Rosemary A. Fisher

Choriocarcinoma and partial hydatidiform moles

BACKGROUND Partial hydatidiform moles (PMs) rarely require chemotherapy and have never previously been proven to transform into choriocarcinoma, the most malignant form of gestational trophoblastic disease (GTD). Consequently, some have questioned whether women with PMs need human chorionic gonadotropin (hCG) follow-up. Here, we investigate whether PMs can transform into choriocarcinomas. METHODS Patients with a PM who developed a subsequent choriocarcinoma were identified from our GTD database. The histology of both PM and ensuing choriocarcinoma was reviewed and flow cytometry used to verify the triploid status of the PMs. To determine whether the choriocarcinoma arose from the PM, DNA from the PM and choriocarcinoma in each patient was compared using microsatellite polymorphisms. FINDINGS Of the 3000 patients with PM, 15 required chemotherapy for persisting GTD. This was identified as choriocarcinoma in three cases. In one patient, the local pathologist could not differentiate between a PM or a hydropic abortion and neither central histological review nor hCG follow-up were obtained. This patient nearly died before the diagnosis of choriocarcinoma was made. Fortunately, the local pathologists correctly diagnosed PM in the two other patients who were then registered for hCG follow-up. Some months later, the hCG was rising and repeat uterine evacuation revealed choriocarcinoma. The PM was confirmed to be triploid in all three cases and genetic analysis showed that the subsequent choriocarcinomas contained identical single maternal and two paternal alleles at several independent loci. INTERPRETATION Our results show that PMs can transform into choriocarcinoma. All patients with suspected PM should be reviewed centrally and, if confirmed, need hCG follow-up.

A prospective genetic study of complete and partial hydatidiform moles

Two hundred two hydatidiform moles were classified by pathologic features and ploidy into partial or complete moles. Further classification was made by using genetic polymorphism, the diagnosis being refined by deoxyribonucleic acid technology. Among 51 partial hydatidiform moles, 44 triploids, two tetraploids, and one diploid were identified. Informative triploid partial hydatidiform moles had one maternal and two paternal sets of chromosomes, the likely origin being dispermy. Among 149 complete hydatidiform moles, one was haploid, one was triploid, and 105 were shown to be diploid or androgenetic; 39 of these were proved homozygous, indicating duplication of the male genome, whereas heterozygous origin by dispermy was likely in 13. The locus-specific minisatellite deoxyribonucleic acid probes were particularly useful for the identification of heterozygous complete hydatidiform moles. None of the patients with partial hydatidiform moles had development of a gestational trophoblastic tumor. No difference was detected in the frequency of requirement for chemotherapy between patients with homozygous or heterozygous complete hydatidiform moles.

Mutations Causing Familial Biparental Hydatidiform Mole Implicate C6orf221 as a Possible Regulator of Genomic Imprinting in the Human Oocyte

Familial biparental hydatidiform mole (FBHM) is the only known pure maternal-effect recessive inherited disorder in humans. Affected women, although developmentally normal themselves, suffer repeated pregnancy loss because of the development of the conceptus into a complete hydatidiform mole in which extraembryonic trophoblastic tissue develops but the embryo itself suffers early demise. This developmental phenotype results from a genome-wide failure to correctly specify or maintain a maternal epigenotype at imprinted loci. Most cases of FBHM result from mutations of NLRP7, but genetic heterogeneity has been demonstrated. Here, we report biallelic mutations of C6orf221 in three families with FBHM. The previously described biological properties of their respective gene families suggest that NLRP7 and C6orf221 may interact as components of an oocyte complex that is directly or indirectly required for determination of epigenetic status on the oocyte genome.

Histopathological Diagnosis of Partial and Complete Hydatidiform Mole in the First Trimester of Pregnancy

The diagnosis of molar pregnancy is a continuing diagnostic problem for many practicing histopathologists who are required to examine specimens of products of conception, particularly since changes in gynecological management in recent years have resulted in uterine evacuation at earlier gestations. The aim of this review is to provide practical, up-to-date, diagnostically useful information regarding the histological diagnosis of molar disease in early pregnancy. Pathophysiological issues relevant to molar pregnancies, such as genetic abnormalities, will be briefly summarized, but nonhistopathological aspects of molar disease will not be covered in detail in this review.

