Villous Parenchyma Research Articles

Altered placental macrophage numbers and subsets in pregnancies complicated with intrahepatic cholestasis of pregnancy (ICP) compared to healthy pregnancies

IntroductionIntrahepatic cholestasis of pregnancy (ICP) can result in adverse outcomes for both mother and fetus. Inflammatory (M1 subset) or anti-inflammatory (M2 subset) macrophage polarisation is associated with various complications of pregnancy. However, the influence of ICP on macrophage numbers and polarisation remains unknown. This study analyses macrophage density and distribution in placentas of patients with ICP compared to controls. Clinical parameters were correlated to macrophage distribution and ursodeoxycholic acid use (UDCA). MethodsThis study included routinely collected placental tissue samples of 42 women diagnosed with ICP and of 50 control pregnancies. Immunohistochemical staining was performed on placental tissue using CD68 antibody as a pan-macrophage marker, CD206 antibody as an M2 and HLA-DR antibody as an M1 macrophage marker. Macrophage density (cells/mm2) and distribution (CD206+/CD68+ or CD206+/CD68+HLA-DR+) in both decidua (maternal tissue) and villous parenchyma (fetal tissue) were compared between groups. Macrophage density and distribution were correlated to clinical parameters for ICP patients. ResultsThe density of CD68+ macrophages differed significantly between groups in villous parenchyma. In both decidua and villous parenchyma, CD206+/CD68+ ratio was significantly lower in ICP patients compared to controls (p = 0.003 and p=<0.001, respectively). No difference was found based on UDCA use or in CD68+HLA-DR+ cell density. Significant correlations were found between macrophage density and peak serum bile acids and liver enzymes. DiscussionIn ICP patients, an immune shift was observed in both decidual and villous tissue, indicated by a lower CD206+/CD68+ ratio. ICP seems to affect placental tissue, however more research is required to understand its consequences.

Epigenetic phenotype of plasma cell-free DNA in the prediction of early-onset preeclampsia

Background In the current study, we sought to characterise the methylation haplotypes and nucleosome positioning patterns of placental DNA and plasma cell-free DNA of pregnant women with early-onset preeclampsia using whole genome bisulphite sequencing (WGBS) and methylation capture bisulphite sequencing (MCBS) and further develop and examine the diagnostic performance of a generalised linear model (GLM) by incorporating the epigenetic features for early-onset preeclampsia. Methods This case-control study recruited pregnant women aged at least 18 years who delivered their babies at our Hospital. In addition, non-pregnant women with no previous history of diseases were included. Placental samples of the villous parenchyma were taken at the time of delivery and venous blood was drawn from pregnant women during non-invasive prenatal testing at 12–15 weeks of pregnancy and nonpregnant women during the physical check-up. WGBS and MCBS were carried out of extracted genomic DNA. Then, we established the GLM by incorporating preeclampsia-specific methylation haplotypes and nucleosome positioning patterns and examined the diagnostic performance of the model by receiver operating characteristic (ROC) curve analysis. Results The study included 135 pregnant women and 50 non-pregnant women. Our high-depth MCBS revealed notably different DNA methylation and nucleosome positioning patterns between women with and without preeclampsia. Preeclampsia-specific hypermethylated sites were found predominantly in the promoter regions and particularly enriched in CTCF on the X chromosome. Totally, 2379 preeclampsia-specific methylation haplotypes were found across the entire genome. ROC analysis showed that the area under the ROC curve (AUC) was 0.938 (95%CI 0.877, 1.000). At a GLM cut-off of 0.341, the AUC was the maximum, with a sensitivity of 95.6% and a specificity of 89.7%. Conclusion Pregnant women with early-onset preeclampsia exhibit DNA methylation and nucleosome positioning patterns in placental and plasma DNA.

