Criteria for placental examination for obstetrical and neonatal providers.

Pathologic examination of the placenta can provide insight into likely (and unlikely) causes of antepartum and intrapartum events, diagnoses with urgent clinical relevance, prognostic information for mother and infant, support for practice evaluation and improvement, and insight into advancing the sciences of obstetrics and neonatology. Although it is true that not all placentas require pathologic examination (although alternative opinions have been expressed), prioritization of placentas for pathologic examination should be based on vetted indications such as maternal comorbidities or pregnancy complications in which placental pathology is thought to be useful for maternal or infant care, understanding pathophysiology, or practice modifications. Herein we provide placental triage criteria for the obstetrical and neonatal provider based on publications and expert opinion of 16 placental pathologists and a pathologists' assistant, formulated using a modified Delphi approach. These criteria include indications in which placental pathology has clinical relevance, such as pregnancy loss, maternal infection, suspected abruption, fetal growth restriction, preterm birth, nonreassuring fetal heart testing requiring urgent delivery, preeclampsia with severe features, or neonates with early evidence of multiorgan system failure including neurologic compromise. We encourage a focused gross examination by the provider or an attendant at delivery for all placentas and provide guidance for this examination. We recommend that any placenta that is abnormal on gross examination undergo a complete pathology examination. In addition, we suggest practice criteria for placental pathology services, including a list of critical values to be used by the relevant provider. We hope that these sets of triage indications, criteria, and practice suggestions will facilitate appropriate submission of placentas for pathologic examination and improve its relevance to clinical care.

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).

Interobserver Reliability for Identifying Specific Patterns of Placental Injury as Defined by the Amsterdam Classification.

CONTEXT.­: Placental pathology is an essential tool for understanding neonatal illness. The recent Amsterdam international consensus has standardized criteria and terminology, providing harmonized data for research and clinical care. OBJECTIVE.­: To evaluate the interobserver reliability of these criteria between pathologists at different levels of experience using digitally scanned slides from placentas in a birth population including a large proportion of normal deliveries. DESIGN.­: This was a secondary analysis of selected placentas from a large case-control study of placental lesions associated with neonatal encephalopathy. Histologic slides from 80 placentas were digitally scanned and blindly evaluated by 6 pathologists. Interobserver reliability was assessed by positive and negative agreement, Fleiss κ, and interrater correlation coefficients. RESULTS.­: Overall agreement on the diagnosis, grading, and staging of acute chorioamnionitis and villitis of unknown etiology was moderate to good for all observers and good to excellent for a subset of 4 observers. Agreement on the diagnosis and subtyping of fetal vascular malperfusion was poor to fair for all observers and fair to moderate for the subset of 4 pathologists. Agreement on accelerated villous maturation was poor. CONCLUSIONS.­: This study critically evaluates interobserver reliability for lesions defined by the Amsterdam consensus using scanned images with a low frequency of pathologic lesions. Although reliability was good to excellent for inflammatory lesions, lower reliability for vascular lesions emphasizes the need to more explicitly define the specific histologic features and boundaries for these patterns.

Pediatric Primary Hepatic Tumors: Diagnostic Considerations.

The liver is the third most common site of abdominal tumors in children. This review article aims to summarize current evidence surrounding identification and diagnosis of primary hepatic tumors in the pediatric population based upon clinical presentation, epidemiology, and risk factors as well as classical imaging, histopathological, and molecular diagnostic findings. Readers will be able to recognize the features and distinguish between benign and malignant hepatic tumors within different age groups.

Four major patterns of placental injury: a stepwise guide for understanding and implementing the 2016 Amsterdam consensus.

