Pseudo-partial moles: placental stem vessel hydrops and the association with Beckwith-Wiedemann syndrome and complete moles.

AIMS: To describe the clinical and histological features of a series of cases of placentas originally diagnosed as partial moles in which the final diagnosis was that of placental stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann syndrome. METHODS AND RESULTS: We searched a computerized database containing cases of suspected or proven trophoblastic disease examined at the Trophoblastic Disease Unit at Charing Cross Hospital, London, to identify cases in which stem vessel hydrops was present without other histological features of partial mole. For each case, histological sections were examined and the histological features present recorded. There were 15 cases identified. Placental weight was above the 95th centile of the normal for gestation in all cases in which this information was documented. In an additional five cases the placenta was described as 'large'. All cases had marked stem vessel hydropic change with cyst formation and in the majority of cases some terminal villous hydrops was also present. In 13 of the 15 cases there was marked aneurysmal dilatation of stem villous vessels. Nine had focal chorioangiomatoid change and in four of these extramedullary haematopoiesis was focally present in these areas. No excessive trophoblast proliferation was noted in any case and no trophoblastic inclusions typical of partial mole were identified. CONCLUSIONS: This study has identified cases of stem villous hydrops, mesenchymal dysplasia or Beckwith-Wiedemann spectrum in pregnancies initially diagnosed as partial hydatidiform mole in the second half of pregnancy and has highlighted the need for detailed pathological examination and clinicopathological correlation in all such cases.

Extravillus endovascular implantation site trophoblast invasion is abnormal in complete versus partial molar pregnancies.

This study examines endovascular trophoblast invasion in pregnancies complicated by complete hydatidiform mole (CM), partial hydatidiform mole (PM) and non-molar abortions (HA). Two hundred consecutive cases from a supra-regional referral centre for suspected trophoblastic disease were examined histologically with particular regard to the presence or absence of endovascular trophoblast invasion of decidual vessels. There were 57 CM, 75 PM and 68 HA. The prevalence of normal endovascular invasion of decidual vessels was significantly lower in CM compared to all other clinical groups, amongst which there were no significant differences. Endovascular trophoblast was identified in about 80 per cent of HA and PM moles, compared to only around 25 per cent of CM (Z = -4.0, P< 0.0001). The majority of cases of complete mole demonstrated a similar appearance, of implantation site showing florid interstitial extravascular trophoblast invasion with surrounding of decidual vessels but without normal endovascular trophoblast invasion or 'plugging' seen. In many cases, there also appeared to be destruction of decidual vessels with interstitial haemorrhage and extensive fresh blood clot present in the histological sections. These findings may provide some explanation regarding the mechanism of clinical findings in molar pregnancy.

Expression of ZO-1 and occludin in normal human placenta and in hydatidiform moles.

Zonula occludens-1 (ZO-1) and occludin are key molecules in cell-cell contacts. They are tight junction constituents and therefore play a pivotal role in tissue differentiation and organogenesis. In the present report we have investigated the expression of ZO-1 and occludin in normal human placentae and in hydatidiform moles using immunohistochemical and Western blot analyses. In normal placentae, ZO-1 and occludin were mainly localized in the apical part of the syncytium, in cell-cell contacts between syncytium and villous cytotrophoblastic cells as well as between the latter. Extravillous cytotrophoblast of cell islands and cell columns was positive for ZO-1 and occludin in the cell layers proximally located to the villous stroma whereas the cytotrophoblastic cells, distally located from the villous stroma, were totally negative. Furthermore, fetal vessels showed a positive staining pattern for ZO-1 throughout gestation, whereas a positive reaction for occludin was produced mainly at term. A striking result was the altered expression of ZO-1 and occludin in partial and complete moles. In 11 moles, these two molecules were not expressed at all, while in the other nine, their expression was only cytoplasmic in syncytium and villous cytotrophoblastic cells. These findings suggest that ZO-1 and occludin participate in normal placental development, maintaining the organization and functions of different tissue components. The down-regulation and/or dysregulation of these two molecules may be related to phenotypic changes associated with epithelial cell transformation of the chorionic villi in partial and complete moles.

The diagnostic implications of routine ultrasound examination in histologically confirmed early molar pregnancies.

