Proteomic studies of VEGFR2 in human placentas reveal protein associations with preeclampsia, diabetes, gravidity, and labor.

VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10-8), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.

Giant Placental Chorangioma and Severe Ductal Arch Constriction: A Case Report With a Favorable Outcome.

Giant chorangiomas are uncommon yet frequently associated with adverse pregnancy outcomes. A 37-year-old female was referred due to findings of a placental mass during a second-trimester ultrasound. A fetal survey at 26 weeks revealed a 69×97×75 mm heterogenous placental tumor with two prominent feeding vessels. Her prenatal course was complicated by worsening polyhydramnios requiring amnioreduction, gestational diabetes, and transient severe ductal arch (DA) constriction. Placental pathology confirmed the diagnosis of giant chorioangioma following delivery at 36 weeks. To our knowledge, this represents the first case of DA constriction in the setting of a giant chorangioma.

Regulation of Proinflammatory Molecules and Tissue Factor by SARS-CoV-2 Spike Protein in Human Placental Cells: Implications for SARS-CoV-2 Pathogenesis in Pregnant Women.

SARS-CoV-2 infects cells via binding to ACE2 and TMPRSS2, which allows the virus to fuse with host cells. The viral RNA is detected in the placenta of SARS-CoV-2-infected pregnant women and infection is associated with adverse pregnancy complications. Therefore, we hypothesize that SARS-CoV-2 infection of placental cells induces pro-inflammatory cytokine release to contribute to placental dysfunction and impaired pregnancy outcomes. First, expression of ACE2 and TMPRSS2 was measured by qPCR in human primary cultured term cytotrophoblasts (CTBs), syncytiotrophoblast (STBs), term and first trimester decidual cells (TDCs and FTDCs, respectively), endometrial stromal cells (HESCs) as well as trophoblast cell lines HTR8, JEG3, placental microvascular endothelial cells (PMVECs) and endometrial endothelial cells (HEECs). Later, cultured HTR8, JEG3, PMVECs and HEECs were treated with 10, 100, 1000 ng/ml of recombinant (rh-) SARS-CoV-2 S-protein ± 10 ng/ml rh-IFNγ. Pro-inflammatory cytokines IL-1ß, 6 and 8, chemokines CCL2, CCL5, CXCL9 and CXCL10 as well as tissue factor (F3), the primary initiator of the extrinsic coagulation cascade, were measured by qPCR as well as secreted IL-6 and IL-8 levels were measured by ELISA. Immunohistochemical staining for SARS-CoV-2 spike protein was performed in placental specimens from SARS-CoV-2-positive and normal pregnancies. ACE2 levels were significantly higher in CTBs and STBs vs. TDCs, FTDCs and HESCs, while TMPRSS2 levels were not detected in TDCs, FTDCs and HESCs. HTR8 and JEG3 express ACE2 and TMPRSS2, while PMVECs and HEECs express only ACE2, but not TMPRSS2. rh-S-protein increased proinflammatory cytokines and chemokines levels in both trophoblast and endothelial cells, whereas rh-S-protein only elevated F3 levels in endothelial cells. rh-IFNγ ± rh-S-protein augments expression of cytokines and chemokines in trophoblast and endothelial cells. Elevated F3 expression by rh-IFNγ ± S-protein was observed only in PMVECs. In placental specimens from SARS-CoV-2-infected mothers, endothelial cells displayed higher immunoreactivity against spike protein. These findings indicated that SARS-CoV-2 infection in placental cells: 1) induces pro-inflammatory cytokine and chemokine release, which may contribute to the cytokine storm observed in severely infected pregnant women and related placental dysfunction; and 2) elevates F3 expression that may trigger systemic or placental thrombosis.

Report of a novel variant in the FAM111A gene in a fetus with multiple anomalies including gracile bones, hypoplastic spleen, and hypomineralized skull.

Kenny-Caffey syndrome type 2 (KCS2) and osteocraniostenosis (OCS) are allelic disorders caused by heterozygous pathogenic variants in the FAM111A gene. Both conditions are characterized by gracile bones, characteristic facial features, hypomineralized skull with delayed closure of fontanelles and hypoparathyroidism. OCS and KCS2 are often referred to as FAM111A-related syndromes as a group; although OCS presents with a more severe, perinatal lethal phenotype. We report a novel FAM111A mutation in a fetus with poorly ossified skull, proportionate long extremities with thin diaphysis, and hypoplastic spleen consistent with FAM111A-related syndromes. Trio whole exome sequencing identified a p.Y562S de novo missense variant in the FAM111A gene. The variant shows significant similarity to other reported pathogenic mutations fitting proposed pathophysiologic mechanism which provide sufficient evidence for classification as likely pathogenic. Our report contributed a novel variant to the handful of OCS and KCS2 cases reported with pathogenic variants.

Reversed halo sign on CT as a presentation of lymphocytic interstitial pneumonia.

