Imaging characteristics of infantile fibrosarcoma.

AIM: To highlight the imaging findings in a case series of histologically confirmed infantile fibrosarcoma (IF) and identify any features specific to this entity. MATERIALS AND METHODS: Retrospective identification was undertaken of patients with histologically confirmed IF from the electronic patient databases of two institutions between 1 January 2010 and 1 May 2021. Available pre-treatment imaging, histopathological reports, and clinical records were reviewed. RESULTS: Eighteen patients with IF met the inclusion criteria. There were 10 male and eight female patients with a mean age at presentation of 3 weeks. All patients had the t (12; 15) chromosomal translocation. Eleven (61%) tumours were located in the extremities, three were in the craniofacial region, two were intrathoracic, one abdominal and one paraspinal. A single patient had extensive metastases. The tumours were generally isointense to skeletal muscle on T1-weighted sequences and hyperintense on T2 with heterogeneous enhancement and high cellularity seen as diffusion restriction. Fifteen of the 18 lesions were evaluated on ultrasound and appeared as heterogeneous, hypervascular solid or mixed solid/cystic masses, mimicking benign vascular lesions in two cases. CONCLUSION: The present two-centre, retrospective study of the largest case series described thus far demonstrates that IF is always highly cellular on magnetic resonance imaging but has no other specific imaging features. It should be considered in the differential diagnosis of any enlarging soft-tissue, solid mass arising in the limbs or neck at birth or in infancy.

The significance of internal calcifications on perinatal post-mortem radiographs.

AIM: To determine whether the presence of internal calcifications on perinatal post-mortem skeletal surveys (PMSS) are associated with certain diagnoses of fetal loss. METHODS AND MATERIALS: A 6-month retrospective, single-centre, cohort study was conducted on PMSS performed for perinatal death assessment. One reader re-reviewed all PMSS images for the presence and location of internal calcifications, and noted whether these were included within the original radiology report. Findings at autopsy were then reviewed independently by a second researcher and cause of fetal loss or main diagnosis recorded. Chi-squared tests were conducted to identify differences between those with and without internal calcifications at PMSS. RESULTS: Two hundred and thirty perinatal deaths (mean gestational age 18 weeks; average 12-35 weeks) were included in the study, of which 42 (18.3%) demonstrated intra-abdominal calcifications, and 16/42 (38.1%) were mentioned in the radiology reports. Most calcifications were found to be within the lumen of the gastrointestinal tract, and in the left upper quadrant of the abdomen. There was no statistical difference between identifiable causes for fetal loss at autopsy in cases with and without calcification at PMSS (59.5% versus 58.5% respectively, p=0.904). Nevertheless, where calcification and a cause for fetal loss were found, the aetiology was more likely to be due a fetal rather than placental issue. CONCLUSION: The presence of internal calcifications on PMSS was not associated with an increased likelihood of explainable fetal loss or particular diagnosis at autopsy.

Does the gene matter? Genotype-phenotype and genotype-outcome associations in congenital melanocytic naevi.

BACKGROUND: Genotype-phenotype studies can identify subgroups of patients with specific clinical features or differing outcomes, which can help shape management. OBJECTIVES: To characterize the frequency of different causative genotypes in congenital melanocytic naevi (CMN), and to investigate genotype-phenotype and genotype-outcome associations. METHODS: We conducted a large cohort study in which we undertook MC1R genotyping from blood, and high-sensitivity genotyping of NRAS and BRAF hotspots in 156 naevus biopsies from 134 patients with CMN [male 40%; multiple CMN 76%; projected adult size (PAS) > 20 cm, 59%]. RESULTS: Mosaic NRAS mutations were detected in 68%, mutually exclusive with BRAF mutations in 7%, with double wild-type in 25%. Two separate naevi were sequenced in five of seven patients with BRAF mutations, confirming clonality. Five of seven patients with BRAF mutations had a dramatic multinodular phenotype, with characteristic histology distinct from classical proliferative nodules. NRAS mutation was the commonest in all sizes of CMN, but was particularly common in naevi with PAS > 60 cm, implying more tolerance to that mutation early in embryogenesis. Facial features were less common in double wild-type patients. Importantly, the incidence of congenital neurological disease, and apparently of melanoma, was not altered by genotype; no cases of melanoma were seen in BRAF-mutant multiple CMN, however, this genotype is rare. CONCLUSIONS: CMN of all sizes are most commonly caused by mutations in NRAS. BRAF is confirmed as a much rarer cause of multiple CMN, and appears to be commonly associated with a multinodular phenotype. Genotype in this cohort was not associated with differences in incidence of neurological disease in childhood. However, genotyping should be undertaken in suspected melanoma, for guidance of treatment. What's already known about this topic? Multiple congenital melanocytic naevi (CMN) have been shown to be caused by NRAS mosaic mutations in 70-80% of cases, by BRAF mosaicism in one case report and by inference in some previous cases. There has been debate about genotypic association with different sizes of CMN, and no data on genotype-outcome. What does this study add? NRAS mosaicism was found in 68%, BRAF in 7% and double wild-type in 25% of cases of CMN. NRAS was the commonest mutation in all sizes of CMN, but was nearly universal in projected adult size > 60 cm. BRAF is often associated with a distinct multinodular clinical/histological phenotype. Adverse outcomes did not differ between genotypes on current numbers.

