Incidence of NUT carcinoma in Western Australia from 1989 to 2014: a review of pediatric and adolescent cases from Perth Children's Hospital.

BACKGROUND: NUT carcinoma (NC), previously known as NUT midline carcinoma, is a rare and very aggressive cancer that occurs in both children and adults. NC is largely chemoresistant, with an overall survival of less than 7 months. Because the carcinoma is not restricted to a particular organ, diagnosis is often a challenge. In the absence of a clearly determined incidence for NC, we sought to study the diagnosis of patients in a well-defined population. METHODS: We systematically reviewed records of all patients that presented to the Oncology Department of the Princess Margaret Hospital for Children from 1989 to 2014. This institution in the geographically isolated state of Western Australia has a catchment population of around 2 million. We then identified all high grade undifferentiated sarcomas or carcinomas in the 0-16 year age group. RESULTS: Over 26 years, we found 14 patients of 16 years or younger with undifferentiated malignant tumors. Of these, five tumors were positive by immunohistochemistry for the NUT/NUTM1 (Nuclear Protein in Testis) protein and/or the translocation t(15;19). Three patients presented with thoracic tumors, one with a para-spinal tumor, and one had an upper airway nasopharyngeal carcinoma. In all five cases, there was an initial response to therapy and then progression. This 26-year survey was conducted in a geographically isolated state with a well-defined population, and we determined an estimated incidence of NC of around 0.41 per million child years (0-16 yrs. of age) at risk. From three patients it was feasible to derive cell lines for further genetic analyses and drug screening. CONCLUSIONS: For the first time, the incidence of NC could be determined in a well-defined geographic area. The calculated rate of NC incidence is consistent with a history of under-recognition for this malignancy. These findings indicate that improved diagnostic detection of NC would enable better management and counselling of patients. Our findings emphasize the heterogeneity of NC, and they highlight the need to develop personalised therapy options, and to consider a diagnosis of NC in undifferentiated malignant tumors.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

The potential impact of NIPT as a second-tier screen on the outcomes of high-risk pregnancies with rare chromosomal abnormalities.

AIM: To describe the potential impact of using noninvasive prenatal testing (NIPT) as a second-tier test, on the diagnosis and outcomes of pregnancies identified as high risk through first trimester screening (FTS) in a cohort of real pregnancies. MATERIALS AND METHODS: Western Australian FTS and diagnostic data (2007-2009) were linked to pregnancy outcomes. Karyotype results from invasive prenatal testing in high-risk women were analysed. The outcomes of abnormal results that would not be detected by NIPT, assuming a panel of trisomy 21/18/13 and sex chromosome aneuploidies, and the likelihood of diagnosis in a screening model using NIPT as a second-tier test are described. RESULTS: Abnormal karyotype results were reported in 224 of 1488 (15%) women with high-risk pregnancies having invasive diagnostic testing. NIPT potentially would have identified 85%. The 33 abnormalities unidentifiable by NIPT were triploidies (n = 7, 21%), balanced (n = 8, 24%) and unbalanced rearrangements (n = 10, 30%) and level III mosaicisms (n = 8, 24%). For conditions not identifiable by NIPT, fetal sonographic appearance was likely to have led to invasive testing for 10 of 17 (59%) pathogenic abnormalities. If a policy was adopted recommending invasive testing for FTS risk >1:50 and/or ultrasound detected abnormality, the residual risk of an unidentified pathogenic chromosomal abnormality in those without a diagnosis would have been 0.33% (95% CI 0.01-0.65%). CONCLUSIONS: A screening model with NIPT as a second-tier for high-risk pregnancies would be unlikely to have changed the outcome for the majority of pregnancies. Optimising the diagnosis of rare pathogenic abnormalities requires clear indicators for invasive testing over NIPT.

Evaluation of fluorescence in-situ hybridization in monomorphic endometrial stromal neoplasms and their histological mimics: a review of 49 cases.