The Amsterdam classification system defines four major patterns of placental injury, maternal vascular malperfusion, fetal vascular malperfusion, acute chorioamnionitis, and villitis of unknown etiology, and lists the histologic findings that characterize each. However, there continues to be uncertainty regarding specific definitions, histologic mimics, grading and staging, and what combination of findings is required to diagnose each pattern of injury in a reproducible fashion. The purpose of this review is to clarify some of these issues by suggesting a stepwise approach to more fully realize the potential of this new classification system. In our view, the critical steps for correctly identifying and communicating each pattern of injury are (1) familiarity with the underlying pathophysiology and known clinical associations, (2) incorporation of important gross findings, (3) learning to recognize underlying architectural alterations and defining features at low power, (4) using higher magnification to narrow the differential diagnosis and assess severity (grading) and duration (staging), and (5) adopting a template for generating standardized placental reports that succinctly provide useful information for patient care and research applications.

The Association of Fetal Congenital Cardiac Defects and Placental Vascular Malperfusion.

OBJECTIVES: Abnormal early angiogenesis appears to impact both placental disorders and fetal congenital heart defects (CHD). We sought to assess the association of placental perfusion defects (PPD) and fetal (CHD). METHODS: Singleton pregnancies with isolated severe fetal CHD were compared to controls without congenital anomalies or maternal malperfusion (MVM) risk factors. CHD was categorized into group 1: single left ventricle morphology and transposition of the great vessels (TGA) and group 2: single right ventricle and two ventricle morphology. Malperfusion was defined as fetal vascular malperfusion (FVM), MVM, and both FVM and MVM. RESULTS: PPD was increased for all CHD (n = 47), CHD with or without risk factors, and CHD groups compared to controls (n = 92). Overall CHD cases and CHD with risk factors had an increased risk of FVM (30% and 80% vs 14%), and MVM (43% and 50% vs 21%), respectively. MVM rates were similar in CHD with and without maternal risk factors. FVM (38% vs 14%) and MVM (44% vs 21%) were increased in Group 1. MVM (42% vs 21%) and both FVM and MVM (16% vs 3%) were increased in Group 2. CONCLUSIONS: PPD risk is increased in severe isolated fetal CHD. The highest risk is seen in fetal CHD with maternal risk factors.

Massive Perivillous Fibrin Deposition in Congenital Cytomegalovirus Infection: A Case Report.

Cytomegalovirus (CMV) infection is one of the most common congenital viral infections. Classically associated placental findings include chronic villitis with plasma cells, stromal hemosiderin deposition, and identification of viral inclusions in villous endothelial and stromal cells. We present a case of confirmed congenital CMV infection that lacked these classical findings, but demonstrated massive perivillous fibrin deposition (MPVFD). This is the first report of CMV associated with MPVFD. MPVFD is an uncommon placental lesion associated with adverse fetal outcomes and a high risk of recurrence. However, the recurrence risk in patients with an infectious cause may be lower in than patients with other associated clinical conditions.

Predictors of High Grade and Other Clinically Significant Placental Findings by Indication for Submission in Singleton Placentas From Term Births.

Indications for placental submission are variable. Established guidelines are largely based on expert opinion, and there is a need for more evidence-based criteria. A 10-year database of term placentas was used to evaluate indications significantly associated with placental pathology. Lesions in 5 categories were separated into high- and low-grade subgroups. Two additional high-grade lesions were also evaluated. Indications associated with high-grade placental lesions were chronic monitoring abnormalities, severe preeclampsia, pregestational diabetes, maternal signs of infection, postdates pregnancy, artificial reproductive technology, drug abuse, umbilical cord entanglements, selected gross placental abnormalities, stillbirth, Apgar 5 minutes <6, small-for-gestational age infant, and macrosomia. Indications for which placental findings did not differ from the population as a whole were acute monitoring abnormalities, chronic hypertension, maternal obesity, vaginal bleeding, accessory lobe/multilobed placenta, meconium-stained fluid, single umbilical artery, and borderline large-for-gestational age infant. Other indications for submission were intermediate showing significant or borderline elevations in the prevalence of low- and high-grade lesions combined. We suggest on the basis of this study that guidelines for the submission of singleton term placentas could be modified to exclude cases with clinical indications that lack a significant association with placental lesions.

What Obstetricians Need to Know About Placental Pathology.