Feasibility of INTACT (INcisionless TArgeted Core Tissue) biopsy procedure for perinatal autopsy.

OBJECTIVES: To determine the feasibility and tissue yield of a perinatal incisionless ultrasound-guided biopsy procedure, the INcisionless Targeted Core Tissue (INTACT) technique, in the context of minimally invasive autopsy. METHODS: Cases of perinatal death in which the parents consented for minimally invasive autopsy underwent postmortem magnetic resonance imaging and an INTACT biopsy procedure, defined as needle biopsy of organs via the umbilical cord, performed under ultrasound guidance. In each case, three cores of tissue were obtained from seven target organs (both lungs, both kidneys, heart, spleen and liver). Biopsy success was predefined as an adequate volume of the intended target organ for pathological analysis, as judged by a pathologist blinded to the case and biopsy procedure. RESULTS: Thirty fetuses underwent organ sampling. Mean gestational age was 30 weeks (range, 18-40 weeks) and mean delivery-to-biopsy interval was 12 days (range, 6-22 days). The overall biopsy success rate was 153/201 (76.1%) samples, with the success rates in individual organs being highest for the heart and lungs (93% and 91%, respectively) and lowest for the spleen (11%). Excluding splenic samples, the biopsy success rate was 150/173 (86.7%). Histological abnormalities were found in 4/201 (2%) samples, all of which occurred in the lungs and kidneys of a fetus with pulmonary hypoplasia and multicystic kidney disease. CONCLUSIONS: Incisionless ultrasound-guided organ biopsy using the INTACT procedure is feasible, with an overall biopsy success rate of over 75%. This novel technique offers the ideal combination of an imaging-led autopsy with organ sampling for parents who decline the conventional invasive approach. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Lung metastases in low-risk gestational trophoblastic neoplasia: a retrospective cohort study.

OBJECTIVE: Presence of lung metastases in low-risk gestational trophoblastic neoplasia (GTN) is generally considered not to influence prognosis. However, in a recent study in the Netherlands, GTN patients with lung metastases had a higher recurrence rate and more disease-specific deaths compared with patients without metastases. The aim of the present study was to validate these findings in a different country. DESIGN: Historical cohort study. SETTING: Charing Cross Hospital, United Kingdom. POPULATION: A total of 1040 low-risk GTN patients treated with methotrexate (MTX) between 2002 and 2016 were identified: 65 with lung metastases (group 1) and 975 without metastases (group 2). METHODS: Baseline characteristics, MTX resistance, survival and recurrence rates were recorded and compared between both groups. MAIN OUTCOME MEASURES: MTX resistance, recurrence rate and survival. RESULTS: The occurrence of MTX resistance and median number of MTX courses to achieve remission was significantly higher in patients with lung metastases than patients without metastases (60% versus 38.9%, P = 0.001; and nine versus six courses, P < 0.001). All choriocarcinoma patients (n = 4) with lung metastases developed MTX resistance. The recurrence rate was also higher in group I (9.2% versus 2.7%; P = 0.012). Disease-specific survival was 100% in both groups. CONCLUSIONS: The presence of lung metastases at the start of MTX therapy is associated with increased incidence of MTX resistance and recurrence in low-risk GTN without affecting overall survival, which remains 100%. However, individuals with low-risk choriocarcinoma with lung metastases are likely to become resistant to MTX and primary multi-agent chemotherapy should be considered. TWEETABLE ABSTRACT: The presence of lung metastases appears to increase the risk of recurrence in low-risk GTN, but does not affect overall cure rates and survival.

