合征.孕前曾口服克罗米芬促排卵,服药后1个月查尿绒毛膜促性腺激素(HCG)阳性,早孕反应较严重.     

DNA polymorphism analysis of a case of complete hydatidiform mole coexisting with a fetus

A complete hydatidiform mole coexisting with a fetus is a rare condition. The diagnosis is often difficult because of the morphological similarity to a partial mole, but is crucial to management in the postmolar course. We present a case of molar pregnancy coexisting with a fetus in which DNA polymorphism analysis revealed a different genetic origin for the fetal and molar parts. This is the only known case of a complete mole in a twin pregnancy complicated by pre-eclampsia followed by maternal pulmonary oedema. During follow-up, the patient developed a clinically invasive mole which was successfully treated with chemotherapy. In this case, genetic analysis unequivocally diagnosed a twin pregnancy consisting of a complete hydatidiform mole and a fetus.      

A case of membranoproliferative glomerulonephritis associated with a hydatidiform mole

We treated a 54-year-old woman who was suffering from membranoproliferative glomerulonephritis associated with a complete type of hydatidiform mole. The renal manifestations were proteinuria and hematuria. A renal biopsy, performed before gynecologic management, disclosed focal and segmental subendothelial deposits with a proliferation of the mesangial cell and showed irregularly thickened capillary loops by light and electronmicroscoy. Genralized edema, proteinuria and hematuria were completely recovered by suction and curettage of the hydatidiform mole with prophylactic chemotherapy. The clinical manifestation of earlier presented 3 cases have been the nephrotic syndrome. The common feature of them was a complete remission of the nephropathy after the removal of the hydatidiform mole. The relationship between the hydatidiform mole and glomerulonephritis remains unresolved at present. But we concluded that the hydatidiform mole might be a cause of glomerulonephritis in this case.     

Complete hydatidiform moles combine maternal mitochondria with a paternal nuclear genome

The parental origin of mitochondria in hydatidiform moles has been investigated by analysis of genetic variants of mtDNA restriction enzyme patterns. In six complete moles the mtDNA was found to be maternal in origin, with no contribution from the sperm mitochondria, while the nuclear genome was shown to be exclusively paternal in five cases. The occurrence of mtDNA variation in the healthy population was investigated using white blood cells and placentae, and the most common variation occurred at the Ava II restriction sites. The variants exhibited by molar mtDNA were the same as those found in material from healthy individuals.     

Twin pregnancy with a complete hydatidiform mole and co-existing fetus following in-vitro fertilization: case report.

Hydatidiform mole with a co-existing live fetus is a rare event. We report the case of a 41 year old Caucasian woman who attended for in-vitro fertilization. Three embryos, containing two apparently normal pronuclei, were transferred into the uterus. A twin pregnancy with a live fetus and a complete mole ensued. The pregnancy was managed conservatively until 28 weeks gestation when, following an episode of major antepartum haemorrhage, a live female infant was delivered by Caesarean section. The mole, weighing over 1.7 kg, was successfully evacuated. Following delivery, serum human chorionic gonadotrophin concentrations returned to baseline and remain within the normal range at 24 months. Both mother and daughter are well on assessment 24 months later.     

Molecular genetic analysis of complete hydatidiform moles.

Complete hydatidiform moles (CHM) are the most common form of gestational trophoblastic disease and a frequent antecedent to choriocarcinoma. Cytogenetic investigations into the origin of these tumors have shown that they can arise by virtue of unusual fertilization events. In this study we used molecular genetic "fingerprinting" methods to examine the genome of 22 consecutive CHM in order to determine their derivation. We found that 60% contained alleles consistent with a completely homozygous androgenic origin. The remaining 40% were heterozygous for marker alleles; half of these were completely androgenic in origin. The other half of these heterozygous CHM contained alleles from the maternal genome, indicating a biparental contribution. These findings suggest that the pathogenesis of CHM is more heterogenous than previously suspected, and can arise from biparental fertilization events. In addition, we found that mutations occur frequently at many loci in these tumors, which may reflect a generalized genetic instability perhaps related to subsequent malignant change. Thus, molecular genetic analysis of CHM provides new insights into the genesis of CHM and will be a powerful method for understanding their clinical biology.     

Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole

One hundred and six triploids were ascertained during a study of 1500 consecutive spontaneous abortions. The mechanism of origin of the additional haploid complement was investigated by comparing parental and foetal cytogenetic heteromorphisms and a histopathological examination of each triploid was done in a subsequent blind study.
The mechanism of origin of the additional haploid complement was found to be highly correlated with the development of partial hydatidiform mole and with gestational age. All 51 paternally derived triploids in which a pathologic diagnosis could be made were partial moles, whereas only 3 of 15 maternally derived triploids on which a diagnosis could be made were molar. The mean gestational age of the paternally derived triploids was 122 days while that of the maternally derived triploids was only 74 days.
It was suggested that the development of partial mole was primarily associated with the presence of two paternal haploid chromosome complements, the association with relatively long gestational ages being a secondary one consequent upon retention of the molar placentae for many weeks after foetal demise.     

Coexisting true hermaphroditism and partial hydatidiform mole developing metastatic gestational trophoblastic tumors. A case report

We report a fetal autopsy case that was diagnosed with a mole coexistent with a live fetus at an early gestation and finally showed coexisting true hermaphroditism of 46,XX/46,XY mosaicism and partial hydatidiform mole, developing metastatic gestational trophoblastic tumors in the lungs of the mother. A 23-year-old Japanese female had a mole coexistent with a fetus and showed a high chorionic gonadotropin titer in urine and serum at 10 weeks of gestation. The fetus was interrupted for gestational toxicosis and genital bleeding at 20 weeks of gestation. A chromosome analysis demonstrated 46,XX and 46,XY mosaicism in both umbilical cord blood and mole samples. Intrapelvic organs contained a testis in the one gonad, and an ovotestis in the other gonad microscopically. The testis had seminiferous tubules containing primitive germ cells, immature Sertoli cells, and cytomegalic Leydig cells. The ovary in the ovotestis had numerous primitive germ cells and a few stromal cells. Cortical cytomegaly and medullary neuroblastoma in situ were seen in the adrenals. The placenta showed focal villous hydrops and focal trophoblast hyperplasia. The patient presented multiple metastatic pulmonary tumors at 1 month after the interruption, and was treated with chemotherapy for the clinical diagnosis of gestational trophoblastic tumor metastases. She responded well and is alive without any symptoms.     

Characterisation of a rare hydatidiform mole with aberrant p57 expression

Accurate diagnosis and subclassification of hydatidiform mole (HM) are important to stratify the risk of persistent gestational trophoblastic disease (GTD) and gestational trophoblastic neoplasia (GTN). A combination of histomorphology and ancillary studies including p57 immunohistochemistry (IHC) and/or molecular genotyping by short tandem repeat analysis enable subclassification of most HM into partial hydatidiform mole (PHM) or complete hydatidiform mole (CHM). Here we report a rare HM with equivocal morphology and discordant p57 expression within individual villi and divergent p57 expression across villi. Molecular genotyping of DNA extracted from laser capture microdissected (LMD) chorionic villi allowed identification of CHM and rare androgenetic/biparental mosaicism. This study exemplifies a potential diagnostic pitfall and highlights the importance of inter-disciplinary examination such as p57 IHC and molecular genetics in the diagnosis of HMs.     

一例MEGDEL综合征患儿的临床及遗传学分析

目的:探讨1例MEGDEL综合征患儿的临床及基因变异特点。方法:收集患儿的临床资料,采集患儿及其父母的外周血样,应用二代测序技术对患儿进行线粒体基因组及全外显子组分析,用Sanger测序以及荧光定量PCR验证候选变异及其来源。结果:患儿为男性,2岁6个月,主要表现为新生儿期低血糖、智力运动发育落后伴倒退。头颅磁共振成像...     