The placenta can serve as a valuable source of information about maternal and fetal conditions during the pregnancy; however, the abilities to perform a preliminary gross examination and interpret a placental pathology report are variable among obstetricians. This article discusses the indications for placental submission to pathology; the essentials of gross examination, including elements that should be performed in the delivery suite; and the most common and clinically relevant histologic findings that may be encountered in the report.

Ectopic ACTH Production and Cushing's Syndrome in a Patient with Parotid Acinic Cell Carcinoma with High-Grade Transformation: Tumor Context and Clinical Implications.

We report a rare case of Cushing's syndrome in a 59-year-old man who initially presented with concurrent acinic cell carcinoma of the parotid with high-grade transformation and co-existing papillary and medullary thyroid carcinomas, without noticeable cushinoid symptoms. Six-months later, he developed clinical features of Cushing's syndrome which coincided with disease progression in the form of lung metastasis and mediastinal lymphadenopathy. Ectopic adrenocorticotropic hormone (ACTH) production and protein expression was limited to the high-grade transformed component of acinic cell carcinoma and in the lymph node metastasis, and was absent in the conventional acinic cell carcinoma as well as in the papillary and medullary thyroid carcinoma. He received adjuvant chemotherapy and supportive management with interval improvement for 8 months followed by disease progression with increasing serum cortisol levels and bone metastasis. He was offered palliative chemotherapy, however, declined further therapy and was lost to follow up. We discussed clinical and pathologic implications of ectopic ACTH production associated with acinic carcinoma and also reviewed the literature of this rare paraneoplastic syndrome.

The placenta.

Examination of the placenta provides a unique opportunity to explore and understand the intrauterine environment, as well as providing a record of events that may be associated with adverse pregnancy outcomes, one of the most devastating of which is central nervous system (CNS) injury. A number of placental lesions have been described in association with various forms of neurologic injury. They can be divided into four major categories: sentinel events, inflammatory lesions, vascular lesions, and "biomarker" lesions, which are not themselves causative, but are often found in association with other lesions that are causative. The purpose of this review is to outline these placental lesions and summarize the types of CNS injury that have been described in association with each. Finally, one of the most important of all risk factors for CNS injury is the finding of multiple independent placental lesions. The effects of these lesions may be synergistic, particularly when metachronous, with an earlier lesion leaving the CNS more vulnerable to the effects of a later lesion.

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.

Placental findings in feto-maternal hemorrhage in livebirth and stillbirth.

Feto-maternal hemorrhage (FMH) is not an uncommon event during pregnancy with important clinical implications for both maternal and fetal outcomes. The diagnosis is often made using Kleihauer-Betke (KB) test. As FMH occurs transplacentally, examination of the placenta may contribute to the diagnosis of FMH. This retrospective case-control study aims to examine the placental features associated FMH in patients with known positive KB test results. When compared with KB negative placentas (n=88), KB positive placentas (n=49) had significantly higher incidence of pallor (6/49 vs 0/88, p=0.0017), IVT (11/49 vs. 5/88, p=0.0032) and nRBCs (12/49 vs. 4/88, p=0.0008). Autopsy cases with fetal or neonatal death due to FMH, (n=13) compared to a cohort of 162 placentas associated with other, non-FMH causes of death also had significantly higher frequency of pallor (5/13 vs 0/162, p<0.0001), IVT (6/13 vs 24/162, p=0.011) and nRBCs (11/13 vs 67/162, p=0.003). Pallor and nRBC were also associated with higher volume of FMH. Placental parenchymal pallor, intervillous thrombi and presence of nRBCs are significantly associated with documented FMH in both normal pregnancies and pregnancies associated with fetal or neonatal death. The presence of these findings, especially in combination, may suggest the need for maternal KB testing to rule out FMH and neonatal monitoring and/or intervention.

Yolk Sac Tumor in Extragonadal Pelvic Sites: Still a Diagnostic Challenge.