Melanotic neuroectodermal tumour of infancy: Refining the surgical approach.

Melanotic neuroectodermal tumours of infancy (MNTI) are particularly rare and although predominantly benign, are infiltrative and locally aggressive. Presenting in the first year of life, prompt diagnosis and effective management are critical in minimizing morbidity and the risk of recurrence. A retrospective review of 11 MNTI managed at Great Ormond Street Hospital (GOSH) from 2000 to 2017 was undertaken. Eight tumours presented in the maxilla, two in the skull and one in the mandible. The primary modality of treatment was surgery in 10 cases with one patient receiving neoadjuvant chemotherapy. In spite of microscopically incomplete resection in seven cases, only three recurred. Overall, there was a local recurrence rate of 27% with no distant metastases noted. Disease-free survival was 100% with a follow-up ranging from 0.75 to 17 years (median 5 years). Taking our results in conjunction with the available literature, there is a role for conservative initial surgery of MNTI and this should be coupled with delayed reconstruction and intensive short-term follow-up. We propose an adapted treatment algorithm that aims to balance the risk of recurrence and malignant change with surgical morbidity in an infant population.

Minimally invasive perinatal and pediatric autopsy with laparoscopically assisted tissue sampling: feasibility and experience of the MinImAL procedure.

OBJECTIVE: Less invasive autopsy techniques in cases of fetal or infant death have good acceptability among parents, but the published sampling adequacy in needle biopsy studies is generally poor. Minimally Invasive Autopsy with Laparoscopically assisted sampling (MinImAL) has the potential to increase the diagnostic yield of less invasive autopsy by improving the quality and quantity of tissue samples obtained, whilst permitting visualization, extraction and examination of internal organs through a small incision. The aim of this study was to present the findings of our experience with the MinImAL procedure in cases of fetal, neonatal and pediatric death. METHODS: This was a retrospective analysis of 103 prospectively recruited unselected cases of fetal, neonatal or pediatric death that underwent the MinImAL procedure at a tertiary referral center over a 5-year period. Following preprocedure 1.5-T whole-body postmortem magnetic resonance imaging, MinImAL autopsy was performed. Procedure duration, sampling adequacy and cause of death were assessed. Chi-square analysis was used to compare the 'unexplained' rate of intrauterine deaths in the cohort with that in a previously published cohort of > 1000 cases of intrauterine death examined by standard autopsy. RESULTS: MinImAL autopsy was performed successfully in 97.8% (91/93) of the cases undergoing a complete procedure. There was a satisfactory rate of adequate histological sampling in most major organs; heart (100%, 91 cases), lung (100%, 91 cases), kidney (100%, 91 cases), liver (96.7%, 88 cases), spleen (94.5%, 86 cases), adrenal glands (89.0%, 81 cases), pancreas (82.4%, 75 cases) and thymus (56.0%, 51 cases). Procedure duration was similar to that of standard autopsy in a previously published cohort of intrauterine deaths. The unexplained rate in stillbirths and intrauterine fetal deaths that underwent MinImAL autopsy was not significantly different from that following standard autopsy. CONCLUSIONS: The MinImAL procedure provides good histological yield from major organs with minimal cosmetic damage and can be learned by an autopsy practitioner. The MinImAL procedure is an appropriate minimally invasive alternative for the investigation of perinatal and pediatric deaths in which consent to full autopsy is withheld, and may have applications in both high- and low/middle-income settings. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts.

