Stefan Kostadinov

Transthyretin Is Dysregulated in Preeclampsia, and Its Native Form Prevents the Onset of Disease in a Preclinical Mouse Model

Preeclampsia is a major pregnancy complication with potential short- and long-term consequences for both mother and fetus. Understanding its pathogenesis and causative biomarkers is likely to yield insights for prediction and treatment. Herein, we provide evidence that transthyretin, a transporter of thyroxine and retinol, is aggregated in preeclampsia and is present at reduced levels in sera of preeclamptic women, as detected by proteomic screen. We demonstrate that transthyretin aggregates form deposits in preeclampsia placental tissue and cause apoptosis. By using in vitro approaches and a humanized mouse model, we provide evidence for a causal link between dysregulated transthyretin and preeclampsia. Native transthyretin inhibits all preeclampsia-like features in the humanized mouse model, including new-onset proteinuria, increased blood pressure, glomerular endotheliosis, and production of anti-angiogenic factors. Our findings suggest that a focus on transthyretin structure and function is a novel strategy to understand and combat preeclampsia.

Effects of Chemotherapy during Pregnancy on the Placenta

Whereas the effects of chemotherapy during pregnancy for mother and fetus are well described, its effects on the placenta remain largely undetermined. We performed a retrospective clinicopathologic analysis of the placenta following chemotherapy. Charts were reviewed for type of malignancy, type and timing of chemotherapy, and fetal and pregnancy outcome. Placentas were studied by standard pathologic analysis as well as computer-assisted morphometry and fluorescence in situ hybridization (FISH) analysis. Patients (n = 13) underwent chemotherapy during pregnancy for carcinoma of breast (3), ovary (2), cervix (2), salivary gland (1), lymphoma/leukemia (4), or rhabdomyosarcoma (1). Eleven patients were treated with DNA-active cytotoxic agents during the 2nd and/or 3rd trimesters; their placentas showed nonspecific findings, including villous hypermaturity, distal villous hypoplasia, villous edema, and excessive extravillous trophoblast, and 4/11 (36%) were small-for-age. In one case (rhabdomyosarcoma), the mother was exposed to cytotoxic agents throughout the entire pregnancy. In this case, associated with severe congenital anomalies, the placenta showed striking nuclear pleomorphism of the extravillous trophoblast of the chorion laeve, associated with FISH-demonstrated hyperpolyploidy. One patient was treated with the targeted tyrosine kinase inhibitor, imatinib, in 2 consecutive pregnancies; these placentas showed no specific anomalies. Our findings suggest that chemotherapy during the 1st trimester induces excessive polyploidization of the chorion laeve trophoblast, likely representing an adaptive response to intraamniotic toxins. Second and 3rd trimester exposure to cytotoxic agents may predispose to placental underdevelopment. However, without appropriate controls (untreated patients with equivalent malignancies), the specific effects of chemotherapy in this group are difficult to assess.

Placental mesenchymal dysplasia presenting as a twin gestation with complete molar pregnancy.

BACKGROUND: Placental mesenchymal dysplasia is a rare abnormality characterized by placentomegaly, grapelike cystic vesicles, and villous hyperplasia. The clinical and ultrasonographic presentation may mimic molar pregnancy, provoking incorrect diagnoses and unnecessary therapeutic interventions. CASE: A 36-year-old nulliparous woman presented for prenatal ultrasonography that indicated the presence of one gestational sac containing both fetus and cystic mass, concerning for partial molar pregnancy. Amniocentesis returned a 46,XX karyotype, suggesting a twin gestation with complete mole. The patient was monitored closely and, because of fetal growth restriction, was induced successfully at term and delivered a healthy newborn. Histopathologic findings of the placenta were consistent with placental mesenchymal dysplasia. CONCLUSION: Although placental mesenchymal dysplasia is often confused with molar pregnancy, it is important to consider both in a differential to avoid inappropriate treatments.

Placental IL-10 dysregulation and association with bronchopulmonary dysplasia risk

Cytokine profiles in amniotic fluid, cord serum, and tracheal aspirate of premature infants suggest a shift toward a proinflammatory state. Cytokines also contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). We hypothesize that the initiating events for BPD are reflected in the placenta and propose that placental expression of cytokines provide a blueprint of events leading to BPD. This is a retrospective, case-controlled study of placental cytokines of premature infants with (n = 49) and without (n = 49) BPD, matched for gender, birth weight, and year of birth at Women and Infants Hospital between 2003 and 2005. Cytokine expression, including IL-6 and IL-10, was determined by immunohistochemistry in membrane rolls, umbilical cords, and placentas. IL-6 was similarly expressed in all tissues of infants with and without BPD. In contrast, anti-inflammatory cytokine IL-10 was less prominent in the placenta of patients with BPD compared with those without BPD. IL-10 expression in the villous trophoblast layer was associated with a reduced odds ratio of developing BPD (adjusted OR 0.08, 95% CI 0.01–0.70, p = 0.02). These results suggest that a placental balance between inflammatory and anti-inflammatory cytokines is crucial to normal lung organogenesis. Importantly, IL-10 seems to be protective against the development of BPD.

Amniotic Fluid Infection Syndrome and Neonatal Mortality Caused by Eikenella corrodens

Different microorganisms not commonly found in the female genital tract have been implicated as causative agents for amniotic fluid infections. Eikenella corrodens is part of the normal flora in the human oral cavity and upper respiratory tract. It is most commonly found in the clinical setting of polymicrobial infections involving human bite wounds, head and neck infections, and periodontitis. On rare occasions, E. corrodens has been reported as a cause of gynecologic infections. There are only 3 reports of documented E. corrodens chorioamnionitis of the placenta resulting in preterm labor, one of which is associated with early neonatal demise. We report a case of preterm delivery of twin infants at 23 weeks of gestation with documented E. corrodens infection in 1 twin who was not resuscitated.

