Absence of Ductus Venosus: A Comparison of 2 Distinctive Fetal Autopsy Cases and Embryologic Perspectives.

In fetal circulation, oxygenated blood from the placenta flows through the umbilical vein into the ductus venosus (DV), then enters the inferior vena cava, and subsequently reaches the right atrium of the heart. The DV serves as a shunt, allowing this oxygen-rich blood to bypass the liver. The absence of the DV (ADV), also known as agenesis of the DV, is a rare congenital anomaly. Without a DV, blood from the umbilical vein must follow alternative routes to the heart. In ADV cases, blood from the umbilical vein must follow 1 of 2 primary drainage patterns: either an extrahepatic shunt or an intrahepatic shunt. This report details the antenatal ultrasound and postmortem findings of 2 fetuses diagnosed with ADV by prenatal imaging studies. The first case involved a fetus with a persistent right umbilical vein connected directly to the suprahepatic IVC, accompanied by early obliteration of the left umbilical vein and true agenesis of the DV. This fetus also had additional congenital anomalies. In contrast, the second case involved a fetus with a normal left umbilical vein that entered the liver. However, despite an ultrasound diagnosis of "absence" of the DV, a DV was present, though markedly hypoplastic and probably minimally functional or non-functional. In this case, blood from the umbilical vein likely followed an alternate intrahepatic route through the portal and hepatic veins, before reaching the heart (intrahepatic shunt). These contrasting cases emphasize the heterogeneity of vascular anomalies and embryologic origins captured by the term "ADV." Additionally, the terminology of "absence" or "agenesis" may be misleading in some purported ADV cases. Specifically, in the second case, the DV was not absent; it was markedly hypoplastic instead. This also appears to be the first reported case of a hypoplastic DV in a fetus. Both cases underscore the importance of effective collaboration and clear communication between maternal-fetal medicine specialists and pathologists.

Maternal Hemoglobin A1c in the Third-Trimester May Underestimate Maternal Hyperglycemia and Its Impact on Offspring in Perinatal Demise Associated With Gestational Diabetes Mellitus: An Autopsy Case Series.

INTRODUCTION: Gestational diabetes mellitus (GDM) is a common metabolic disorder linked to adverse pregnancy outcomes. Recent research indicates that HbA1c is reliable in detecting maternal glycemia during the first trimester but may underestimate glucose intolerance in the late second to third trimesters. Therefore, it is reasonable to hypothesize that mothers with GDM, despite apparently normal HbA1c levels in the third trimester, may give birth to infants displaying characteristic features often seen in infants of diabetic mothers with suboptimal glycemic control. This study aimed to describe a case series of autopsy cases involving stillborn or deceased neonates delivered in the third trimester to mothers diagnosed with GDM and having normal HbA1c levels at or around the time of delivery. The primary focus was on identifying and documenting the characteristic features commonly associated with "infants of diabetic mothers" with suboptimal glycemic control in this series of cases. MATERIALS AND METHODS: We conducted a retrospective review of autopsy reports from our institution spanning 7.5 years. The study included cases that met the following criteria: (1) stillborn or infants who died in the early neonatal period, delivered in the third trimester; (2) mothers diagnosed with GDM; (3) normal maternal HbA1c levels of ≤6.1% at or around the time of delivery; (4) birthweight or femoral length exceeding the 90th percentile for gestational age; and (5) absence of genetic aberrations. We also examined these cases for other characteristic features associated with "infants of diabetic mothers." RESULTS: Ten autopsy cases met our inclusion criteria, including 9 stillbirths and 1 neonatal death. Gestational age at delivery ranged from 32 to 39 weeks (mean: 35.7 weeks). Femoral length exceeded the 90th percentile in all cases, and 6 cases had birthweights above the 90th percentile. Puffy facies were observed in 6 cases. Among the 9 cases with complete autopsies including internal examination, 6 exhibited excess adipose tissue, 4 had cardiomegaly, and 3 showed pancreatic islet hyperplasia. Hypoxic-ischemic encephalopathy was detected in 7 cases. No structural abnormalities were noted. DISCUSSION: Our findings demonstrated that fetuses and neonates born to mothers with apparently normal HbA1c levels in the third trimester could still display characteristic features commonly observed in infants of diabetic mothers with poor glycemic control, also known as "infants of diabetic mothers." This study underscores the potential of third-trimester maternal HbA1c measurements to underestimate maternal glycemia and its consequential impact on fetal development, as well as the subsequent manifestation of features of "infants of diabetic mothers."