BACKGROUND: Linear morphoea (LM) is a rare connective tissue disorder characterized by a line of thickened skin and subcutaneous tissue and can also affect the underlying muscle and bone. Little is known about the disease aetiology, with treatment currently limited to immune suppression, and disease recurrence post-treatment is common. OBJECTIVES: In order to uncover new therapeutic avenues, the cell-intrinsic changes in LM fibroblasts compared with site-matched controls were characterized. METHODS: We grew fibroblasts from site-matched affected and unaffected regions from five patients with LM, we subjected them to gene expression analysis and investigation of SMAD signalling. RESULTS: Fibroblasts from LM lesions showed increased migration, proliferation, altered collagen processing, and abnormally high basal levels of phosphorylated SMAD2, thereby rendering them less responsive to transforming growth factor (TGF)-ß1 and reducing the degree of myofibroblast differentiation, which is a key component of the wound-healing and scarring process in normal skin. Conditioned media from normal fibroblasts could reverse LM-affected fibroblast migration and proliferation, suggesting that the LM phenotype is driven by an altered secretome. Gene array analysis and RNA-Seq indicated upregulation of ADAMTS8 and downregulation of FRAS1 and SOSTDC1. SOSTDC1 knock-down recapitulated the reduced TGF-ß1 responsiveness and LM fibroblast migration, while overexpression of ADAMTS8 induced myofibroblast markers. CONCLUSIONS: We demonstrate that cell-intrinsic changes in the LM fibroblast secretome lead to changes observed in the disease, and that secretome modulation could be a viable therapeutic approach in the treatment of LM.

Essential variables for reporting research studies on fetal growth restriction: a Delphi consensus.

OBJECTIVE: To determine, by expert consensus using a Delphi procedure, a minimum reporting set of study variables for fetal growth restriction (FGR) research studies. METHODS: A panel of experts, identified based on their publication record as lead or senior author of studies on FGR, was asked to select a set of essential reporting study parameters from a literature-based list of variables, utilizing the Delphi consensus methodology. Responses were collected in four consecutive rounds by online questionnaires presented to the panelists through a unique token-secured link for each round. The experts were asked to rate the importance of each parameter on a five-point Likert scale. Variables were selected in the three first rounds based on a 70% threshold for agreement on the Likert-scale scoring. In the final round, retained parameters were categorized as essential (to be reported in all FGR studies) or recommended (important but not mandatory). RESULTS: Of the 100 invited experts, 87 agreed to participate and of these 62 (71%) completed all four rounds. Agreement was reached for 16 essential and 30 recommended parameters including maternal characteristics, prenatal investigations, prenatal management and pregnancy/neonatal outcomes. Essential parameters included hypertensive complication in the current pregnancy, smoking, parity, maternal age, fetal abdominal circumference, estimated fetal weight, umbilical artery Doppler (pulsatility index and end-diastolic flow), fetal middle cerebral artery Doppler, indications for intervention, pregnancy outcome (live birth, stillbirth or neonatal death), gestational age at delivery, birth weight, birth-weight centile, mode of delivery and 5-min Apgar score. CONCLUSIONS: We present a list of essential and recommended parameters that characterize FGR independent of study hypotheses. Uniform reporting of these variables in prospective clinical research is expected to improve data quality, study consistency and ultimately our understanding of FGR. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Perinatal and long-term effects of maternal uterine artery adenoviral VEGF-A165 gene therapy in the growth-restricted guinea pig fetus.

Uterine artery application of adenoviral vascular endothelial growth factor A165 (Ad.VEGF-A165) gene therapy increases uterine blood flow and fetal growth in experimental animals with fetal growth restriction (FGR). Whether Ad.VEGF-A165 reduces lifelong cardiovascular disease risk imposed by FGR remains unknown. Here, pregnant guinea pigs fed 70% normal food intake to induce FGR received Ad.VEGF-A165 (1×1010 viral particles, n = 15) or vehicle ( n = 10), delivered to the external surface of the uterine arteries, in midpregnancy. Ad libitum-fed controls received vehicle only ( n = 14). Litter size, gestation length, and perinatal mortality were similar in control, untreated FGR, and FGR+Ad.VEGF-A165 animals. When compared with controls, birth weight was lower in male but higher in female pups following maternal nutrient restriction, whereas both male and female FGR+Ad.VEGF-A165 pups were heavier than untreated FGR pups ( P < 0.05, ANOVA). Postnatal weight gain was 10-20% greater in female FGR+Ad.VEGF-A165 than in untreated FGR pups, depending on age, although neither group differed from controls. Maternal nutrient restriction reduced heart weight in adult female offspring irrespective of Ad.VEGF-A165 treatment but did not alter ventricular wall thickness. In males, postnatal weight gain and heart morphology were not affected by maternal treatment. Neither systolic, diastolic, mean arterial pressure, adrenal weight, nor basal or challenged plasma cortisol were affected by maternal undernutrition or Ad.VEGF-A165 in either sex. Therefore, increased fetal growth conferred by maternal uterine artery Ad.VEGF-A165 is sustained postnatally in FGR female guinea pigs. In this study, we did not find evidence for an effect of maternal nutrient restriction or Ad.VEGF-A165 therapy on adult offspring blood pressure.