AIMS: To perform a population-based review of monomorphic endometrial stromal tumours and their histological mimics presenting over a 20-year period, including an evaluation of fluorescence in-situ hybridization (FISH) for the JAZF1 and YWHAE breakaparts. METHODS AND RESULTS: Forty-nine tumours were examined, comprising 13 histological mimics and 36 endometrial stromal tumours [six stromal nodules (ESNs), 25 low-grade stromal sarcomas (ESSs), and five monomorphic undifferentiated sarcomas (mUESs)]. Nine ESSs showed variant histological patterns, including smooth muscle, sex cord-like/glandular, fibrous or rhabdoid differentiation. Three ESSs were initially misclassified as benign uterine lesions, and, conversely, three benign mimics were originally reported as ESSs. One mUES showed a prominent pseudopapillary pattern. Fluorescence in-situ hybridization demonstrated JAZF1 breakaparts in five of six ESNs and 16 of 25 ESSs; however, only three of nine ESS variants were positive. YWHAE breakaparts were present in four of five mUESs. Analysis of a subsequent metastasis in the YWHAE breakapart-negative mUES demonstrated a YWHAE deletion. None of the histological mimics was positive in FISH analysis. Diffuse cyclin D1 expression was restricted to mUESs in this series. CONCLUSIONS: Endometrial stromal neoplasms continue to present diagnostic difficulty. Fluorescence in-situ hybridization analysis is helpful in distinguishing stromal tumours from their histological mimics and in distinguishing ESS from mUES.

Prenatal screening for Down syndrome in Australia: costs and benefits of current and novel screening strategies.

OBJECTIVE: To analyse the cost-effectiveness and performance of noninvasive prenatal testing (NIPT) for high-risk pregnancies following first-trimester screening compared with current practice. METHODS: A decision tree analysis was used to compare the costs and benefits of current practice of first-trimester screening with a testing pathway incorporating NIPT. We applied the model to 32 478 singleton pregnancies screened between January 2005 and December 2006, adding Medicare rebate data as a measure of public health system costs. The analyses reflect the actual uptake of screening and diagnostic testing and pregnancy outcomes in this cohort. RESULTS: The introduction of NIPT would reduce the number of invasive diagnostic procedures and procedure-related fetal losses in high-risk women by 88%. If NIPT was adopted by all women identified as high risk by first-trimester combined screening, up to 7 additional Down syndrome fetuses could be confirmed. The cost per trisomy 21 case confirmed, including NIPT was 9.7% higher ($56,360) than the current prenatal testing strategy ($51,372) at a total cost of $3.91 million compared with $3.57 million over 2 years. CONCLUSION: Based on the uptake of screening and diagnostic testing in a retrospective cohort of first-trimester screening in Western Australia, the implementation of NIPT would reduce the number of invasive diagnostic tests and the number of procedure-related fetal losses and increase the cost by 9.7% over two years. Policy planning and guidelines are urgently required to manage the funding and demand for NIPT services in Australia.

Pre-natal, clonal origin of t(1;11)(p32;q23) acute lymphoblastic leukemia in monozygotic twins.

AIM: Observation of identical genetic changes in leukemia cells from monozygotic twin pairs has provided evidence for the in utero single clonal origin hypothesis of leukemia, with intraplacental metastasis the basis for concordance. Investigation of this rare mixed lineage leukemia (MLL) cytogenetic abnormality aims to provide further evidence of the genetic changes that underpin this aggressive form of leukemia in infants. METHOD: The clinical features of a monozygotic infant twin pair with acute lymphoblastic leukemia (ALL) are reported. Banded chromosomal analysis and fluorescent in situ hybridization were used for cytogenetic characterization of the leukemic cells. Immunophenotype was determined by flow cytometry and polymerase chain reaction was used to determine the presence of FLT3-D835/I836 and FLT3-internal tandem duplication (ITD) mutations. RESULTS: The twins were seven weeks of age at diagnosis. Both had cytogenetic evidence for the t(1;11)(p32;q23) translocation. Trisomy X was present in a subpopulation of cells in one twin. Immunophenotypic profile at diagnosis was consistent with B precursor ALL (CD19, CD24, CD33 positive, weak CD13 positivity, CD10 negative) and both were negative for FLT3-D835/I836 and FLT3-ITD mutations. CONCLUSIONS: This is the first report of monochorionic monozygotic twins harboring the t(1;11)(p32;q23) translocation. Identification of this rare translocation in both twins, indicates a common stem line and provides further evidence for the intrauterine monoclonal origin for infant ALL with concordance explained by the shared circulation. Genetic diversity was observed in a subpopulation of cells from one twin at diagnosis. We must now utilize the sophisticated molecular biology tools available to capture changes at the genome-wide level to gain further insight into the complex events contributing to MLL leukemogenesis in infants.