NEONATAL THROMBOSIS ASSOCIATED WITH FETAL VASCULAR MALPERFUSION: A CASE REPORT

Background: Fetal vascular malperfusion refers to placental lesions indicating reduced or absent perfusion of the villous parenchyma by the fetus. Fetal vascular malperfusion remains an underrecognized condition that is associated with adverse perinatal outcomes. It may also predispose infants to thromboembolic events. There are few cases described of inferior vena cava and renal vein thrombosis in an asymptomatic newborn. Case presentation: We report the case of an asymptomatic female neonate delivered at 32 weeks of gestation to a mother with type 1 diabetes and preeclampsia. Prenatal diagnosis of renal vein and inferior vena cava thrombosis was made at 30 weeks. Thrombophilia work-up was negative. Diagnosis was guided by the placental pathological examination that showed thrombosis of several fetal vessels of the chorionic plate, high-grade poor perfusion lesions and distal villous hypoplasia, suggestive of Fetal vascular malperfusion. Treatment with low-molecular-weight heparin was effective in the complete resolution of the thrombus and preservation of renal function. Conclusion: This case emphasizes the importance of placental pathological examination in the presence of fetal abnormalities. Fetal vascular malperfusion may cause unrecognized neonatal thrombosis, which may result in growth impairment or organic dysfunction. Pregnant women with known risk factors for Fetal vascular malperfusion should be monitored more closely, both antenatally and postnatally, to detect possible placental and fetal target organ involvement at an early stage.

Diffuse and Localized SARS-CoV-2 Placentitis: Prevalence and Pathogenesis of an Uncommon Complication of COVID-19 Infection During Pregnancy.

Coronavirus disease 2019 (COVID-19) infection in pregnancy has been associated with preterm delivery and preeclampsia. A less frequent and underrecognized complication is extensive placental infection which is associated with high rates of perinatal morbidity and mortality. The frequency, early pathogenesis, and range of lesions associated with this infection are poorly understood. We conducted a population-based study of placental pathology from all mothers with COVID-19 (n=271) over an 18-month period delivering within our health system. The overall prevalence of diffuse severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placentitis, as defined by typical histology and immunohistochemical (IHC) staining for SARS-CoV-2 spike protein, was 14.8/1000, but increased to 59/1000 in preterm births. We also identified 3 cases with isolated small foci of localized SARS-CoV-2 placentitis, characterized by focal perivillous fibrin and intervillositis, which illustrate the early pathogenesis and suggest that infection may be contained in some cases. Two other placental lesions were more common in mothers with COVID-19, high-grade maternal vascular malperfusion in preterm deliveries and high-grade chronic villitis at term (5/5 cases tested of the latter were negative by IHC for SARS-CoV-2). Additional investigation of diffuse and localized SARS-CoV-2 placentitis by IHC showed loss of BCL-2, C4d staining in surrounding villi, and an early neutrophil-predominant intervillous infiltrate that later became dominated by monocyte-macrophages. We propose a model of focal infection of syncytiotrophoblast by virally infected maternal leukocytes leading to loss of BCL-2 and apoptosis. Infection is then either contained by surrounding fibrinoid (localized) or initiates waves of aponecrosis and immune activation that spread throughout the villous parenchyma (diffuse).

Trophoblast damage with acute and chronic intervillositis: disruption of the placental barrier by severe acute respiratory syndrome coronavirus 2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was demonstrated in the placenta; however, the data on the prevalence of placental infection and associated histopathology are limited. To identify the frequency and features of SARS-CoV-2 involvement, we performed a clinicopathologic analysis of 75 placental cases from women infected at the time of delivery and 75 uninfected controls. Placental samples were studied with anti–SARS-CoV-2 immunohistochemistry and/or in situ hybridization. Positive results were confirmed by electron microscopy and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). During delivery, only one woman had symptoms of coronavirus disease 2019, six women reported previous symptoms, and 68 women were asymptomatic. All neonates tested negative for SARS-CoV-2 as per nasopharyngeal swab PCR results. Obstetric histories were unremarkable in 29 of 75 SARS-CoV-2–positive and 8 of 75 SARS-CoV-2–negative women. Placental examination was normal in 12 of 75 infected and 3 of 75 uninfected subjects, respectively. In the remaining cases, placental pathology correlated with obstetric comorbidities without significant differences between SARS-CoV-2–positive and SARS-CoV-2–negative women. SARS-CoV-2 was identified in one placenta of an infected, but asymptomatic, parturient. Viral staining was predominantly localized to the syncytiotrophoblast (STB) which demonstrated marked damage accompanied by perivillous fibrin deposition and mixed intervillositis. A significant decrease of viral titers was detected in the attached umbilical cord compared with the villous parenchyma as per qRT-PCR. SARS-CoV-2 is seldom identified in placentas of infected women. Placental involvement by the virus is characterized by STB damage disrupting the placental barrier and can be seen in asymptomatic mothers without evidence of vertical transmission.