OBJECTIVE: Early ultrasound examination is being used increasingly in the diagnosis of molar pregnancy. The aim of this study was to examine the diagnostic implications of routine ultrasound examination for histologically confirmed molar pregnancies. METHODS: This was a retrospective review of sonographic and histological findings in a series of consecutive cases referred to the National Trophoblastic Disease Surveillance Centre with suspected molar pregnancies. In 194 cases referred to the center over a 6-month period in whom results of a preceding ultrasound examination were documented, review of ultrasound findings and final histological diagnosis was carried out. RESULTS: There were 155 cases with a reviewed histological diagnosis of complete or partial hydatidiform mole. In 131 (67%) cases, the sonographic diagnosis was that of a missed miscarriage/anembryonic pregnancy with no documented suspicion of molar pregnancy, referral being on the basis of histological examination of products of conception. In 63 cases, ultrasound examination suggested molar pregnancy; in 53 (84%) of these, the diagnosis of molar pregnancy was correct. Overall, 37 of 64 (58%) complete moles had sonographic evidence of molar pregnancy compared to 16 of 91 (17%) partial moles. Of 155 histologically confirmed complete or partial hydatidiform moles, only 53 (34%) were suspected as molar sonographically. CONCLUSION: The majority of cases of molar pregnancy now present as missed miscarriage/anembryonic pregnancy sonographically, highlighting the importance of histological examination to diagnose gestational trophoblastic disease.

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.

Amniotic tissue in complete hydatidiform moles can be androgenetic.

The purpose of this study was to determine whether amniotic tissue found associated with cases of complete hydatidiform mole (CM) was genetically identical to the CM, and therefore part of the molar pregnancy, or genetically dissimilar to the CM, suggesting derivation from a twin pregnancy. DNA was prepared from formalin-fixed, paraffin-embedded blocks of tissue containing both CM and amnion. Maternal DNA was prepared from decidual tissue in the same blocks, or from a maternal blood sample. Fluorescent microsatellite genotyping was carried out to determine the origin of both the CM and the amniotic tissue. In one of six cases examined, the amniotic tissue was genetically different from the CM and was therefore likely to be derived from a twin pregnancy. In the five remaining cases, the amniotic tissue was genetically identical to the CM and was likely to be derived from the same conceptus. It is concluded that androgenetic CM can support the development of amniotic tissue and that some early embryonic development may occur in CM. The presence of amnion, or other fetal tissues, associated with molar tissue should not therefore always be considered indicative of a diagnosis of partial mole (PM).

Repetitive complete hydatidiform mole can be biparental in origin and either male or female.

Complete hydatidiform mole (CHM) is an abnormality in pregnancy due to a diploid conception which is generally androgenetic in origin, i. e. all 46 chromosomes are paternally derived. We have examined the genetic origin of repetitive hydatidiform moles in a patient having three CHM by two different partners, and no normal pregnancies. Using fluorescent microsatellite genotyping, we have shown all three CHM to be biparental, rather than androgenetic, in origin. Examination of informative markers for each homologous pair of chromosomes, in two of the CHM, failed to reveal any evidence of unipaternal disomy, suggesting that the molar phenotype might result from disruption of normal imprinting patterns due to a defect in the maternal genome. It has been suggested that intracytoplasmic sperm injection (ICSI), followed by selection of male embryos, can prevent repetitive CHM; but examination of sex chromosome-specific sequences in the three CHM described here, showed that, while two were female, the first CHM was male. Selection of male embryos is therefore unlikely to prevent repetitive CHM in this patient. Our results suggest that the genetic origin of repetitive CHM should be determined prior to in-vitro fertilization (IVF) and that current strategies for the prevention of repetitive CHM may not be appropriate where the CHM are of biparental origin.

Triplet pregnancy with hydatidiform mole.

Multiple pregnancies with hydatidiform mole are rare. We describe here a patient who delivered a male fetus and a female fetus together with molar tissue following treatment for infertility. comparing microsatellite polymorphisms in the DNA from the patient, her partner, the two normal placentas and the molar tissue, we were able to show that this was a triplet pregnancy with two normal conceptions and a complete hydatidiform mole of monospermic origin.

[Behavior disorders during REM sleep. Two clinical cases]. / Trastorno de conducta durante el sueño MOR. Dos casos clínicos.

INTRODUCTION: The behavior disorder occurring during REM (Rapid Eye Movement) sleep is a parasomnia characterized by absence of atonia typical of this phase of sleep, although the other characteristics are maintained, namely rapid eye movements and desynchronization of cortical electrical activity. Clinically it is accompanied by abrupt, often violent movements, which may involve a limb or the trunk in relation to dreams typical of this phase of sleep, and which may interrupt sleep. Many pathological processes have been described, including: the Shy-Dragger syndrome, Parkinson's disease, olivopontocerebellar atrophy, multisystemic atrophy, in relation to certain antidepressant drugs, and most frequently the idiopathic form. CLINICAL CASES: We present two cases, one diagnosed as olivopontocerebellar atrophy and another in which there were no pathological findings. Both were referred to our department for the study of possible sleep disorders. In both cases neurophysiological studies, basically polysomnography with monitorization of various muscle groups and video, led to the diagnosis. CONCLUSIONS: We discuss the diagnostic and physiological criteria, and physiopathological explanations of each case, with special reference to N-Methyl-D-Aspartate (NMDA) and non-N-Methyl-D-Aspartate (non-NMDA) receptors. Finally we consider the pharmacological treatment of this disorder.