Structural chromosome disruption of the NR3C2 gene causing pseudohypoaldosteronism type 1 presenting in infancy.

Type I pseudohypoaldosteronism (PHA1) is a rare form of mineralocorticoid resistance presenting in infancy with renal salt wasting and failure to thrive. Here, we present the case of a 6-week-old baby girl who presented with mild hyponatraemia and dehydration with a background of severe failure to thrive. At presentation, urinary sodium was not measurably increased, but plasma aldosterone and renin were increased, and continued to rise during the subsequent week. Despite high calorie feeds the infant weight gain and hyponatraemia did not improve until salt supplements were commenced. Subsequently, the karyotype was reported as 46,XX,inv (4)(q31.2q35). A search of the OMIM database for related genes at or near the inversion breakpoints, showed that the mineralocorticoid receptor gene (NR3C2) at 4q31.23 was a likely candidate. Further FISH analysis showed findings consistent with disruption of the NR3C2 gene by the proximal breakpoint (4q31.23) of the inversion. There was no evidence of deletion or duplication at or near the breakpoint. This is the first report of a structural chromosome disruption of the NR3C2 gene giving rise to the classical clinical manifestations of pseudohypoaldosteronism type 1 in an infant.

Perilobar nephrogenic rests and chromosome 22.

Perilobar nephrogenic rests (NR) are precursor lesions that may display genetic changes similar to their associated Wilms tumor (WT). Two patients presented with WT, both with perilobar NR and 1 with bilateral, multifocal metachronous WT. Both patients' WT displayed monosomy 22 as the predominant cytogenetic change, and the constitutional cytogenetic analysis was normal. The purpose of our study was to identify at what stage in the morphologic progression from NR to WT the monosomy 22 occurred by using a fluorescent in situ hybridization probe for chromosome 22 in the subtypes of perilobar NR and WT present in both cases. Section and core fluorescent in situ hybridization with a chromosome 22 probe was performed on formalin-fixed, paraffin-embedded tissues containing WT and perilobar NR. We also performed fluorescent-based microsatellite analysis on some of the WT in the bilateral case to determine whether there was a preferential loss of the same allele of chromosome 22. Sclerotic and dormant perilobar NR showed a rate of monosomy 22 of only approximately 30%, but this increased to approximately 50% in hyperplastic and adenomatous NR. Monosomy 22 was present in 60%-80% of nuclei in WT. Microsatellite analysis showed loss of homozygosity, with preferential loss of the same allele of chromosome 22 in the tumors examined. There are differences in the rate of detection of monosomy 22 in perilobar NR and WT, suggesting loss of chromosome 22 in the progression of perilobar NR to WT in a subset of tumors.

Pathology, genetics and cytogenetics of Wilms' tumour.

Wilms' tumour (WT) is an embryonal cancer of childhood and is thought to be derived from embryonic kidney precursor cells. The Knudson two hit model was initially thought to occur in WT, but findings emerging from genetic and cytogenetic studies in the past two decades have implicated several genetic events. Recent techniques in genetic analysis have improved our ability to characterise changes in genes involved in WT which include WT1, CTNNB1, IGF2 and WTX. These genetic events have not only provided insight into the pathobiology of this malignancy, but the recognition of these candidate genes may offer potential targets for novel therapies. In this review, we will provide an overview of the pathological, genetic and cytogenetic characteristics of WT.

Socio-demographic disparities in the uptake of prenatal screening and diagnosis in Western Australia.