Visualization of microbes by 16S in situ hybridization in term and preterm placentas without intraamniotic infection

Numerous reports have documented bacteria in the placental membranes and basal plate decidua in the absence of immunopathology using histologic techniques. Similarly, independent metagenomic characterizations have identified an altered taxonomic makeup in association with spontaneous preterm birth. Here we sought to corroborate these findings by localizing presumptive intactbacteria using molecular histology within the placental microanatomy. Here we examined for microbes in term and preterm gestations using a signal-amplified 16S universal in situ hybridization probe set for bacterial rRNA, alongside traditional histologic methods of Warthin-Starry and Gram stains, as well as clinical culture methodologies. We further sought to differentiate accompanying 16S gene sequencing taxonomic profiles from germ-free (gnotobiotic) mouse and extraction and amplicon contamination controls. Placentas were collected from a total of 53 subjects, composed of term labored (n= 4) and unlabored cesarean deliveries (n= 22) and preterm vaginal (n= 18) and cesarean deliveries (n= 8); a placenta from a single subject with clinical and histologic evident choriomanionitis was employed as a positive control (n= 1). The preterm cohort included spontaneous preterm birth with (n= 6) and without (n= 10) preterm premature rupture of membranes, as well as medically indicated preterm births (n= 10). Placental microbes were visualized using an in situ hybridization probe set designed against highly conserved regions of the bacterial 16S ribosome, which produces an amplified stable signal using branched DNA probes. Extracted bacterial nucleic acids from these same samples were subjected to 16S rRNA metagenomic sequencing (Illumina, V4) for course taxonomic analysis, alongside environmental and kit contaminant controls. A subset of unlabored, cesarean-delivered term pregnancies were also assessed with clinical culture for readily cultivatable pathogenic microbes. Molecular in situ hybridization of bacterial rRNA enabled visualization and localization of low-abundance microbes after systematic high-power scanning. Despite the absence of clinical or histologic chorioamnionitis in 52 of 53 subjects, instances of 16S rRNA signal were confidently observed in 13 of 16 spontaneous preterm birth placentas, which was not significantly different from term unlabored cesarean specimens (18 of 22; P > .05). 16S rRNA signal was largely localized to the villous parenchyma and/or syncytiotrophoblast, and less commonly the chorion and the maternal intervillous space. In all term and unlabored cesarean deliveries, visualization of evident placental microbes by in situ hybridization occurred in the absence of clinical or histologic detection using conventional clinical cultivation, hematoxylin-eosin, and Gram staining. In 1 subject, appreciable villous bacteria localized to an infarction, where 16S microbial detection was confirmed by Warthin-Starry stain. In all instances, parallel sample principle coordinate analysis using Bray-Cutis distances of 16S rRNA gene sequencing data demonstrated consistent taxonomic distinction from all negative or potential contamination controls (P= .024, PERMANOVA). Classification from contaminant filtered data identified a distinct taxonomic makeup among term and preterm cohorts when compared with contaminant controls (false discovery rate <0.05). Presumptively intact placental microbes are visualized as low-abundance, low-biomass and sparse populations within the placenta regardless of gestational age and mode of delivery. Their taxonomic makeup is distinct from contamination controls. These findings further support several previously published findings, including our own, which have used metagenomics to characterize low-abundance and low-biomass microbial communities in the placenta.

