An integrated virtual pathology education platform developed using Microsoft Power Apps and Microsoft Teams.

The transition towards digital pathology and an extensive selection of video conferencing platforms have helped provide continuity to education even during the COVID-19 pandemic. Innovative approaches for pathology education, will likely persist beyond the pandemic, as they have powerful didactic potential. While there is a wide selection of software for use as educational tools, an environment to access all resources with ease is clearly lacking. In this technical note, we highlight our customized educational applications built using a low-code approach. Our applications, developed with Microsoft Power Apps, serve both educational and examination purposes and are launched using Microsoft Teams. Building applications using a low-code approach has made our applications very specific to our use and enabled daily distanced education. Combined with existing features on Teams, such as file sharing, meeting scheduling, and messaging, the applications serve as a unique and customizable pathology educational platform.

Unique Case of Congenital Langerhans Cell Histiocytosis Presenting as Intrauterine Fetal Demise.

Congenital Langerhans cell histiocytosis (LCH) (formerly called Letterer-Siwe disease) is characterized by a clonal proliferation of Langerhans cells occurring in children at birth and manifests typically with multifocal cutaneous lesions, hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and destructive osteolytic bone lesions. We present a case of LCH involving multiple systems high-risk organs (LCH MS-RO+), in a 32-week stillborn from a 20-year-old G2A1. The fetus was mildly hydropic and pale. Apart from maceration, the skin showed multiple targetoid lesions over the face, trunk, and limbs. There was hepatosplenomegaly and a pale brain. The placenta was large and bulky. Despite severe autolysis, histological examination showed disseminated histiocytes with multinucleated giant cells in the skin, lungs, thymus, mesenteric lymph nodes, spleen, and brain. By immunohistochemistry, the histiocytes were positive for S100, CD1a, and Langerin (CD207), confirming the diagnosis of LCH. There was extramedullary hematopoiesis in the spleen, brain, and placenta. Targeted next-generation sequencing performed on thymic DNA did not show the BRAF p.V600E variant but did show the MAP2K1 p.F53_Q58delinsL. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. Our case is unusual in that the newborn presented with severe multiorgan involvement including brain and intrauterine death. LCH is still poorly understood requiring further genetic and molecular studies.

Distinctive Neuroimaging Pattern in Term Newborns With Neonatal Placental Encephalopathy: A Case Series.

BACKGROUND: Identifying antepartum versus intrapartum timing and the cause of neonatal encephalopathy (NE) often remains elusive owing to our limited understanding of the underlying pathophysiological processes and lack of appropriate biomarkers. OBJECTIVES: This retrospective observational study describes a case series of term newborns with NE who displayed a recognizable magnetic resonance imaging pattern of immediately postnatal brain abnormalities that rapidly evolved toward cavitation. Our aim is to (1) report this neuroimaging pattern, (2) look for placental determinants, and (3) depict the outcome. DESIGN/METHODS: This is a unicentric retrospective case series reporting the clinical, radiological, and laboratory findings of NE associated with a distinctive neuroimaging pattern, that is, immediately postnatal extensive corticosubcortical T2 hyperintensities, followed by rapid corticosubcortical cavitation that does not match the neuroimaging picture of intrapartum hypoxic-ischemic encephalopathy (HIE). RESULTS: Seven term newborns presented bilateral corticosubcortical hyperintensities that were detected on T2 between day of life (DOL) 1-4, which rapidly evolved toward cystic encephalomalacia, that is, between DOL9 and DOL12. All these newborns presented with moderate/severe NE. The outcome was either neonatal death or quadriplegic cerebral palsy and epilepsy. None of the reported patients fulfilled the criteria of a high likelihood of acute intrapartum hypoxic-ischemic or quadriplegic cerebral palsy. All these newborns were exposed to chronic and/or acute placental inflammation and/or hypoxic-ischemic. CONCLUSIONS: To further define the antepartum causes of NE, early neuroimaging and a placental examination are recommended. Brain T2 hyperintense injuries before DOL4 followed by rapid cavitation before DOL12 might be biomarkers of NE from an antepartum/placental origin.