INTRODUCTION: Since the early 1980s, prenatal screening using ultrasound and biochemical markers has been used to refine the risk of Down syndrome and other fetal anomalies prior to considering fetal karyotyping. The performance of prenatal screening is subject to ongoing monitoring in Western Australia. The collection of these data can also assist in the identification of any potential inequities of access to prenatal screening within the state-wide programme. METHODS: Prenatal screening data (2005-2006) were collected from accredited ultrasound and pathology laboratories in Western Australia. Screening data were linked to diagnostic and pregnancy outcome data. Performance characteristics of screening and uptake by socio-demographic characteristics were analysed. RESULTS: Complete screening data were collected for 35,142 of the estimated 38,081 women screened during 2005 and 2006. There were 59,999 births related to this screening period. The lowest uptake of screening was among women who were Aboriginal (14.9%), living in remote areas (38.0%), under the age of 25 (40.2%), in the lowest quintile of the SEIFA index (41.6%) and with three or more children (48.4%). Logistic regression analysis showed all socio-demographic factors to be strongly associated with screening behaviour, with adjustment for ethnicity, socio-economic status, age, parity and area of residence. DISCUSSION: Our results have important implications for the delivery of prenatal screening services in Western Australia. While the screening programme meets international and national performance standards, the disparities in screening uptake suggest inequity in access to services, particularly for Aboriginal, remote and socio-economically disadvantaged women.

Cytogenetic findings in Wilms' tumour: a single institute study.

AIMS: Cytogenetic abnormalities of Wilms' tumour (WT) treated in a single institution in Western Australia were reviewed. Correlation with histologic subtypes, stage, presence of nephrogenic rests and age of the patient at diagnosis were also evaluated. METHODS: 53 WT specimens were encountered between 1995 and 2009. Tissue culture was obtained in 49 (92%) specimens. Reports documenting histopathological features of the tumour, stage and outcome were also retrieved. RESULTS: A total of 53 tumour specimens from 42 patients/cases were examined and staged in accordance with the National Wilms' Tumor Study (NWTS). Thirty-eight cases were unilateral (34 unifocal, 4 multifocal) and four were bilateral (2 multifocal). Fifty tumours showed favourable histology WT. One tumour was a cystic partially differentiated nephroblastoma (CPDN). Two tumours showed diffuse anaplasia. Eighteen specimens had nephrogenic rests, seven with perilobar rests, 10 with intralobar rests and one with both types of nephrogenic rests. Twelve WTs were assigned as stage 1, 22 as stage 2, 16 as stage 3, and two each for stages 4 and 5. For chromosomal analysis, 92% of the specimens yielded results, of which 70% showed abnormal karyotype and 22% displayed normal karyotypic findings. Hyperdiploidy was more common than hypodiploidy. The most common chromosomal gain involved chromosome 12. Low stage tumours tended to have abnormal karyotypes with hyperdiploidy and hypodiploidy being more common. There was no statistical correlation between abnormal karyotype and stage or abnormal karyotype and age group or abnormal karyotype and non-blastemal WT. Eleven (58%) tumours harbouring nephrogenic rests displayed an abnormal karyotype. 16q loss or der(16)t(1;16) were more common in younger patients but no association was made between this chromosomal abnormality and stage. Monosomy 22 and gain of 1q were more common in older patients. Furthermore, monosomy 22 tended to occur in tumours of earlier stage. No correlation between 11p deletions and age or stage was seen. CONCLUSIONS: WTs are karyotypically heterogeneous tumours. Conventional cytogenetic analysis of WTs still remains a useful technique to assist in the understanding of these tumours.

Rate of X chromosome aneuploidy in young fertile women: Comparison of cultured and uncultured cell preparations using fluorescence in situ hybridisation.

BACKGROUND: X chromosome aneuploidy <10% in female patients is a routinely used reporting limit in diagnostic cytogenetics. X aneuploidy (<10%) is commonly detected in women investigated for infertility or recurrent miscarriages. It is unclear if this aneuploidy is causally relevant or related to the culture process. Information about the background rate of X aneuploidy in young fertile women would be helpful in resolving this issue. AIM: This study aimed to investigate the rate of X aneuploidy in young fertile women in cultured and uncultured samples to determine if the commonly used <10% limit is relevant. METHOD: Volunteers (aged 22-40 years) with proven fertility (n = 78) participated. The number of X chromosome signals in 500 cultured and 500 uncultured preparations were enumerated using FISH. RESULTS: Significantly, all participants had <5% X aneuploidy in both preparations, X chromosome loss occurred (2.4%) more frequently than gain (0.7%). Cultured preparations had a mean of 2.1% cells with X chromosome aneuploidy (95% CI 1.9-2.3%) compared with a mean rate of 0.9% aneuploidy in uncultured preparations (95% CI 0.7-1.1%). The relative risk for cultured preparations having X aneuploidy compared with uncultured cells was 2.33 (P < 0.001) (95% CI 2.1-2.6). CONCLUSION: Young fertile women had <5% X aneuploidy. The rate of X aneuploidy was higher in cultured (2.1%) compared with uncultured (0.9%) preparations (P < 0.001). This data may provide useful background information when considering low level X aneuploidy in other groups of women with clinical indications for karyotype.