636: Autophagy and ZIKV replication co-occur in only some human and primate placental cells: therapeutic implications

We previously demonstrated ZIKV replicates in trophoblasts and other placental cells using human and primate models. Recent evidence also suggests that ZIKV induces autophagy via LC3-II-dependent mechanisms. While inhibition of autophagy restricts ZIKV placental infection in mice and cytotrophoblasts (CT) in vitro, leading to suggestion that anti-autophagal drugs could inhibit transmission, primary human and primate data is missing. To generate preclinical data, we directly assessed placental and trophoblast-specific autophagal activity following ZIKV infection in human cases and primate models. Placentas of clinical cases (n=4) and primates (n=2) with confirmed ZIKV infection and CZS, alongside negative controls (n=4), were assessed for co-localization of LC3-II and the ZIKV virus by histology. Trophoblast cells were isolated (n=10), and infected with ZIKV or mock. Viral replication was confirmed by single molecule FISH, strand-specific PCR, and immunofluorescence. The relative expression of autophagy-associated genes (ULK-1, BECN1, ATG5, ATG7, ATG12, MAP1LC3A, MAP1LC3B, ATG16L1, SQSTM1) were quantitated by TaqMan qPCR. Significance was determined by p<0.05. Blinded histologic exam demonstrated ZIKV replication in case but not control human and primate placentas in syncytiotrophoblasts (ST), CT and Hofbauer cells (Fig 1A). Co-localization of autophagy marker LC3-II in human and primate placentas however is limited to decidua and villous parenchyma and sparse in ST (Fig 1B). In validation studies, 4G2 antibody labeling confirmed ZIKV replication in ex vivo trophoblasts (Fig 2A). Of 9 autophagy related genes, ATG5 and SQSTM1 were decreased ∼2 fold in these ZIKV-infected trophoblasts (p=0.04 and p=0.03) (Fig 2B). Two alternate transcripts of LC3-II (MAP1LC3A and MAP1LC3B) were unchanged. We have demonstrated for the first time that while ZIKV replicates in CT, ST, and Hofbauer cells, autophagy appears limited to cells in the decidual and villous parenchyma and not ST. These findings explain observations that the placenta serves as a conduit and a reservoir for infection, and why the ST still function during ongoing low level ZIKV replication. Second, they provide preclinical evidence supporting use of an anti-autophagal drug as potential adjunctive therapy to prevent vertical ZIKV transmission.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Maternal vascular malperfusion of the placental bed.

Maternal vascular malperfusion (MVM) of the placental bed represents a recognizable pattern of placental injury related to altered uterine and intervillous blood flow. MVM consists of a constellation of placental pathologic findings seen in the maternal decidual vessels, reflecting abnormal spiral artery remodeling, as well as in the villous parenchyma, reflecting abnormalities in oxygenation and flow dynamics in the intervillous space. This review is dedicated to the gross pathology, microscopic pathology, updated terminology, and clinical implications of MVM.

Fetal vascular malperfusion, an update.

Fetal vascular malperfusion is the most recent term applied to a group of placental lesions indicating reduced or absent perfusion of the villous parenchyma by the fetus. The most common etiology of malperfusion is umbilical cord obstruction leading to stasis, ischemia, and in some cases thrombosis. Other contributing factors may include maternal diabetes, fetal cardiac insufficiency or hyperviscosity, and inherited or acquired thrombophilias. Severe or high grade fetal vascular malperfusion is an important risk factor for adverse pregnancy outcomes including fetal growth restriction, fetal CNS injury, and stillbirth. Overall recurrence risk for subsequent pregnancies is low.

Maternal Income during Pregnancy is Associated with Chronic Placental Inflammation at Birth.