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.

Expression pattern alterations of syndecans and glypican-1 in normal and pathological trophoblast.

Syndecans (syn-1, -2, -3, -4) and glypican-1 are proteoglycans expressed during development in association with changes in tissue organization and differentiation. They participate in the modulation of growth factor actions and in cell-cell and cell-matrix adhesion. The expression of syn-1, -2, -3, -4, and glypican-1 has been studied in normal human placenta and in gestational trophoblastic disease such as hydatidiform mole, invasive mole, and choriocarcinoma, using immunohistochemistry and western blots. Syndecan-3 was not expressed in normal or pathological tissues. During normal gestation, the other proteoglycans showed a specific staining pattern, which for some was modified during pregnancy. For instance, syn-1 was only expressed in syncytiotrophoblast; syn-4 was mainly localized in the villous and extravillous cytotrophoblast in the first trimester, whereas at term it was expressed in the syncytiotrophoblast. The most striking results are the altered expression patterns of syndecans and glypican-1 in pathological tissues. These proteoglycans showed a progressive decrease of immunostaining related to the increase of severity of trophoblastic disease, in particular in invasive mole and choriocarcinoma. In addition, dysregulation in the localization of the expression patterns was observed for syn-2 and -4. Because changes in syndecan expression enable cells to become more or less responsive to their micro-environment, the down-regulation and/or dysregulation of syndecans in relation to the degree of severity of trophoblastic diseases provides new insights into the progression of these pathologies.

A molecular cytogenetic approach to studying platinum resistance.

The technique of comparative genomic hybridisation (CGH) has until recently been used to screen for common genomic abnormalities in fresh tumour material; it has identified previously unrecognised regions of amplification associated with poor prognosis subtypes of breast cancer and lymphoma. Our group has applied this technique to resistant cell lines and their sensitive counterparts in order to define chromosomal abnormalities associated with acquired drug resistance. We have demonstrated the applicability of this technique to the study of drug resistance using cell lines with known mechanisms of resistance. The ability to detect novel genomic alterations in cell lines with novel mechanisms of resistance was also demonstrated. We subsequently examined the CGH profiles of seven different cell lines made resistant to three platinum analogues and showed the most consistent abnormalities to involve over-representation of regions 4q and 6q. More recently, we have applied the CGH technique to a series of testicular germ cell tumours (TGCTs) collected as formalin-fixed paraffin-embedded biopsy specimens from patients, both pre- and post-therapy using a platinum-based regimen (POMB/ACE). Previous reports have shown over-representation of X, 7q, 8q and 12p and loss of 13q to occur in 25% of primary TGCTs. Over-representation of 12p was confirmed in the majority of these biopsy samples; deletion of 13q was noted in the initial biopsies of several patients. We also demonstrated alterations of 4p, 4q, 5q and 6q in this series of patients. Newly acquired deletions of 2q and 18q and amplifications of 8q were frequently observed in post-chemotherapy samples from resistant tumours. The CGH studies on these patients with TGCT will not only enable us to correlate our observations on clinical material with those from long-term cell lines, but should also identify sites of key genes involved in clinical platinum resistance.

The diagnosis and prognosis of molar pregnancy: the experience of the National Referral Centre in London.

Since 1973, hCG follow up and treatment of patients with hydatidiform moles in the UK has been centralised. Registrations of moles have increased from 475 to 1248 in 2 years but histological review shows that first trimester non-molar hydropic abortions (HAs) and complete moles (CMs) are often called partial moles (PMs) by pathologists. The introduction and widespread acceptance of the term PM in 1977, coincided with improvements in ultrasound which brought forward 6 weeks the average time of evacuation of CMs, when hydrops is not yet complete but partial and when vessels are present in most CMs, leading to erroneous diagnoses of PM. Many true PMs are dismissed as HAs and often, HAs are called PMs. Valid diagnostic criteria for younger CMs and for PMs have been available for over 10 years and when used, PM is overwhelmingly associated with triploidy. Reported diploid PMs are partly explained by misdiagnosed HAs, rare cases of Beckwith-Widemann syndrome, CMs with partially developed hydrops, twin pregnancies and rare androgenetic CMs with fetal red cells in villi. A rare mole with "normal" diploid biparental karyotype probably exists but morphologically resembles CM. CM and PM have widely different prognosis but the present diagnostic confusion means much of the published epidemiological, clinical and genetic information on PM based on suspect diagnostic criteria ia also suspect.