Time Required for Gross Examination of Routine Second and Third Trimester Singleton Placentas by Pathologists' Assistants.

INTRODUCTION: In both Canada and the United States, workload measurement for anatomic pathology is mainly based on complexity and clinical significance of specimens, with gross examination being a considerable contributor. While Pathologists' Assistants (PAs) play an increasing role in gross examination, there is little known regarding the time required for PAs to complete grossing tasks. This information is essential for effective staffing and workload management in pathology laboratories. The objective of our study was to determine the time required for PAs to gross second and third trimester singleton placentas in a large tertiary hospital with a significant perinatal pathology service. MATERIALS AND METHODS: For our study, 7 certified PAs each grossed a minimum of 10 second and third trimester singleton placentas using a standard placental grossing protocol, an electronic laboratory information system, and voice recognition dictation software. Placental specimens requiring photography, sampling for ancillary studies, or immediate pathologist's consultation were excluded. We calculated average and standard deviation of grossing times for each PA, overall average grossing time, and 95% confidence interval using a mixed linear regression model. We analyzed the impact of PA job experience, degree obtained, and number of blocks prepared on overall average in a multivariate analysis. RESULTS: The mean grossing times for each PA ranged from 11.0 (standard deviation [sd] = 2.0) to 17.8 (sd = 4.5) minutes. The overall average grossing time was 14.5 minutes, with a 95% confidence interval of 11.7 to 17.3 minutes. In multivariate analysis, an increase in the number of blocks prepared was significantly associated with longer overall average grossing time. If 4 blocks were prepared consistently, the model predicted a slightly lower overall average of 13.3 minutes, with a 95% confidence interval of 10.9 to 15.7 minutes. DISCUSSION: To our knowledge, our study is the first to objectively report time required for PAs to perform gross examinations of routine second and third trimester singleton placentas. The methodology of our study is replicable and can be applied to other specimen types and laboratory settings. Previously, estimated grossing times for specimens were primarily based on retrospective surveys, which were susceptible to recall errors and subjectivity. However, our study demonstrates objective data collection is achievable. Furthermore, the data collected from this study offer valuable insights into the accuracy of previous and current pathology workload models for second and third trimester singleton placentas.

Maturation of metastases in peripheral neuroblastic tumors (neuroblastoma) of children.

Peripheral neuroblastic tumors of childhood exhibit 3 principal neural crest lineages: primitive neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. They are unique in undergoing maturation of neurons (ganglion cells) and Schwann cells, thereby recapitulating normal fetal neuronal development in the brain. Precision in estimating neurogenesis is enhanced by immunoreactivities of markers of neuronal maturation. Whether organ tissue factors in different sites of metastases influence rates of maturation and whether metastases are similar to their primary neuroblastic tumor are incompletely documented. Four young children, 1 with a mixed primary adrenal tumor and 3 with metastases were studied at surgery or autopsy. Immunocytochemical reactivities included microtubule-associated protein-2, synaptophysin, chromogranin-A, somatostatin, keratan sulfate, vimentin, S-100ß protein, and PHOX2B. Primary tumors were non-uniform with regions of either poor or enhanced maturation. Both neuronal and Schwannian lineages were represented in each tumor type but differed in proportions. Bi- or multi-nucleated ganglion cells matured equal to mononuclear forms. Ganglion cell maturation was similar in metastases regardless of the target organ. Metastases resembled primary tumors. Immunocytochemical markers of neuronal and of Schwann cell maturation provide greater diagnostic precision to supplement histological criteria. Interval between diagnosis of primary tumor and metastases, metastatic target tissues, and chemotherapy over an interval of time do not appear to influence neuroblastic or Schwann cell differentiation.