Objective This study aims to examine whether maternal household income is associated with histological evidence of chronic placental inflammation. Study Design A total of 152 participants completed surveys of household income and consented to placenta collection at delivery and postpartum chart review for birth outcomes. Placental inflammatory lesions were evaluated via histological examination of the membranes, basal plate, and villous parenchyma by a single, experienced pathologist. Associations between household income and the presence of inflammatory lesions were adjusted for known perinatal risk factors. Results Overall, 45% of participants reporting household income below $30,000/y had chronic placental inflammation, compared with 25% of participants reporting income above $100,000 annually (odds ratio [OR] = 4.23, 95% confidence interval [CI] = 1.25, 14.28; p = 0.02). Middle-income groups showed intermediate rates of chronic inflammatory lesions, at 40% for those reporting $30,000 and 50,000 (OR = 3.60, 95% CI = 1.05, 12.53; p = 0.04) and 38% for those reporting $50,000 to 100,000 (OR = 1.57, 95% CI = 0.60, 4.14; p = 0.36). Results remained significant after adjustment for maternal age, race, and marital status. Conclusion Chronic placental inflammation is associated with maternal household income. Greater occurrence of placental lesions in low-income mothers may arise from a systemic inflammatory response to social and physical environmental factors.

Placental massive perivillous fibrinoid deposition is associated with adverse pregnancy outcomes: a clinicopathological study of 12 cases

Abstract Introduction: Massive perivillous fibrinoid deposition (MPFD) is a very rare placental condition characterized by abnormally extensive fibrinoid deposition in the placental villous parenchyma. The aim of this study is to document clinical and pathological features with special focus on pregnancy outcomes of this condition in consecutive cases of MPFD in our local population. Methods: This is a retrospective clinico-pathological study of cases affected by MPFD over the period January 2010–July 2014 in our hospital. We document clinical features (including perinatal outcome and subsequent pregnancies) and placental pathological characteristics. Results: Twelve cases of MPFD were identified among 3640 placentas (0.33%). There was no identified recurrence. The affected infants had adverse outcomes, including intrauterine growth restriction (IUGR) (75%), preterm birth (58.3%), and fetal loss (25%). A high frequency of reduced PAPP-A in the first trimester (25%), and concurrent gestational hypertension or pre-eclampsia (25%) was noted. Conclusion: MPFD is associated with adverse perinatal outcomes. Further research to better understand its pathogenesis and to improve clinical diagnosis and management is warranted.

Storage conditions and stability of global DNA methylation in placental tissue for Epidemiology Studies.

Background: There is growing interest on the epigenetic effects of in-utero environmental exposures on DNA methylation and its relation to childhood or adult-life health outcomes. The placenta is a well-established target of environmental toxicants that can be easily collected in epidemiological studies. However, no study has yet analyzed to what extent storage conditions of placental tissue after delivery affect DNA methylation. We designed a study to address this issue providing informative results for on-going and future cohort studies. Methods: Two full term placentas were biopsied in three different regions of the villous parenchyma. Biopsies were sequentially stored at -80°C after standing at room temperature (RT) for 30 minutes, 1 hour, 2 hours, 6 hours and 24 hours. Global DNA methylation was measured by two common techniques: analysis of retrotransposons by pyrosequencing (10 different repetitive elements in LINE, Alu and HERV families) and the Luminometric Methylation Assay (LUMA). Time-to storage at RT, technique-related and regional variability in methylation levels were compared by coefficients of variation (COV). Results: The time-to storage COV was 2.49% (placenta 1) and 2.86% (placenta 2) 5-methylcytosine (5mC), similar to the mean technical variation we observed for the pyrosequencing technique (COV=1.91% and 1.51% for each placenta, respectively). LUMA yielded more variable results, both among time points and as well as between technical replicates. Conclusion: DNA methylation levels are not affected by storage delays at RT. DNA methylation studies using samples stored in unknown or suboptimal conditions should avoid using techniques sensitive to DNA degradation such as the LUMA Assay.

Pathological characteristics of a series of rare chronic histiocytic intervillositis of the placenta

Chronic histiocytic intervillositis of the placenta (CHI) is a rare and poorly understood pathology which may occur in all trimesters. The most conspicuous feature is a histiocytic infiltration of the intervillous space without involvement of the villous parenchyma. In this report on CHI, we re-evaluate a series of four cases and focus on histological, immunohistological and fluorescence in situ hybridisation-derived findings, fetal status and clinical data for previously unrecognised CHI-associated features. Our approach revealed that assisted reproduction-induced pregnancy had been performed in 2 of 4 CHI cases, but other factors and comorbidities are likely to contribute to CHI.