Maturation of the developing human fetal prostate in a rodent xenograft model.

Prostate cancer is the most commonly diagnosed nonskin cancer in men. The etiology of prostate cancer is unknown, although both animal and epidemiologic data suggest that early life exposures to various toxicants, may impact DNA methylation status during development, playing an important role.

Fetal Craniopharyngioma: Management, Postmortem Diagnosis, and Literature Review of an Intracranial Tumor Detected in Utero

Postmortem Diagnosis, and Literature Review of an Intracranial Tumor Detected in Utero STEFAN KOSTADINOV, COREY L. HANLEY, TERAKEITH LERTSBURAPA, BARBARA O’BRIEN, AND MAI HE Department of Pathology & Laboratory Medicine, Women & Infants Hospital of Rhode Island, Providence, RI, USA Department of Pathology, Memorial Hospital, Pawtucket, RI, USA Department of Obstetrics & Gynecology, Women & Infants Hospital of Rhode Island, Providence, RI, USA Alpert Medical School of Brown University, Providence, RI, USA

A Case of Galactosialidosis with Novel Mutations of the Protective Protein/Cathepsin A Gene: Diagnosis Prompted by Trophoblast Vacuolization on Placental Examination

Galactosialidosis (GS) is a rare autosomal recessive lysosomal storage disease caused by a combined deficiency of lysosomal β-galactosidase and neuraminidase as a result of a genetic defect in the protective protein/cathepsin A gene. We report a case of unsuspected fetal galactosialidosis presenting as severe intrauterine growth restriction and oligohydramnios prenatally and as hyperinsulinemic hypoglycemia in the immediate postnatal period. Placental pathology examination showed striking vacuolations of the villous syncytiotrophoblast, extravillous trophoblast, and villous Hofbauer cells. Electron microscopy revealed numerous membrane-bound electron-lucent lysosomes, mainly within the syncytiotrophoblast. The characteristic histologic and ultrastructural placental findings prompted biochemical and molecular genetic testing for fetal storage disease. Enzyme activity of β-galactosidase was decreased in leukocytes and fibroblasts. Sialic acid content was elevated. Molecular genetic studies revealed 3 variants—c.108, 110delGCT(L37del), c.1045T>A (C349S), and c.1321C>T(R441C)—of the cathepsin A gene, the latter 2 of which have not been previously reported. These findings are consistent with galactosialidosis. We emphasize the importance of following the accepted practice guideline for the examination of the placenta in discovering unsuspected fetal metabolic disorders.

Pregnancy and Perinatal Outcomes Associated with Acinetobacter baumannii Infection

Objective To determine perinatal and pregnancy outcomes of Acinetobacter baumannii infection using clinicopathologic material from pregnant women, neonates, and perinatal postmortem examinations with positive cultures. Study Design This is a retrospective record review with placental and postmortem examination. Results During a 5-year period, 40 positive cultures were found. Three pregnancies with positive cultures close in the peripartum period were all associated with adverse outcomes including spontaneous abortion, preterm labor, and one full-term birth with histological chorioamnionitis. Two positive cultures were found in preterm neonates in the neonatal intensive care unit. Two of three cases of perinatal death grew pure cultures from blood and/or fetal tissue with placental or fetal examination demonstrating evidence of infection/inflammation with fetal inflammatory response. Conclusion This is the first case series report of A. baumannii-positive cultures in maternal, fetal, and neonatal specimen, with histopathologic evidence of infection. The results suggest a significant role of A. baumannii infection in adverse pregnancy and perinatal outcomes.

Large solitary luteinized follicle cyst of pregnancy and puerperium: report of two cases

We describe two cases of large solitary luteinized follicle cyst of pregnancy and puerperium (LSLFCPP) with new clinicopathologic findings. The first case occurred in a 40-year old woman who was found to have a left ovarian mass during the third trimester of pregnancy. The patient delivered a full term healthy female infant via caesarean section. The ovarian mass was removed by oophorectomy. The specimen showed a unilocular, thin-walled, clear fluid filled cyst measuring 15 × 12 × 5 cm. Microscopically, the cyst was lined by single to multiple layers of luteinized cells with mainly small, round and regular nuclei and focally enlarged, bizarre, and hyperchromatic nuclei. Occasional mitotic figures were seen. The cyst wall showed marked edema and nests of luteinized cells that were morphologically similar to the cyst lining cells. Groups of lesional cells were surrounded by reticulin fibers. The patient has been healthy without disease after 7 years. The second patient was a 29-year old pregnant woman who was found to have a right ovarian cyst by ultrasound at 14-week gestation. She then presented with preterm labor at 33-week gestation and delivered a healthy female infant via caesarean section. A right salpingo-oophorectomy was performed. Gross inspection of the specimen revealed a unilocular, brown mucoid fluid filled cyst measuring 14 × 11 × 9 cm. The cyst surfaces were smooth, and the cyst wall exhibited marked edema. Microscopic examination showed features similar to the first case: cyst lined by luteinized cells with focal large nuclei, scattered nests of luteinized cells in the edematous fibrous wall, and reticulin fibers surrounding large nests of lesional cells. No mitoses, however, were identified in the second case. The patient has been well without disease 1 year after surgery. These two cases contribute to a better understanding of LSLFCPP. Our case in the 40-year old patient is the first to show mitotic figures in LSLFCPP and suggests that the presence of occasional mitoses should not exclude a diagnosis of LSLFCPP. The lesion in the second patient caused preterm labor. Nevertheless, absence of disease recurrence in our patients demonstrates a benign nature of LSLFCPP.