Post-mortem magnetic resonance (PMMR) imaging of the brain in fetuses and children with histopathological correlation.

Post-mortem magnetic resonance (PMMR) imaging is rapidly emerging as an alternative, "less invasive", and more widely accepted investigative approach for perinatal deaths in the UK. PMMR has a high diagnostic accuracy for congenital and acquired fetal neuropathological anomalies compared to conventional autopsy, and is particularly useful when autopsy is non-diagnostic. The main objectives of this review are to describe and illustrate the range of common normal and abnormal central nervous system (CNS) findings encountered during PMMR investigation. This article covers the standard PMMR sequences used at our institution, normal physiological post-mortem findings, and a range of abnormal developmental and acquired conditions. The abnormal findings include diseases ranging from neural tube defects, posterior fossa malformations, those of forebrain and commissural development as well as neoplastic, haemorrhagic, and infectious aetiologies. Neuropathological findings at conventional autopsy accompany many of the conditions we describe, allowing readers to better understand the underlying disease processes and imaging appearances.

Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset.

BACKGROUND: Worldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible. PATIENTS AND METHODS: Between January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified. RESULTS: Of the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5-10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7-44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0-16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3-3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9-12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4-30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system. CONCLUSION: Our simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.

Inter-observer variability of the histological classification of lupus glomerulonephritis in children.

The gold standard for the classification of lupus nephritis is renal histology but reporting variation exists. The aim of this study was to assess the inter-observer variability of the 2003 International Society of Nephrology/Royal Pathology Society (ISN/RPS) lupus nephritis histological classification criteria in children. Histopathologists from a reference centre and three tertiary paediatric centres independently reviewed digitalized renal histology slides from 55 children with lupus nephritis. Histological ISN/RPS Class was assigned and features scored; lupus nephritis-activity [scored 0-24], lupus nephritis-chronicity [0-12] and tubulointerstitial activity [0-21]. In the cohort (73% females), the age at the time of biopsy was 15.5 ± 0.39 (mean ± standard error) years. Based on the reference centre, 42% (23/55) had ISN/RPS Class IV with lupus nephritis-activity score 4.23 ± 0.50, lupus nephritis-chronicity 1.81 ± 0.18 and tubulointerstitial activity 4.45 ± 0.35. There were 4-54 (mean 16.7) glomeruli per biopsy. Pathologists had fair agreement for ISN/RPS assignment (kappa; 0.26 ± 0.12), lupus nephritis-chronicity (intra-class correlation 0.36 ± 0.09) and tubulointerstitial activity (0.22 ± 0.09) scores. There was good agreement for lupus nephritis-activity scores (intra-class correlation 0.69 ± 0.06). When categorized into proliferative and non-proliferative disease, poor agreement among sites remained (kappa 0.24 ± 0.11). Despite unified criteria for the interpretation of histological features of lupus nephritis, marked reporting variation remains in clinical practice. As proliferative lupus nephritis is managed more intensively, this may influence renal outcomes.

Melanoma in congenital melanocytic naevi.

Congenital melanocytic naevi (CMN) are a known risk factor for melanoma, with the greatest risk currently thought to be in childhood. There has been controversy over the years about the incidence of melanoma, and therefore over the clinical management of CMN, due partly to the difficulties of histological diagnosis and partly to publishing bias towards cases of malignancy. Large cohort studies have demonstrated that melanoma risk in childhood is related to the severity of the congenital phenotype. New understanding of the genetics of CMN offers the possibility of improvement in diagnosis of melanoma, identification of those at highest risk, and new treatment options. We review the world literature and our centre's experience over the last 25 years, including the molecular characteristics of melanoma in these patients and new melanoma incidence and outcome data from our prospective cohort. Management strategies are proposed for presentation of suspected melanoma of the skin and the central nervous system in patients with CMN, including use of oral mitogen-activated protein kinase kinase inhibitors in NRAS-mutated tumours.