Pathological assessment of intrauterine growth restriction

Intrauterine growth restriction (IUGR) is a major cause of foetal and neonatal morbidity and mortality. During post mortem, the pathologist is well placed to diagnose the presence and cause of IUGR in a stillborn baby. This article describes the approach of the pathologist in diagnosing IUGR and some of the pitfalls. We distinguish between reduced growth potential (formerly symmetrical IUGR) and nutritional IUGR (formerly asymmetrical IUGR). Aetiologically, restricted growth can be of foetal, maternal and placental origin. We discuss the importance of identifying the cause of IUGR in a clinicopathological context and the pathological findings in some of the more frequent causes of IUGR presenting at post mortem. Based on an accurate gestational age, ideally determined by the obstetrician in early pregnancy, the pathologist can derive a birth weight centile. However, the pathologist is also able to identify other indicators of IUGR, such as an elevated brain/liver weight ratio, atrophic thymus and changes in other internal organs. Placental examination plays a major role in the investigation as the majority of IUGR cases have significant placental pathology. This includes pre-eclampsia-related changes, abnormalities of the villous parenchyma and pathology of the umbilical cord. The potential benefit of a meticulous workup of IUGR foetuses is to provide an explanation of the pathological condition and to identify avoidable causes.

Elevated circulating fetal nucleated red blood cells and placental pathology in term infants who develop cerebral palsy

An elevated circulating fetal nucleated red blood cell count has long been recognized as an indicator of significant intrauterine stress. However, the nature of the causative events and their timing remain controversial. In this study, subacute and chronic placental lesions known to be associated with neurodisability were used as surrogates for antenatal stress. Mother-infant pairs with complete blood counts within 2 hours of delivery (n = 81) were drawn from a larger database of 152 term infants with cerebral palsy. An elevated nucleated red blood cell count (2.5 x 10(3)/mm(3)) in these infants was associated with a significantly increased prevalence of subacute or chronic placental lesions, whereas clinical findings did not significantly differ. The number of nucleated red blood cells per 10 high-power fields of villous parenchyma was directly correlated with the nucleated red blood cell count, and a threshold of 10 or more nucleated red blood cells predicted a nucleated red blood cell count greater than 2.5 x 10(3)/mm(3). Among individual placental lesions, multiple foci of avascular villi and chronic villitis were significantly associated with an elevated nucleated red blood cell count, whereas meconium-associated vascular necrosis showed a borderline association. Acute chorioamnionitis was the only placental lesion more common in the group without elevated nucleated red blood cell count. The presence of significant placental lesions was associated with an elevated nucleated red blood cell count in infants with or without either acidosis (cord pH <7.0) or birth asphyxia (American College of Obstetrics and Gynecology criteria). Acidosis and birth asphyxia were not significantly related to an elevated nucleated red blood cell count in infants without these placental lesions.

Tissue microarray: An effective high-throughput method to study the placenta for clinical and research purposes