Congenital SARS-CoV-2 Infection in Two Neonates with Confirmation by Viral Culture of the Placenta in One Case.

Congenital infections with SARS-CoV-2 are uncommon. We describe two confirmed congenital SARS-CoV-2 infections using descriptive, epidemiologic and standard laboratory methods and in one case, viral culture. Clinical data were obtained from health records. Nasopharyngeal (NP) specimens, cord blood and placentas when available were tested by reverse transcriptase real-time PCR (RT-PCR). Electron microscopy and histopathological examination with immunostaining for SARS-CoV-2 was conducted on the placentas. For Case 1, placenta, umbilical cord, and cord blood were cultured for SARS-CoV-2 on Vero cells. This neonate was born at 30 weeks, 2 days gestation by vaginal delivery. RT-PCR tests were positive for SARS-CoV-2 from NP swabs and cord blood; NP swab from the mother and placental tissue were positive for SARS-CoV-2. Placental tissue yielded viral plaques with typical morphology for SARS-CoV-2 at 2.8 × 102 pfu/mL confirmed by anti-spike protein immunostaining. Placental examination revealed chronic histiocytic intervillositis with trophoblast necrosis and perivillous fibrin deposition in a subchorionic distribution. Case 2 was born at 36 weeks, 4 days gestation. RT-PCR tests from the mother and infant were all positive for SARS-CoV-2, but placental pathology was normal. Case 1 may be the first described congenital case with SARS-CoV-2 cultivated directly from placental tissue.

C4d Staining Is Present in Normal Placentas From Pregnancies Prior to Pregnancy Loss Associated With Chronic Histiocytic Intervillositis and Is Reduced by Immunomodulatory Therapy in Subsequent Pregnancies.

INTRODUCTION: Chronic histiocytic intervillositis (CHI) is associated with adverse pregnancy outcomes and high recurrence risk. Recent studies suggest that CHI may represent a host-vs-graft rejection, and that C4d immunostain can be used as a marker for complement activation and antibody-mediated rejection in the CHI. MATERIALS AND METHODS: This retrospective cohort study focused on 5 fetal autopsy cases associated with CHI (5 index cases) from 5 women. We analyzed placentas from the index cases (fetal autopsy cases associated with CHI) and placentas from the women's previous and subsequent pregnancies. We assessed the presence and extent of CHI and C4d immunostaining in these placentas. We evaluated each available placenta and graded the severity of CHI as either <50% or ≥50%. Additionally, we conducted C4d immunostaining on one representative section from each placenta and graded the staining levels as follows: 0+ for staining <5%; 1+ for staining between 5% and <25%; 2+ for staining between 25% and <75%; and 3+ for staining ≥75%. RESULTS: Three of the 5 women had pregnancies prior to their index cases (fetal autopsy cases associated with CHI). Despite the absence of CHI in their initial pregnancies, the placentas displayed positive C4d staining with grades of 1+, 3+, and 3+, respectively. These results suggest the presence of complement activation and antibody-mediated rejection in placentas from their prior pregnancies without CHI. Three of the 5 women received immunomodulatory therapy after experiencing pregnancy losses associated with CHI. After treatment, 2 of these women had live births at 35 and 37 gestational weeks, respectively, while the third had a stillbirth at 25 gestational weeks. The severity of CHI and the degree of C4d staining in the placentas decreased in all 3 cases following immunomodulatory therapies. Specifically, the level of C4d staining decreased from 3+ to 2+, 2+ to 0+, and 3+ to 1+ in these 3 cases, respectively. DISCUSSION: In women with a history of recurrent pregnancy loss associated with CHI, C4d immunostaining was present in the placentas from their previous non-CHI pregnancies, suggesting activation of the classical complement pathway and antibody-mediated reaction in their prior non-CHI pregnancies before the development of CHI in subsequent pregnancies. Immunomodulatory therapy may improve pregnancy outcomes by reducing complement activation, as shown by the reduction of C4d immunopositivity in the placentas after immunomodulatory treatment. Although we believe that the study provides valuable insights, we acknowledge that there are limitations to the findings. Therefore, to further elucidate the pathogenesis of CHI, additional research efforts with a collaborative and multidisciplinary approach are necessary.