The selective use of rapid aneuploidy screening in prenatal diagnosis.

AIMS: To evaluate the diagnostic utility and costing of the selective use of rapid aneuploidy screening (RAS) for chorion villus sampling (CVS) and amniocentesis specimens. METHODS: CVS and amniocenteses performed between 2000 and 2006 were identified. Cases were subdivided into two groups: (i) RAS in addition to long-term culture and (ii) long-term chromosome culture alone. The frequency of RAS, the proportion of abnormal results and the cytogenetic costings were reviewed. RESULTS: A total of 3315 procedures were performed: 730 CVS and 2585 amniocenteses. An abnormal karyotype culture was present in 366 of 3315 (11%). For CVS an abnormal culture was present in 164 (22.5%). RAS (short-term culture/direct preparation) was selectively used in 399 cases (54.6%) with an abnormal result in 128 (32% of RAS). For amniocentesis, 206 chromosome abnormalities were present (8.0% of specimens). RAS (interphase FISH) was selectively used in 580 amniocenteses (22.4%). FISH was requested in 95 (66.4%) of the 143 abnormal cases potentially detectable with standard probes. There was a progressive increase in utilisation of RAS for amniocentesis (8.9% in 2000 to 43.3% of cases in 2006, P < 0.001). CVS RAS was stable. This liberalisation resulted in a fourfold increase in expenditure for FISH and cost/abnormality detected ($A970 per abnormal result in 2000 to $A4015 per abnormal result in 2006). CONCLUSION: The selective use of prenatal RAS results in a reasonably high detection rate for chromosomal anomalies. Liberalisation of RAS, however, is an expensive cytogenetic model. An approach based on some predictive level of risk combined with resource funding levels may be a more pragmatic approach.

Clear cell renal cell carcinoma with smooth muscle stroma.

A recent publication described 5 unusual clear cell renal tumors with prominent smooth muscle stroma that were characterized only by immunostaining. We report 3 additional tumors composed of clear cell renal cell carcinoma intimately admixed with abundant smooth muscle stroma. Epithelial differentiation of the malignant clear cell components and smooth muscle differentiation of the benign spindle cell stroma was confirmed by the immunostaining profiles and by electron microscopy. Fluorescence in situ hybridization analysis of chromosome 3 showed loss of the entire chromosome in 2 cases and loss of 3p in the third case. We therefore interpret these tumors as unique low-grade variants of clear cell renal cell carcinoma that have induced a prolific metaplastic stromal reaction. Extensive tissue sampling and immunostaining are recommended to distinguish cases with an extensive smooth muscle component from morphologically similar but benign lesions including angiomyolipoma, leiomyoma, or mixed epithelial and stromal tumor of the kidney.

Classic and desmoplastic medulloblastoma: complete case reports and characterizations of two new cell lines.

Medulloblastoma (MB) is the most common type of brain tumor affecting children. These tumors are a significant cause of childhood mortality and morbidity, and more effective and less invasive treatment options are urgently required. To achieve these aims, it will be critical to develop a more comprehensive understanding of the molecular pathogenesis of MB. At present, there are relatively few well-characterized MB cell lines available to the research community for the study of MB molecular and cellular biology. Here we present the case reports of two children diagnosed with classic and desmoplastic MB, and describe the characteristics of two new MB cell lines derived from these individuals. A number of genes encoding components of the sonic hedgehog (SHH) and WNT pathways were up-regulated in the desmoplastic relative to the classic MB cell line consistent with aberrant activation of these pathways in desmoplastic MB. These cell lines represent an additional resource for the analysis of diverse aspects of MB biology.

First trimester predictors of adverse pregnancy outcomes.