Gestational trophoblastic disease: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

M. J. Seckl1, N. J. Sebire2, R. A. Fisher1, F. Golfier3, L. Massuger4 & C. Sessa5, on behalf of the ESMO Guidelines Working Group* Department of Cancer Medicine; Department of Histopathology, Charing Cross Gestational Trophoblastic Disease Centre, Charing Cross Hospital Campus of Imperial College London, London, UK; Centre de Référence des Maladie Trophoblastiques, Hospices Civils de Lyon, Lyon, France; Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland;

EMA/CO for High-Risk Gestational Trophoblastic Neoplasia: Good Outcomes With Induction Low-Dose Etoposide-Cisplatin and Genetic Analysis

PURPOSE Patients with high-risk (International Federation of Gynecology and Obstetrics score ≥ 7) gestational trophoblastic neoplasia (GTN) frequently receive etoposide, methotrexate, and dactinomycin alternating weekly with cyclophosphamide and vincristine (EMA/CO). Between 1979 and 1995, overall survival (OS) with this regimen at our institute was 85.4% with a significant proportion of early deaths (< 4 weeks). Here, we determine whether survival rates have improved in a more recent patient cohort (1995 to 2010). PATIENTS AND METHODS Patients receiving EMA/CO were identified using the Charing Cross GTN database. Genetic analysis identified nongestational trophoblastic tumors (nGTTs). The use of induction low-dose etoposide 100 mg/m(2) and cisplatin 20 mg/m(2) (EP; days 1 and 2 every 7 days) since 1995 to reduce early deaths before commencing EMA/CO was noted. RESULTS Four hundred thirty-eight patients received EMA/CO between 1995 and 2010. Six patients had nGTTs, 140 had high-risk disease, and 250 had relapsed/resistant low-risk GTN. OS was 94.3% in high-risk patients (90.4% including nGTTs) and 99.6% in the low-risk group, with a median follow-up time of 4.2 years. All patients with nGTT and seven patients with high-risk GTNs died as a result of drug-resistant disease. EP induction chemotherapy was given to 23.1% of high-risk patients (33 of 140 patients) with a large disease burden, and the early death rate was only 0.7% (n = 1; 95% CI, 0.1% to 3.7%) compared with 7.2% (n = 11 of 151 patients; 95% CI, 4.1% to 12.6%) in the pre-1995 cohort. CONCLUSION OS after EMA/CO for high-risk GTN has increased by nearly 9%. This reflects a more accurate estimate of OS by excluding nGTTs (3.9%) in patients with atypical presentations using genetic diagnosis. Low-dose induction EP in selected individuals also allows near complete elimination of early deaths. The latter should be considered routinely in high-risk GTN.

Complete hydatidiform mole retaining a chromosome 11 of maternal origin: molecular genetic analysis of a case

Hydatidiform moles are pregnancies characterized by abnormal development of both embryonic and extraembryonic tissues and are associated with the misexpression of imprinted genes. The vast majority of complete hydatidiform moles are diploid and androgenetic, whereas partial hydatidiform moles are triploid, with an extra set of chromosomes of paternal origin. Here, we present an unusual complete mole that showed strong expression of two imprinted, maternally transcribed genes, CDKN1C (encoding p57KIP2) and PHLDA2 (TSSC3/IPL), both part of a large imprinted gene domain on chromosome 11. Using microsatellite genotyping and fluorescent in situ hybridization, we show that this paradoxical gene expression was due to retention of a maternal copy of chromosome 11 in addition to the two paternal copies normally present in complete moles. These findings demonstrate that, despite being predominantly androgenetic, some complete moles contain small amounts of DNA of maternal origin. Furthermore, these results provide an explanation for rare false negatives that can arise when p57KIP2 is used as a diagnostic marker for complete moles.

Recent advances in gestational trophoblastic disease

Advances in the last 20 years have led to a better understanding of the process of gestational trophoblastic disease (GTD), and consequently, to improved diagnosis, management, and prognosis. Patients with GTD should be registered at a trophoblastic disease center for follow-up, and those with persistent disease should receive chemotherapy, methotrexate, and folinic acid for low-risk disease, and EMACO (etoposide, actinomycin-D, methotrexate, vincristine, and cyclophosphamide) for high-risk disease, without loss of fertility. Most patients with relapsing or resistant disease can be treated effectively with surgery and/or cisplatin in EP/EMA (etoposide, platinum-etoposide, methotrexate, actinomycin-D) combination.

Diploid hydatidiform moles with fetal red blood cells in molar villi. 1--Pathology, incidence, and prognosis.

It is believed that fetal development does not occur in complete mole (CM); when present, it is usually interpreted as proof of partial mole (PM), in most cases a triploid conception with a low incidence of persistent trophoblastic disease (PTD). However, histological examination of 3180 moles in 8 years showed 60 moles (1·8 per cent) with features of CM and either embryonic tissues or amnion in the sample. Flow cytometry (FC) in 40 showed diploid complement in all. In ten of the 40, there was evidence of a twin; in 17, there was only amnion, which could belong to a twin; in the remaining 13, there was no evidence of a twin and nucleated fetal red blood cells (FRCs) were seen within molar vessels in ten (0·3 per cent). Seven of the 40 patients (17·5 per cent) and one of the ten with FRCs in villi (10 per cent) developed PTD, an incidence comparable to that of CM. Genetic studies in seven of these ten are reported separately. Finding fetal tissues with a mole or FRCs in molar vessels is not enough to classify it as PM, since it can be a CM with a twin, fetal development in CM, or possibly a third type of mole. These rare diploid moles with fetal tissues have histological appearances and prognosis similar to those of CM.

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48–60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.