Obstructed Hemivagina and Ipsilateral Renal Anomaly (OHVIRA) - A Fetal Autopsy Case.

BACKGROUND: Obstructed hemivagina and ipsilateral renal anomaly (OHVIRA) is a rare congenital anomaly characterized by uterus didelphys, unilateral obstructed hemivagina, and ipsilateral renal anomaly. CASE: Autopsy performed on a third trimester stillborn fetus unexpectedly revealed uterine didelphys, an obstructed left hemivagina, and a left pelvic, atrophic, duplex kidney, with both left ureters entering the obstructed left hemivagina. Furthermore, the fetus had an imperforate anus, a single right umbilical artery, and spina bifida occulta. SUMMARY AND CONCLUSION: Although rare, OHVIRA is a well-documented congenital anomaly. However, prior to this case, there had been no description of OHVIRA in an autopsy or in a fetus. Furthermore, the association of OHVIRA, anorectal malformation, and spinal bifida has never been reported. By sharing this case, we hope to increase the awareness of this entity among perinatal healthcare providers and to help further elucidate genitourinary embryology, which is still not fully understood.

Recurrence risk of villitis of unknown etiology: Analysis of a large retrospective cohort study, systematic review and meta-analysis.

INTRODUCTION: Recurrence risk of villitis of unknown etiology (VUE) remains uncertain because of few studies and their methodologic limitations. We calculated recurrence risk in a large population of deliveries after minimizing important biases and compared it to others via systematic review and meta-analysis. METHODS: Over 11 years of placenta pathology reports on singleton deliveries were retrieved and searched for 'villitis' or 'VUE'. Cases of acute villitis and chronic villitis from infections were eliminated via pathologist review. Reports were merged to data containing gestational age, parity and gravida. Recurrence risk of VUE per patient, per parity and per gravida was determined among patients with ≥2 placentas examined for deliveries ≥20 weeks gestation. Results were compared to those from articles and their references identified by a MEDLINE® search. Recurrence risks among methodologically similar studies were pooled using a random effects model. RESULTS: Among 29 124 placenta pathology reports from 27 087 patients, there were 2423 cases of VUE among 2382 patients, of which 153 had ≥2 placentas examined. There were 41 recurrent cases of VUE for a recurrence risk of 27% per patient, 22% per parity, and 19% per gravida. We identified 64 articles, of which 4 were retained. One examined all placentas from all births over a ∼3-year period, finding a recurrence risk of 27%. The remaining 3 studies, along with our own, used indications for placental examination and had a pooled recurrence risk of 30% (95% Confidence Interval: 0.21-0.41). DISCUSSION: In our study, which is the largest, most comprehensive, and methodologically robust to date, VUE recurrence risk was ∼30%.

Massive ascites and severe pulmonary hypoplasia in a premature infant with meconium peritonitis and congenital cytomegalovirus infection.

Background: Meconium peritonitis (MP) is an infrequent prenatal complication. Association between MP and pulmonary hypoplasia has never been reported. Case Report: A female infant with antenatally diagnosed MP and ascites was delivered at 36 gestational weeks. She died shortly after birth due to pulmonary insufficiency. Autopsy confirmed the presence of MP and ascites, and additionally revealed intestinal malrotation, volvulus, necrosis and perforation, and pulmonary hypoplasia. Congenital cytomegalovirus (CMV) infection was also noted. This was an unexpected finding as the mother was tested negative for CMV IgM at 26 gestational weeks after sonographic detection of fetal ascites. Conclusions: This is the first reported case of lethal pulmonary hypoplasia in a neonate with MP-associated ascites complicated by congenital CMV infection. This case illustrates that a negative maternal CMV IgM might not be sufficient to rule out congenital CMV, and that a concomitant infectious etiology should always be considered even when a primary cause for fetal ascites (e.g., MP in this case) is identified.