Objective. Tissue microarray (TMA) technology allows simultaneous examination of the expression of many molecular markers (protein, mRNA, DNA, etc.) with high-throughput. The application of this technology, to date, has been largely confined to the study of cancer. Placental pathology poses unique challenges because of the size of the organ, its complex anatomy, as well as its histological heterogeneity. The objective of this study was to assess the feasibility and efficiency of TMAs for immunohistochemistry and in situ hybridization of placental tissues.Study design. TMAs were constructed using an automated tissue arrayer. Standard 0.6-mm or 1-mm microarray needles were used. Villous parenchyma, basal plate, and chorioamniotic membranes were targeted in each block. Five μm-thick TMA sections underwent immunohistochemical analysis of both cytoplasmic and nuclear antigens using a panel of antibodies against a variety of cytoplasmic [cytokeratin-7, vascular endothelial growth factor (VEGF), and protein Z], membranous (endoglin), and nuclear (c-fos and c-jun) antigens. mRNA in situ hybridization for surfactant protein A (SP-A) and chromogenic in situ hybridization for the Y chromosome (DYZ1) were also performed.Results. Validation of TMA immunoreactivity demonstrated comparable results with corresponding whole sections. When a two-tiered scoring system (positive/negative) was employed, there was agreement between two and three cores and whole tissue sections (kappa>0.7). When a three-tiered scoring system (negative, weak-positive, or strong-positive) was used, the data from three cores showed the highest agreement with whole tissue sections (kappa >0.7). In situ hybridization experiments for mRNA and DNA were also successful in that the signals were readily detectable. Successful transfer from the donor block to the recipient block differed according to the anatomical compartment. The transfer efficiency of villous parenchyma, basal plate, and chorioamniotic membranes were 96.9% (875/903), 76.7% (115/150), and 75.4% (224/297), respectively.Conclusion. TMA is a practical and effective tool for high-throughput molecular analysis of the human placenta. Duplicate and triplicate cores offer agreement with whole tissue sections for two-category distinction immunostaining. TMA also affords relevant results from in situ hybridization experiments for mRNA and DNA. The major advantages are the conservation of tissues and reagents, simultaneous comparison of molecular markers in different anatomical compartments of the placenta, and reduction of experimental error.

Hepatic (hepatocellular) adenoma of the placenta: a study of four cases.

Hepatic (hepatocellular) adenoma of the placenta is an extremely rare nontrophoblastic placental lesion of disputed histogenesis, four examples of which were diagnosed over a 10-year period. The lesions, which were incidental findings in women 21 to 30 years of age (mean, 25; median, 24.5), ranged from 0.3 to 1.0 cm in greatest dimension. Two were found within the villous parenchyma and two in subchronic locations. On cross section, two examples were tan to dark red nodules without necrosis or hemorrhagic foci, whereas two were not visible grossly. The lesions were composed of semidistinct lobules of cords and nests of polygonal epithelial cells resembling fetal liver. Extramedullary hematopoiesis was a constant feature. The lesional cells contained glycogen and were immunoreactive for cytokeratin, alpha-fetoprotein, alpha-1-antitrypsin, and carcinoembryonic antigen. Although the histogenesis of these lesions remains uncertain, an origin from displaced yolk sac elements with hepatocytic differentiation is the most likely hypothesis. It is important to distinguish hepatic adenoma of the placenta from placental cell island, heterotopic adrenocortical nodule, chorangioma, and placental metastasis of maternal and fetal malignancies.

Fetal thrombotic vasculopathy: The clinical significance of extensive avascular villi

Thrombosis of large fetal vessels in the placenta leads to regions of downstream avascular villi (AV). Avascular villi have been associated with adverse outcomes in anecdotal reports, but no controlled study of their significance has been done. We prospectively gathered cases of extensive AV (n = 29) occurring over a 2-year period at the Institute of Pathology at Case Western Reserve University and compared obstetric history, coexistent placental pathology, and neonatal outcome to gestational age-matched controls in a case control study. The diagnosis of extensive AV required one or more of the following characteristics: 2.5% or more of total villous parenchyma affected, foci in multiple sections, or a single lesion measuring 0.25 cm 2 or larger. Women with AV placentas had increased rates of intrauterine growth retardation (IUGR), acute and chronic monitoring abnormalities, oligohydramnios, and maternal coagulation disorders. Placentas with AV were more likely to have coexistent chronic villitis, membrane hemosiderin, meconium in all three membrane layers, and villous chorangiosis. Finally, among the subgroup of neonates older than 34 weeks gestation without congenital malformations or coexistent placental pathology (n = 18), we identified significant abnormalities, including major thrombotic events (n = 5), neonatal death (n = 2), umbilical artery pH less than 7.10 (n = 4), platelet count less than 150,000 (n = 4), increased nucleated red blood cell (NRBC) counts (n = 7), and transient hypoglycemia (n = 4). Placental features correlating with clinical abnormalities included percentage of greater than 30% AV, recent platelet and fibrin aggregates, and multifocal disease involving more than one histological section.