A 52 year-old African American female with a past medical history of symptomatic uterine fibroids and increasing abdominal circumference underwent abdominal computed tomography (CT) as part of her workup. Because of an abnormality in the left lower lobe, CT of the chest was subsequently performed and showed a focal region of discontinuous crescentic consolidation with central ground glass opacification in the right lower lobe, suggestive of the reversed halo sign. The patient underwent percutaneous CT-guided core biopsy of the lesion, which demonstrated lymphocytic interstitial pneumonia, a benign lymphoproliferative disease characterized histologically by small lymphocytes and plasma cells. This case report describes the first histologically confirmed presentation of lymphocytic interstitial pneumonia with the reversed halo sign on CT.

The perforated appendiceal carcinoid in children: a surgical dilemma.

The decision for aggressive reoperation after discovery of an appendiceal carcinoid is generally based upon criteria such as size, grade, degree of involvement of the mesoappendix or the appendiceal base, lymphovascular invasion, and the presence of goblet cell or adenocarcinoid features. No guidelines currently exist for the management of perforated appendiceal carcinoids. We present a case of perforated appendiceal carcinoid that was subsequently treated with right hemicolectomy, and we review the pertinent literature.

Intraluminal tracheal occlusion using a modified 8-mm Z-stent in a sheep model of left-sided congenital diaphragmatic hernia.

OBJECTIVE: To evaluate pulmonary growth and development after fetoscopic intraluminal tracheal occlusion (FITO) using a modified 8-mm Z-stent in an ovine model of congenital left-sided diaphragmatic hernia (CDH). METHODS: Thirty-three time-dated ewes were studied: Group I: healthy controls; Group II: CDH controls (untreated); Group III: CDH treated with FITO. CDH was created in Groups II and III at 70-80 days' gestation. FITO was performed at 100-110 days. Left lung histological, morphometric, immunohistochemical and biochemical studies were conducted after delivery and euthanasia at 138 days. RESULTS: Fifteen (45%) animals (Group I: 3; Group II: 5; Group III: 7) were available for analysis. The left lung parenchymal volume to fetal weight ratios were similar between Groups I and III (p = 0.24), and higher than Group II (p < 0.05III (79 versus 75%, p = 0.26), compared to 41% in Group II (p < 0.05). Pulmonary hypoplasia occurred in 1/7 (16%) in the FITO group, compared to 100% in Group II and 0% in Group I (p = .003). DNA and protein were significantly increased in Group III (p < 0.001). The concentration of type II pneumocytes was similar between healthy controls and the FITO group, and was paradoxically increased in untreated hernia fetuses. There was no histological evidence of tracheal injury. CONCLUSION: FITO with a modified 8-mm Z-stent is associated with lung growth and maturation similar to controls without obvious deleterious effects. A phase I clinical trial of FITO with the modified 8-mm Z-stent in severe CDH patients seems warranted.

De novo translocation t(5;9)(q11.2;p22) associated with hydrops fetalis and cystic hygroma.

We report on a case of a prenatally diagnosed non-immune hydrops fetalis and cystic hygroma associated with the balanced translocation t(5;9)(q11.2;p22), an association that to our knowledge has not been reported previously. Both parents had normal karyotypes. The infant was born prematurely at 33 and 3/7 weeks gestation and expired 12 h after delivery.

Presentation of ileal Burkitt lymphoma in children.

Burkitt lymphoma is a highly aggressive form of Non-Hodgkin lymphoma that responds favorably if diagnosed accurately and treated early. Recognition of the various radiologic manifestations of Burkitt lymphoma can help guide the clinician to expedite appropriate chemotherapy. We present two cases that illustrate different radiologic presentations of this aggressive gastrointestinal malignancy in children. Case 1 features a 7-year-old boy who presented to our hospital with recurrent ileocecal intussusception. Case 2 describes a 16-year-old male with history of blood-streaked stools. Ileocectomy was performed in both cases and histologic analysis showed the "starry sky pattern" and t(8;14) translocation, classic for Burkitt lymphoma. Both patients remain disease-free following surgical excision and chemotherapy.

Clinicopathologic conference: multiple fetal demises, lactic acidosis and hepatic iron accumulation.

A case of a premature infant with lactic acidosis and hepatic iron accumulation, born to a mother with multiple fetal demises, is presented and discussed by both clinician and pathologist, in this traditional clinico-pathologic conference. The discussion includes the differential diagnoses of lactic acidosis and hepatic iron accumulation in infants.

Spondyloepiphyseal dysplasia congenita.

We report a case of spondyloepiphyseal dysplasia congenita (SED congenita), diagnosed at autopsy of a term infant. Prenatal ultrasound at 20 weeks of gestation had shown shortening of all the fetal long bones, with bowing of the femora and humeri, clubfeet, and small thoracic cage. We discuss the diagnostic features of SED and the main differential diagnoses.

Massive pericardial effusion treated with in utero pericardioamniotic shunt in a fetus with intrapericardial teratoma.