Atypical Prenatal Ultrasound Presentation and Neuropathological Findings in a Neonate With Alpha Thalassemia Major: A Case Report.

Alpha thalassemia major is a hemoglobinopathy caused by the inactivation or deletion of all 4 α-globin alleles. We describe a case of α-thalassemia major with atypical ultrasound and neuropathological findings. The mother had her first prenatal visit at 27 4/7 gestational weeks. Ultrasound revealed a hydropic fetus with multiple anomalies. However, the middle cerebral artery peak systolic velocity (MCA-PSV) suggested that the likelihood of fetal anemia was low. Given the poor prognosis of hydrops fetalis, the parents opted for termination of pregnancy. The neonate died shortly after birth. Autopsy revealed a markedly hydropic female infant with severe limb reduction defects and, in contrast to what was suggested by the prenatal MCA-PSV measurement, unequivocal signs of severe anemia. The brain showed diffuse white matter gliosis. Genetic testing subsequently identified HBA1 and HBA2 deletions, consistent with α-thalassemia major. This case highlights the potential pitfall of MCA-PSV, which is nowadays considered the gold standard for noninvasive detection of fetal anemia. In addition, this is 1 of 2 published case reports detailing neuropathological findings in a fetus or neonate with α-thalassemia major and the first to link α-thalassemia major with diffuse white matter gliosis.

Pulmonary effects of i.v. injection of crushed oral tablets: "excipient lung disease".

OBJECTIVE: When crushed oral tablets are injected i.v., their filler material (excipient) can induce a potentially fatal foreign-body reaction in pulmonary arterioles, presenting as dyspnea and pulmonary hypertension with centrilobular nodules on CT. We will describe the imaging and pathologic features of "excipient lung disease." CONCLUSION: The radiologist has a critical role in recognizing and reporting excipient lung disease because the referring clinician may be unaware of the patient's i.v. drug abuse.

Liver failure due to hepatic angiosarcoma in an adolescent with dyskeratosis congenita.

Dyskeratosis congenita (DC) is a multisystem disease caused by genetic mutations that result in defective telomere maintenance. Herein, we describe a 17-year-old patient with severe DC, manifested by bone marrow failure, severe immunodeficiency, and enterocolitis requiring prolonged infliximab therapy, who developed fatal hepatic failure caused by an aggressive, infiltrating hepatic angiosarcoma. Although DC patients have known increased risk of developing liver failure and multiple types of malignancy, this report is the first to describe angiosarcoma in a DC patient. Malignancy should thus be considered in the differential diagnosis of progressive liver dysfunction in DC patients.

Immunohistochemical expression of glypican-3 in pediatric tumors: an analysis of 414 cases.