Stillbirth and intrauterine fetal death: contemporary demographic features of >1000 cases from an urban population.

OBJECTIVES: Of 780 000 births annually in the UK, around 3300 are stillborn, a rate of approximately 4 per 1000 births. Traditional epidemiological associations are based on historic data. The aim of this study was to document contemporary demographic findings in a large series of > 1000 deaths in utero in London and compare these with national datasets. METHODS: From a dedicated database, including > 400 data fields per case, of fetal, infant and pediatric autopsies performed at Great Ormond Street Hospital and St George's Hospital, London, we extracted information on all intrauterine deaths, excluding terminations of pregnancy, from 2005 to 2013, inclusive. Demographic data were analyzed according to the gestational age at which fetal death occurred (second-trimester intrauterine fetal death (IUFD), subdivided into early (< 20 weeks) and late (20-23 weeks) IUFD, and third-trimester stillbirth (≥ 24 weeks)) and compared with national datasets when available, using Mann-Whitney U-test and comparison of proportions testing as appropriate. RESULTS: Data were available from 1064 individual postmortem reports examining intrauterine deaths delivered between 12 and 43 weeks' gestation, including 425 IUFDs (246 early and 179 late) and 639 stillbirths. Compared with the overall UK pregnant population, women in whom an intrauterine death occurred were significantly older and more obese. White mothers had a higher proportion of stillbirths (as opposed to IUFDs) than did non-white mothers, whereas black mothers had a higher proportion of IUFDs relative to stillbirths. Increased body mass index was associated with increased risk across all groups. Women who had uterine fibroids, those who had a history of vaginal bleeding in early pregnancy and those who had undergone assisted conception had a relatively higher proportion of IUFDs than stillbirths. CONCLUSIONS: Based on a large series of >1000 autopsies in cases of intrauterine death, these data highlight the increased risk for fetal loss associated with maternal demographic factors in contemporary clinical practice, particularly associations with increased maternal age and body mass index. Among women in whom an intrauterine death occurs, maternal ethnicity, mode of conception and gynecological history are associated with differing timing of fetal loss. Further research is required to understand the mechanisms involved in such maternal factors in order to develop preventative strategies. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Intraplacental choriocarcinoma: Systematic review and management guidance.

BACKGROUND: Intraplacental choriocarcinoma (IC) is a rare form of malignant gestational trophoblastic disease (GTD). We present a review of 62 cases, including four previously unreported, and a suggested management algorithm. PATIENTS AND METHODS: IC cases and clinical data were identified within the Charing Cross Hospital (CXH) national GTD database (1986-2014) and by systematic literature search (1949-2014). RESULTS: 62 cases were identified including eight from CXH representing 0.03% of all GTD (n=27,101) diagnosed between 1986 and 2014. Most cases were identified in the third trimester (n=52; 84%) among asymptomatic women (n=31; 50%) and with macroscopically normal placenta in 29% (18/62). In 29 non-metastatic cases with available data, 4 (14%) underwent adjuvant chemotherapy and 25 (86%) surveillance only, one of whom relapsed with metastatic disease cured with multi-agent chemotherapy. In 32 patients with metastatic disease (31 at presentation and one with relapse during surveillance), all 18 treated since 1990 achieved complete remission with multi-agent chemotherapy. Among 58 cases with available data, there were 20 fetal deaths and 38 live births with 2 neonatal deaths. Of the two (5%) cases of infantile choriocarcinoma, one was cured with intensive therapy and the other died shortly after commencing single agent treatment. A further neonatal death was due to fetomaternal haemorrhage. CONCLUSIONS: IC usually occurs in the third trimester and is often asymptomatic with no macroscopic placental abnormalities. Prognosis with current therapy is generally excellent, even for patients presenting with metastatic disease. Around 60% of pregnancies affected by IC result in a live birth with a low neonatal mortality.