Single haplotype assembly of the human genome from a hydatidiform mole

A complete reference assembly is essential for accurately interpreting individual genomes and associating variation with phenotypes. While the current human reference genome sequence is of very high quality, gaps and misassemblies remain due to biological and technical complexities. Large repetitive sequences and complex allelic diversity are the two main drivers of assembly error. Although increasing the length of sequence reads and library fragments can improve assembly, even the longest available reads do not resolve all regions. In order to overcome the issue of allelic diversity, we used genomic DNA from an essentially haploid hydatidiform mole, CHM1. We utilized several resources from this DNA including a set of end-sequenced and indexed BAC clones and 100× Illumina whole-genome shotgun (WGS) sequence coverage. We used the WGS sequence and the GRCh37 reference assembly to create an assembly of the CHM1 genome. We subsequently incorporated 382 finished BAC clone sequences to generate a draft assembly, CHM1_1.1 (NCBI AssemblyDB GCA_000306695.2). Analysis of gene, repetitive element, and segmental duplication content show this assembly to be of excellent quality and contiguity. However, comparison to assembly-independent resources, such as BAC clone end sequences and PacBio long reads, indicate misassembled regions. Most of these regions are enriched for structural variation and segmental duplication, and can be resolved in the future. This publicly available assembly will be integrated into the Genome Reference Consortium curation framework for further improvement, with the ultimate goal being a completely finished gap-free assembly.The production of a reference sequence assembly for the human genome was a milestone in biology and clearly has impacted many areas of biomedical research (McPherson et al. 2001; International Human Genome Sequencing 2004). The availability of this resource allows us to investigate genomic structure and variation at a depth previously unavailable (Kidd et al. 2008; The 1000 Genomes Project Consortium 2012). These studies have helped make clear the shortcomings of our initial assembly models and the difficulty of comprehensive genome analysis. While the current human reference assembly is of extremely high quality and is still the benchmark by which all other human assemblies must be compared, it is far from perfect. Technical and biological complexity lead to both missing sequences as well as misassembled sequence in the current reference, GRCh38 (Robledo et al. 2002; Eichler et al. 2004; International Human Genome Sequencing 2004; Church et al. 2011; Genovese et al. 2013).The two most vexing biological problems affecting assembly are (1) complex genomic architecture seen in large regions with highly homologous duplicated sequences and (2) excess allelic diversity (Bailey et al. 2001; Mills et al. 2006; Korbel et al. 2007; Kidd et al. 2008; Zody et al. 2008). Assembling these regions is further complicated due to the fact that regions of segmental duplication (SD) are often correlated with copy-number variants (CNVs) (Sharp et al. 2005). Regions harboring large CNV SDs have been misrepresented in the reference assembly because assembly algorithms aim to produce a haploid consensus. Highly identical paralogous and structurally polymorphic regions frequently lead to nonallelic sequences being collapsed into a single contig or allelic sequences being improperly represented as duplicates. Because of this complexity, a single, haploid reference is insufficient to fully represent human diversity (Church et al. 2011).The availability of at least one accurate allelic representation at loci with complex genomic architecture facilitates the understanding of the genomic architecture and diversity in these regions (Watson et al. 2013). To enable the assembly of these regions, we have developed a suite of resources from CHM1, a DNA source containing a single human haplotype (Taillon-Miller et al. 1997; Fan et al. 2002). A complete hydatidiform mole (CHM) is an abnormal product of conception in which there is a very early fetal demise and overgrowth of the placental tissue. Most CHMs are androgenetic and contain only paternally derived autosomes and sex chromosomes resulting either from dispermy or duplication of a single sperm genome. The phenotype is thought to be a result of abnormal parental contribution leading to aberrant genomic imprinting (Hoffner and Surti 2012). The absence of allelic variation in monospermic CHM makes it an ideal candidate for producing a single haplotype representation of the human genome. There are a number of existing resources associated with the “CHM1” sample, including a BAC library with end sequences generated with Sanger sequencing using ABI 3730 technology (https://bacpac.chori.org/), an optical map (Teague et al. 2010), and a BioNano genomic map (see Data access), some of which have previously been used to improve regions of the reference human genome assembly.BAC clones have historically been used to resolve difficult genomic regions and identify structural variants (Barbouti et al. 2004; Carvalho and Lupski 2008). A BAC library constructed from CHM1 DNA (CHORI-17, CH17) has also been utilized to resolve several very difficult genomic regions, including human-specific duplications at the SRGAP2 gene family on Chromosome 1 (Dennis et al. 2012). Additionally, the CHM1 BAC clones were used to generate single haplotype assemblies of regions that were previously misrepresented because of haplotype mixing (Watson et al. 2013). Both of these efforts contributed to the improvement of the GRCh38 reference human genome assembly, adding hundreds of kilobases of sequence missing in GRCh37, in addition to providing an accurate single haplotype representation of complex genome regions.Because of the previously established utility of sequence data derived from the CHM1 resource, we wished to develop a complete assembly of a single human haplotype. To this end, we produced a short read-based (Illumina) reference-guided assembly of CHM1 with integrated high-quality finished fully sequenced BAC clones to further improve the assembly. This assembly has been annotated using the NCBI annotation process and has been aligned to other human assemblies in GenBank, including both GRCh37 and GRCh38. Here we present evidence that the CHM1 genome assembly is a high-quality draft with respect to gene and repetitive element content as well as by comparison to other individual genome assemblies. We will also discuss current plans for developing a fully finished genome assembly based on this resource.     