We present the clinicopathologic features of 15 cases of extragonadal yolk sac tumor (EGYST) detected in female patients and reviewed at our institution from 1988 to 2016. We recorded: patient age, clinical presentation, tumor location, FIGO stage (where applicable), histologic patterns including presence/absence of Schiller-Duval bodies, other germ cell or somatic components, immunoperoxidase results, treatment, and outcome. Patients' ages ranged from 17 to 87 (median, 62) years and presentation included: abnormal uterine bleeding, 12; hematuria, 1; labial mass, 1; abdominal pain, 1. Primary sites were as follows: uterus (11), vagina (1), vulva (1), bladder (1), and peritoneum (1). Seven patients presented at FIGO stage III or IV. The following histologic patterns were observed: microcystic/reticular (7), glandular (8), solid (8), papillary (5), and hepatoid (1). An admixture of histologic patterns was present in 10 cases. Schiller-Duval bodies were seen in only 3 (23%) cases. Eight cases (46%), all uterine primaries, had associated somatic components, and 2 (15%) had a second germ cell component. In 13/14 (93%) cases, the yolk sac tumor component was either missed or misclassified as adenocarcinoma. Immunoperoxidase studies facilitated the diagnosis in all cases as follows: SALL4, 12/12; CDX2, 10/12; α fetoprotein, 7/14; glypican-3, 9/10; cytokeratin 20, 5/9 (rare cells); cytokeratin 7, 3/12 (nondiffuse); PAX8, 2/9 (variable expression). All patients received chemotherapy and all except 1 underwent surgical resection. Follow-up from 5 to 86 months was available for 13 patients: 5 died of disease, 6 are alive with disease, and 2 have no evidence of disease. EGYST arising in the female pelvis of peri/postmenopausal patients may be associated with a somatic component and represent either somatically derived YST or YST differentiation within a somatic carcinoma. EGYST in younger patients is likely a true germ cell neoplasm, and may respond to germ cell appropriate chemotherapy. The benefit of germ cell appropriate chemotherapy in somatically derived EGYST is less clear. Awareness that the presence of glandular or microcystic patterns may lead to under-recognition or misdiagnosis of EGYST in combination with immunomarkers for germ cell and yolk sac differentiation will facilitate the diagnosis.

Enterovirus D68 and Panton-Valentine Leukocidin-Positive Staphylococcus aureus Respiratory Coinfection with Fatal Outcome.

A previously healthy 10-year-old girl with a 2-day history of upper respiratory illness and fever rapidly developed respiratory failure and sepsis with leukopenia, and expired despite attempts at resuscitation. Postmortem examination revealed bilateral necrotizing pneumonia and evidence of disseminated intravascular coagulation. Nasopharyngeal swabs and lung tissue submitted to the Centers for Disease Control and Prevention (CDC) were positive for Enterovirus D68 (EV-D68). Blood and lung cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA). The isolates were submitted to the CDC and were found to be positive for the toxin Panton-Valentine leukocidin. We describe a fatality related to invasive toxin-mediated MRSA associated with EV-D68 coinfection, along with the clinical, laboratory, and autopsy findings, which provided important clues, prompting further investigation at the CDC to arrive at the correct diagnosis.

Unusual Sertoli Cell Tumor Associated With Sex Cord Tumor With Annular Tubules in Peutz-Jeghers Syndrome: Report of a Case and Review of the Literature on Ovarian Tumors in Peutz-Jeghers Syndrome.

We report the case of an 11-year-old girl with Peutz-Jeghers syndrome and a unilateral ovarian tumor most consistent with Sertoli cell tumor associated with sex cord tumor with annular tubules. The ovary was replaced by a lobular, solid, yellow tumor. Microscopic examination showed 2 components that focally merged. The first was composed of uniform, cytologically bland cells arranged mostly in diffuse sheets and focally in tubules. The second showed typical sex cord tumor with annular tubules with extensive calcification. The predominant component of the tumor clearly fell in the sex cord category and most closely resembled Sertoli cell tumor. This case adds to the limited information on ovarian sex cord tumors, other than typical sex cord tumor with annular tubules, arising in association with Peutz-Jeghers syndrome, a topic reviewed herein.