Teratoma is the leading neoplasm diagnosed in neonates and infants. Although over 99% of teratomas found in the fetus and newborn are histologically benign, those tumors may cause death if vital structures are involved or if the airway is compromised. We review the literature on antenatal intrapericardial teratomas and report a case of intrapericardial teratoma, with massive pericardial effusion and fetal hydrops, diagnosed on antenatal ultrasound at 21 weeks of gestation. Pericardioamniotic shunt was placed at 22 weeks and 6 days gestational age. In spite of successful drainage of the pericardial effusion, fetal demise was documented 8 days later, likely due to tumor compression of the heart.

Aromatase may play a critical role in the pathogenesis of juvenile nasopharyngeal angiofibroma.

The pathophysiology of juvenile nasopharyngeal angiofibroma (JNA) has yet to be fully elucidated, but the influence of steroid hormones in their growth has been suggested. This neoplasm is known to afflict adolescent males. However, only a minority of the neoplastic cells express androgen receptors. The expression of estrogen receptor beta by the tumor cells recently has been demonstrated. Aromatase (P450) is an enzyme which is responsible for converting androgens to estrogens. However, the rule of aromatase in the pathogenesis of JNA is unknown. In this study we attempt to explain the hormone-induced growth theory by characterizing the aromatase (P450) in JNA. We examined five sinonasal JNA from adolescent males, all of which stained positive for aromatase. We propose that this enzyme is responsible for the local conversion of androgens into estrogens, which subsequently bind to the estrogen receptors leading to the growth of these tumors.

Thirteen-year-old child with a malignant chest tumor: clinicopathologic conference.

A case of pleuropulmonary blastoma in a 13-year-old child, exposed to the Chernobyl disaster while in-utero, is presented and discussed by both clinician and pathologist, in this traditional clinical-pathologic conference. The discussion includes the differential diagnoses of chest mass in children.

Cardiac conduction disorders in children.

Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy, Arrhythmogenic right ventricular dysplasia, Isolated noncompaction of the left ventricle, Long QT syndrome (LQTS) and Brugada syndrome, are all well described. Congenital short QT syndrome is a new familial primary electrical disease of the heart, which is characterized by abnormally short QT interval and paroxysmal atrial and ventricular tachyarrhythmias, including sudden cardiac death. An autosomal dominant mode of inheritance has been suggested. Catecholaminergic polymorphic ventricular tachycardia is an inherited disease and occurs in the absence of structural heart disease or known associated syndromes. Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.

Cerebellar migration defects in aicardi syndrome: an extension of the neuropathological spectrum.

The Aicardi syndrome is characterized by infantile spasms, corpus callosum agenesis, and chorioretinal lacunae and almost exclusively affects females (very rarely, 47, XXY males). The crucial genetic mishap likely occurs in the postzygotic stage, but the variable clinical phenotype among the approximately 450 known cases has not been explained. No consistent mutations or deletions exist among patients. We encountered a baby girl with early onset infantile spasms. She had left-sided cleft lip/palate, costovertebral defects, scoliosis, callosal agenesis, and microphthalmia. She expired at the age of 3 months of respiratory infection. On autopsy she had thoracic hemivertebrae with rib defects, bilateral microphthalmia, microcornea, posterior colobomata, abnormalities of the retinal pigment epithelium, absence of normal ganglion cells in the retina, gross asymmetry of the brain with cerebral polymicrogyria, total callosal agenesis, cerebral subcortical and subependymal nodular heterotopias, cerebellar nodular heterotopias, and tegmental/basal unilateral brainstem hypoplasia. Cerebellar and retinal migration defects have not been described before in Aicardi syndrome and may have had a bearing on this patient's eventual outcome.

Clinical pathologic correlation: primary amenorrhoea and bilateral adnexal tumors.

A case of bilateral gonadoblastoma in 46,XY gonadal dysgenesis is presented and discussed by both clinician and pathologist, in this traditional clinico-pathologic conference. The discussion includes the differential diagnoses of primary amenorrhoea.

Human chorionic gonadotrophin producing epithelioid sarcoma metastatic to the placenta.

Pregnancy complicated by sarcoma is a rare event, and metastasis to the placenta is exceptionally rare. Of reported malignancies involving the products of conception, only 8% are sarcomas. We report the first case of placental metastasis of an epithelioid sarcoma, an uncommon malignancy which most frequently affects young adults. In addition to the typical histological features and immunophenotypic profile expected of epithelioid sarcoma, this tumor also expressed human chorionic gonadotrophin (HCG). Although uncharacteristic, the production of HCG has been previously reported in other nontrophoblastic tumors. It may have contributed to the pathogenesis of the tumor metastatic to the placenta in this case.

Simple (unicameral) bone cyst of the calcaneus: a pathologic variant revisited.

A 17-year-old girl was admitted to the hospital for surgery of an enlarging, painful mass of the left calcaneus. Preoperative imaging studies suggested either a simple (unicameral) or aneurysmal bone cyst. Intraoperative biopsy of the lesion revealed a simple bone cyst with extensive cholesterol clefts. Such cysts are not uncommon in the calcaneus. However, the pathology of this case is unusual and often overlooked. The typical presentation, treatment, and pathology of these lesions are reviewed.