Refining the diagnosis of hydatidiform mole: image ploidy analysis and p57KIP2 immunohistochemistry

AIM: To determine whether image analysis of ploidy status and immunohistochemical analysis of p57KIP2 (a paternally imprinted, maternally expressed gene) can be used to refine the diagnosis of molar pregnancy. METHODS AND RESULTS: The original histological diagnosis in 40 randomly selected cases of hydatidiform mole was reviewed and confirmed in 38 cases (22 complete moles, 16 partial moles). These cases were anonymized and submitted for further analysis. Tissue from each case was submitted for flow cytometric assessment of DNA ploidy using a FACSort flow cytometer and for automated image cytometric assessment using a novel digital imaging system. Tissue sections from each case were immunostained with a monoclonal mouse antibody to p57KIP2. Correlations between the histopathological diagnosis, image cytometry, flow cytometry and p57KIP2 immunohistochemistry were determined using kappa statistics. The concordance between histological diagnosis and p57KIP2 was very good (kappa = 0.89). Twenty of the 22 (90.9%) complete moles showed no immunoreactivity for p57KIP2. The remaining two cases showed nuclear immunoreactivity in villous cytotrophoblast. In one of these, the pattern of staining resembled that of a partial mole. In the other, the staining pattern supported the diagnosis of a twin molar/non-molar pregnancy. All 16 partial moles were p57KIP2 immunoreactive. On flow cytometry, all 22 complete moles were diploid and 12/16 partial moles were triploid (the remaining four cases originally diagnosed as partial moles were found to be diploid). On image cytometry, one case originally diagnosed as complete mole was found to contain a triploid population. Thus, by using a combination of image cytometry and p57KIP2 status we were able to refine the diagnosis of molar pregnancy in five (13%) of the cases studied. CONCLUSIONS: Automated image cytometry is a readily performed investigation which is comparable to, but more sensitive than, flow cytometry. Complementary use of ploidy analysis and p57KIP2 status can now help to distinguish a diploid hydropic miscarriage (p57KIP2-positive), diploid complete mole (p57KIP2-negative) and triploid partial mole (p57KIP2-positive).