Comparison of the aetiology of stillbirth over five decades in a single centre: a retrospective study.

OBJECTIVE: To compare the rates and aetiologies of stillbirth over the past 50 years. STUDY DESIGN: We reviewed all autopsy reports for stillbirths occurring between 1989 and 2009 at the McGill University Health Centre to determine the pathological aetiology of stillbirths. We also reviewed maternal characteristics. We compared our results with a previous study published in 1992 on aetiologies of stillbirth from 1961 to 1988 at the same institution. RESULTS: From among the 79 410 births between 1989 and 2009, 217 stillbirths were included in our study. The mean maternal age was 31.05 (±5.8) years. In 28.1% of cases, there was a history of subfertility. The mean gestational age at diagnosis was 32.69 (±5.58) weeks, with a birthweight of 1888 (±1084) g. The main causes of stillbirth were unknown (26.7%), placental factors (19.8%) and abruptio placentae (12.9%). Other causes included haematogenous or ascending infection (10.6%), fetal malformations (8.3%), maternal hypertension (3.2%), intrauterine growth restriction (2.8%), diabetes (1.8%) and intrapartum asphyxia (1.4%). Other fetal causes were found in 12.4% of cases. CONCLUSIONS: Owing to detailed pathological examination of most stillbirth cases over the past five decades at our tertiary obstetrical centre, we could study the trends in the aetiology of stillbirths in a cohort of more than 150 000 births. In 50 years, the rate of stillbirth has decreased from 115 to 32 cases/10 000 births from the 1960s to 2000s, which represents a reduction of 72%. Stillbirth from unknown cause remains the most common contributor, with 40% of these cases occurring in late pregnancy.

Placental mesenchymal dysplasia and an estimation of the population incidence.

Placental mesenchymal dysplasia (PMD) is a rare placental malformation of as yet undetermined etiology. We report a single center's experience of this diagnosis and present an estimation of the population incidence. Within our institution, all placentae are examined within a pathology department that provides a dedicated perinatal service. In this study, we evaluated the incidence of PMD over a period of 18 years following the description and recognition of PMD as a pathological diagnosis. During the period 1991-2009, only two cases were identified amongst over 95 000 deliveries at our institution. This series of placental examinations is by far the largest in a normal population within which the occurrence of PMD is reported, and the resulting incidence of only 0.02 per 1000 deliveries is some 10 times less than that which has previously been estimated.

NLRP7 in the spectrum of reproductive wastage: rare non-synonymous variants confer genetic susceptibility to recurrent reproductive wastage.

BACKGROUND: NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. METHODS/RESULTS: All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1ß and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. CONCLUSIONS: The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.

Vaginal douching, bacterial vaginosis, and spontaneous preterm birth.

OBJECTIVE: Vaginal douching and bacterial vaginosis (BV) are independently associated with spontaneous preterm birth. Because the interrelationships among these variables remain unclear, we sought to examine the associations in a prospective study. METHODS: We conducted a nested case-control study within a prospectively recruited cohort of pregnant women. We prospectively collected demographic and health status data, data on pre-pregnancy vaginal douching, vaginal smears for bacterial vaginosis as defined by Nugent's criteria, fetal fibronectin at 26 weeks of pregnancy, and placental pathology at delivery. Spontaneous preterm births before 37 weeks' gestation were selected as cases. All spontaneous births occurring after 37 weeks were potential control subjects. To limit costs, some tests were performed only in selected control subjects. RESULTS: Preterm birth occurred in 207 of 5092 women (4.1%). In bivariate analysis, BV was not associated with preterm birth (OR 1.2; 95% CI 0.5 to 2.4). Vaginal douching was significantly associated with bacterial vaginosis (P < 0.05) and preterm birth (P < 0.05). On multivariate analysis, vaginal douching was no longer associated with preterm birth, but a significant association with early preterm birth < 34 weeks (OR, 6.9; 95% CI 1.7 to 28.2) and preterm birth due to preterm labour (OR 3.0; 95% CI 1.1 to 8.5) persisted after controlling for the presence of bacterial vaginosis and placental inflammation. CONCLUSION: Vaginal douching and bacterial vaginosis were not associated with spontaneous preterm birth overall. However, vaginal douching appears to be an independent and potentially modifiable risk factor for early preterm birth (32-34 weeks), although the mechanism remains unclear.