Glypican-3 (GPC3) is a proteoglycan thought to play an important role during development. Germline GPC3 mutations are seen in the rare Simpson-Golabi-Behmel syndrome (SGBS), which predisposes patients to Wilms tumor, hepatoblastoma, and neuroblastoma. While numerous adult tumors have been evaluated by immunohistochemistry for GPC3, no comprehensive assessment has been done in pediatric tumors. We therefore investigated GPC3 expression in 143 pediatric central nervous system (CNS) tumors and 271 non-CNS tumors. Among non-CNS tumors, GPC3 expression was seen in 9/9 (100%) hepatoblastomas, 4/6 (67%) malignant rhabdoid tumors, 5/13 (38%) Wilms tumors, 11/37 (30%) alveolar rhabdomyosarcomas, and 8/45 (18%) embryonal rhabdomyosarcomas. All 136 neuroblastomas, 14 Ewing sarcoma/primitive neuroectodermal tumors, and 11 synovial sarcomas were immunonegative for GPC3. Among CNS tumors, GPC3 had restricted expression, with positivity in 6/6 (100%) atypical teratoid rhabdoid tumors and 1/4 (25%) craniopharyngiomas. The remaining 136 CNS tumors-23 medulloblastomas, 21 pilocytic astrocytomas, 13 gangliogliomas, 12 ependymomas, 12 glioblastomas, 11 choroid plexus neoplasms, 10 diffuse astrocytomas (grade II/III), 10 meningiomas, 8 dysembryoplastic neuroepithelial tumors, 8 oligodendrogliomas, 3 craniopharyngiomas, 3 germinomas, and 2 neurocytomas-were entirely negative for GPC3. These results showed GPC3 positivity in a number of non-CNS tumors, with no consistent discrimination between tumors that were or were not associated with SGBS. Within the CNS, GPC3 positivity was limited to a small subset of CNS neoplasms and may thus serve as a useful positive diagnostic biomarker (P < 0.0001) in addition to negative INI1/BAF47/SMARCB1 staining to differentiate atypical teratoid rhabdoid tumors from other high-grade pediatric brain tumors.

PDX-1, CDX-2, TTF-1, and CK7: a reliable immunohistochemical panel for pancreatic neuroendocrine neoplasms.

Neuroendocrine tumors (NETs) occur in virtually all sites of the body. As NETs arising in different organs share similar morphologic features, distinguishing metastatic from primary NETs on the basis of morphologic grounds alone is difficult. Pancreatic duodenal homeobox 1 (PDX-1) is a Hox-type transcription factor that is essential for both exocrine and endocrine pancreatic differentiation and maintenance of ß-cell function. We investigated PDX-1 as an immunohistochemical (IHC) marker in primary pancreatic NETs. Eighty primary NETs [25 pancreatic, 29 bronchopulmonary, and 26 in the gastrointestinal (GI) tract] and 13 metastatic NETs in the liver were studied. Clinical and radiologic data were reviewed to confirm the stated primary sites. IHC analysis for PDX-1, CDX-2, thyroid transcription factor-1 (TTF-1), keratin 7 (CK7), and keratin 20 (CK20) was performed, and the results were based on review blinded to the primary sites. PDX-1 was seen in 18 of 25 (72%) pancreatic NETs; in contrast, only 3 of 29 (10%) bronchopulmonary NETs and 1 of 26 (4%) GI NETs were positive. PDX-1 was therefore 93% specific and 72% sensitive for pancreatic NETs. TTF-1 was expressed only in bronchopulmonary NETs; all other NETs were negative for TTF-1. CK7 was also very specific (92%) and moderately sensitive (66%) for bronchopulmonary NETs. CDX-2 was seen in 22 of 26 (85%) cases of GI NETs and in only 1 of 51 (2%) cases of extra-GI NETs. Thus, CDX-2 was 98% specific and 85% sensitive for GI NETs. In terms of metastatic NETs found in the liver, PDX-1 was positive in 5 of 5 cases of metastatic pancreatic NETs and 2 of 2 cases of metastatic duodenal NETs. PDX-1 is highly specific, with very good overall diagnostic accuracy for pancreatic NETs. An IHC panel including PDX-1, CDX-2, TTF-1, CK7, and CK20 may be useful in distinguishing NETs of pancreatic origin from other primaries.

The use of immunohistochemistry in liver tumors.

A variety of benign and malignant neoplasms can be encountered in the liver. Hematoxylin and eosin-stained tissue sections alone may not yield sufficient information to definitively diagnose liver tumors; therefore, ancillary studies with immunohistochemical markers can play a crucial role in differentiating the different hepatic neoplasms. The recent development of oncofetoprotein glypican-3 has added to the value of immunohistochemistry in diagnosing liver cancer. This review discusses the immunohistochemical markers used most often in the diagnosis of hepatic tumors.