[Neurophysiological study in Alpers syndrome]. / Estudio neurofisiológico en el síndrome de Alpers.

INTRODUCTION: Infantil progressive polydystrophy was described by Alpers in a child with psychomotor retardation, crises which were resistant to treatment and diffuse loss of cortical neurons. OBJECTIVE: The aim of this study was to review the neurophysiological aspects of Alpers syndrome and their clinical correlation. MATERIAL AND METHODS: We present three children with subacute encephalopathy, progressive psychomotor retardation, myoclonic epilepsy which was resistant to treatment and crises of apnea, who had degeneration of the cerebral grey matter. Serial EEG, polysomnographs, auditory evoked potentials of the brain stem and visual evoked potentials were done. RESULTS: The electroencephalogram findings showed the presence of complex bursts of acute waves, small many-pointed or slow waves of great amplitude which were irregular and arrhythmical, lasting one to five seconds, separated by periods of inactivity on the tracing which lasted from three to ten seconds. The EEG was distinctive, changing over the course of the illness, and with increasing numbers and duration of the bursts of suppression of cerebral bioelectric activity. Polysomnography showed cerebral bioelectric activity which was markedly unstructured and with little difference between the tracings when asleep and when awake, together with a large number of apneas of obstructive and mixed types. The PEAT showed reduced amplitude and altered morphology in all the waves, and even absence of some of them. The visual evoked potentials were asymmetrical and with delay in the latency of the P100 wave. CONCLUSIONS: Although definite diagnosis of progressive neurone degeneration requires post mortem examination of the brain, clinico-pathological studies, including electrophysiological, radiological and biochemical studies are sufficiently characteristic to suggest the diagnosis during life.

Management of placental site trophoblastic tumors.

OBJECTIVE: To analyze the genetic background of tumors in patients with placental site trophoblastic tumors (PSTTs) and clinical outcome in patients treated for this rare variant of trophoblastic disease at a single center. STUDY DESIGN: Analysis of all patients with PSTTs treated at the Charing Cross Hospital between 1975 and 1995. RESULTS: We studied the molecular genetics of a group of PSTTs using polymerase chain reaction allelotyping and GeneScan software. We were able to show, in the seven cases in which detailed molecular analysis was successful, that four of these PSTTs were from diploid, bi-parental pregnancies and three were androgenetic tumors following monospermic complete hydatidiform moles. For patients with PSTT localized to the uterus, the treatment of choice is hysterectomy. The sensitivity of PSTT to current cytotoxic chemotherapy is variable. Several patients have been cured using the etoposide, methotrexate, actinomycin D/cyclophosphamide, vincristine schedule, but clinical impressions suggest that cisplatinum probably should be introduced into the chemotherapy schedule from the outset in a schedule such as etoposide, cisplatin/etoposide, methotrexate, actinomycin D. CONCLUSION: PSTT is a very rare variant of gestational trophoblastic tumor, and its biologic behavior is clearly heterogeneous. The treatment of choice for patients whose disease is limited to the uterus is hysterectomy; for patients with more extensive or metastatic disease, chemotherapy is indicated, but the clinical outcome is variable. A long interval from the antecedent pregnancy to clinical presentation is a major adverse prognostic variable, and the outcome in patients whose last known pregnancy was > 2 years prior to presentation with PSTT is poor.

The diagnosis and prognosis of molar pregnancy: The experience of the National Referral Centre in London.

Since 1973, hCG follow up and treatment of patients with hydatidiform moles in the UK has been centralised. Registrations of moles have increased from 475 to 1248 in 2 years but histological review shows that first trimester non-molar hydropic abortions (HAs) and complete moles (CMs) are often called partial moles (PMs) by pathologists. The introduction and widespread acceptance of the term PM in 1977, coincided with improvements in ultrasound which brought forward 6 weeks the average time of evacuation of CMs, when hydrops is not yet complete but partial and when vessels are present in most CMs, leading to erroneous diagnoses of PM. Many true PMs are dismissed as HAs and often, HAs are called PMs. Valid diagnostic criteria for younger CMs and for PMs have been available for over 10 years and when used, PM is overwhelmingly associated with triploidy. Reported diploid PMs are partly explained by misdiagnosed HAs, rare cases of Beckwith-Widemann syndrome, CMs with partially developed hydrops, twin pregnancies and rare androgenetic CMs with fetal red cells in villi. A rare mole with "normal" diploid biparental karyotype probably exists but morphologically resembles CM. CM and PM have widely different prognosis but the present diagnostic confusion means much of the published epidemiological, clinical and genetic information on PM based on suspect diagnostic criteria ia also suspect.