Mid-trimester maternal plasma cytokines and CRP as predictors of spontaneous preterm birth.

Most previous studies of maternal cytokines and preterm birth have analyzed immunologic biomarkers after the onset of labor or membrane rupture; fewer have examined the systemic (blood) immune response prior to labor onset. We carried out a case-control study nested in a large (n=5337) prospective, multi-center cohort. Cohort women had an interview, examination, and venipuncture at 24-26 weeks. Frozen plasma samples in women with spontaneous preterm birth (n=207) and approximately 2 term controls per case (n=444) were analyzed using Luminex multianalyte profiling technology. Fresh placentas were fixed, stained, and blindly assessed for histologic evidence of infection/inflammation, decidual vasculopathy, and infarction, and vaginal swabs were analyzed for bacterial vaginosis and fetal fibronectin concentration. High maternal matrix metalloproteinase-9 (MMP-9) concentration, but none of the other cytokines or C-reactive protein (CRP), was significantly associated with spontaneous preterm birth [adjusted OR=1.7 (1.1-2.4)] and showed a dose-response relation across quartiles. No association was observed, however, between maternal MMP-9 and placental infection/inflammation, bacterial vaginosis, or vaginal fetal fibronectin concentration. Our results require confirmation in future studies but suggest that a systemic immune response implicating MMP-9 may have an etiologic role in spontaneous preterm birth.

Antioxidant vitamins, long-chain fatty acids, and spontaneous preterm birth.

BACKGROUND: Neither macro- nor micronutrient supplements have been clearly demonstrated to reduce the risk of preterm birth. However, there has been little attention to carotenoids, tocopherols, and long-chain fatty acids other than n-3 polyunsaturates. METHODS: We conducted a case-control study nested in a large (n = 5337) prospective, multicenter cohort. All cohort women had an interview, examination, and venipuncture at 24-26 weeks' gestation. Frozen plasma samples in spontaneous preterm births (n = 207) and approximately 2-term controls per case (n = 443) were analyzed for carotenoids, retinol, tocopherols, and long-chain fatty acids. Fresh placentas were fixed, stained, and assessed (without knowledge of pregnancy outcome) for histologic evidence of infection or inflammation, decidual vasculopathy, and infarction. RESULTS: High (above the median) plasma concentrations of alpha- and beta-carotene, alpha- and beta-cryptoxanthin, and lycopene were all associated with reductions in risk of spontaneous preterm birth, with evidence of dose-response effects across quartiles. Modest increases in risk were observed with elevated total monounsaturated, total polyunsaturated, and total n-6 polyunsaturated long-chain fatty acids concentrations. Paradoxically, a high gamma-tocopherol concentration was associated with increased preterm birth risk (adjusted odds ratio = 1.8 [95% confidence interval = 1.2-2.6]). Only one of the studied micronutrients (lutein) was independently associated with a reduced risk of decidual vasculopathy (0.5 [0.3-0.9]). CONCLUSIONS: Carotenoids and long-chain fatty acids warrant further investigation in in vitro, animal, and human studies of preterm birth.

Vasculopathic and thrombophilic risk factors for spontaneous preterm birth.