AIM: To identify first trimester indicators of adverse pregnancy outcomes. METHOD: Data were obtained from the statewide evaluation of first trimester screening for Down syndrome in Western Australia which included 22,695 pregnancies screened between August 2001 and October 2003. Screening data were linked with pregnancy outcome information from the Hospital Morbidity Database and the Birth Defects Registry. The odds ratios (OR) of adverse outcomes were analysed for combined risk incorporating maternal age, nuchal translucency (NT) and biochemical parameters and then separately for each parameter (pregnancy-associated plasma protein-A (PAPP-A), free beta human chorionic gonadotropin (beta-hCG) and NT). RESULTS: Risk assessments for first trimester combined screening are derived from maternal age, ultrasound measurement of fetal NT, maternal serum free beta-hCG and PAPP-A. Increased combined risk for Down syndrome was significantly (P < 0.01) associated with spontaneous loss at or before 24 weeks gestation (OR 13.51), birth defects (OR 6.58) and preterm birth at or before 32 weeks gestation (OR 3.2). Maternal serum PAPP-A below the 5th centile was associated with Down syndrome (OR 8.43), spontaneous loss before 24 weeks (OR 5.04) and later than 24 weeks (OR 4.50), preterm delivery before 32 weeks (OR 3.11) and before 37 weeks (OR 2.24). NT above the 95th centile was associated with Down syndrome (OR 43.91), birth defects (OR 4.02) and spontaneous loss before 24 weeks (OR 6.24). Low levels of free beta-hCG and increased NT were less consistently associated with adverse outcomes and high levels of free beta-hCG showed limited use as an indicator. The detection rates for all outcomes other than Down syndrome were less than 40%. CONCLUSION: Biochemical indicators and NT that are measured during first trimester screening for Down syndrome show a number of associations with adverse outcomes, but do not show appropriate performance characteristics for screening tests. These data are consistent with the view that the individual components, specifically low PAPP-A levels alone, do not provide an effective screening tool for adverse pregnancy outcomes.

First-trimester combined screening for Down syndrome and other fetal anomalies.

OBJECTIVE: This study assessed fetal outcomes for pregnancies identified at increased risk for Down syndrome by first-trimester combined ultrasound examination and maternal serum biochemistry screening. METHODS: First-trimester combined screening data were obtained from ultrasound clinics across Western Australia between August 2001 and October 2003. Prenatal screening data were linked with pregnancy outcome information held in state health database registers using probabilistic record-linkage techniques. RESULTS: In 50 of the 60 pregnancies affected by Down syndrome, the adjusted risk was greater than 1 in 300, providing a detection rate of 83% (95% confidence interval [CI] 74-93%). Among all women screened (n = 22,280), 827 had increased risk results but did not have a Down syndrome pregnancy, representing a false-positive rate of 3.7% (95% CI 3.5-3.9%). Ten cases of Down syndrome were detected among women considered not at increased risk, consistent with a false-negative rate of 1 in 2,227. First-trimester combined screening reduced the number of Down syndrome births by 50 in 22,280 (2.24 cases per 1,000 births), which represents the detection of one case of fetal Down syndrome for every 446 women screened. Furthermore, 25% of pregnancies with other birth defects occurred among those identified at increased risk of Down syndrome, and 1 in 8 pregnancies at increased risk were found to have a significant chromosomal or structural defect. CONCLUSION: First-trimester combined screening in Western Australia detected 83% (95% CI 74-93%) of Down syndrome pregnancies at a 3.7% (95% CI 3.5-3.9%) false-positive rate. LEVEL OF EVIDENCE: II-2.

Primary renal synovial sarcoma confirmed by cytogenetic analysis: a lesion distinct from sarcomatoid renal cell carcinoma.

Primary synovial sarcoma rarely originates in the renal parenchyma. When this occurs, origin of this unusual tumor type has been the subject of debate in the literature, with a suggestion that previously reported cases may be more correctly described as renal cell carcinoma with sarcomatoid dedifferentiation. Synovial sarcoma and sarcomatoid renal cell carcinoma may be indistinguishable on pure histologic and immunohistochemical grounds, but these tumors contain distinctly different sets of chromosomal abnormalities. Most previous cases of primary renal synovial sarcoma were confirmed by molecular biology techniques, which detected the SYT-SSX gene fusion transcript typical of this tumor, but no details of the other chromosomal anomalies have been published. We report a case of primary renal synovial sarcoma confirmed by standard cytogenetic analysis, showing the characteristic t(X; 18)(p11.2:q11.2) translocation and other chromosomal aberrations that are typical of synovial sarcoma as opposed to sarcomatoid renal cell carcinoma.