BACKGROUND: Mothers who give birth to preterm infants are at increased risk of mortality from coronary heart disease and stroke, but the biological pathways underlying these associations have not been explored. METHODS: We carried out a case-control study nested in a large (n = 5337) prospective, multicentre cohort. All cohort women had an interview, examination and venipuncture at 24-26 weeks. Frozen plasma samples in spontaneous preterm births (n = 207) and 444 term controls were analysed for plasma homocysteine, folate, cholesterol (total, low-density lipoprotein and high-density lipoprotein) and thrombin-antithrombin (TAT) complexes. DNA was extracted and analysed for seven gene polymorphisms involved in thrombophilia or folate or homocysteine metabolism. Fresh placentas were fixed, stained and blindly assessed for histologic evidence of infarction and decidual vasculopathy. RESULTS: High (above the median) plasma homocysteine and HDL cholesterol were significantly and independently associated with the risk of spontaneous preterm birth [adjusted odds ratios (OR)s = 1.9 (95% 1.1-3.3) and 0.5 (0.3-0.9), respectively]. A higher proportion of women with high homocysteine concentrations had decidual vasculopathy [(13.0 vs 6.8%; OR = 1.9 (1.1-3.5)], although the positive association between decidual vasculopathy and preterm birth did not achieve statistical significance [OR = 1.5 (0.9-2.7)]. No significant associations were observed with the DNA polymorphisms or with plasma TAT or folate levels. CONCLUSIONS: Similar vasculopathic risk factors may underlie preterm birth and adult coronary heart disease and stroke.

Stress pathways to spontaneous preterm birth: the role of stressors, psychological distress, and stress hormones.

The authors investigated a large number of stressors and measures of psychological distress in a multicenter, prospective cohort study of spontaneous preterm birth among 5,337 Montreal (Canada)-area women who delivered from October 1999 to April 2004. In addition, a nested case-control analysis (207 cases, 444 controls) was used to explore potential biologic pathways by analyzing maternal plasma corticotrophin-releasing hormone (CRH), placental histopathology, and (in a subset) maternal hair cortisol. Among the large number of stress and distress measures studied, only pregnancy-related anxiety was consistently and independently associated with spontaneous preterm birth (for values above the median, adjusted odds ratio = 1.8 (95% confidence interval: 1.3, 2.4)), with a dose-response relation across quartiles. The maternal plasma CRH concentration was significantly higher in cases than in controls in crude analyses but not after adjustment (for concentrations above the median, adjusted odds ratio = 1.1 (95% confidence interval: 0.8, 1.6)). In the subgroup (n = 117) of participants with a sufficient maternal hair sample, hair cortisol was positively associated with gestational age. Neither maternal plasma CRH, hair cortisol, nor placental histopathologic features of infection/inflammation, infarction, or maternal vasculopathy were significantly associated with pregnancy-related anxiety or any other stress or distress measure. The biologic pathways underlying stress-induced preterm birth remain poorly understood.

Inherited thrombophilia and preeclampsia within a multicenter cohort: the Montreal Preeclampsia Study.

OBJECTIVE: We sought to evaluate the association between inherited thrombophilia and preeclampsia. STUDY DESIGN: From a multicenter cohort of 5337 pregnant women, we prospectively identified 113 women who developed preeclampsia and selected 443 control subjects who did not have preeclampsia or nonproteinuric gestational hypertension. Blood samples were tested for DNA polymorphisms affecting thrombophilia (factor V Leiden mutation, prothrombin G20210A mutation, methylenetetrahydrofolate reductase C677T polymorphism), homocysteine, and folate levels, and placentae underwent pathological evaluation. RESULTS: Thrombophilia was present in 14% of patients and 21% of control subjects (adjusted logistic regression odds ratio, 0.6; 95% confidence interval, 0.3-1.3). Placental underperfusion was present in 63% of patients vs 46% of control subjects (P < .001) and was more frequent in women with folate levels in the lowest quartile (P = .04), but was not associated with thrombophilia. CONCLUSION: We did not find evidence to support an association between inherited thrombophilia and increased risk of preeclampsia. Placental underperfusion is associated with preeclampsia, but this does not appear to be consequent to thrombophilia.

Intra- and interobserver agreement and statistical clustering of placental histopathologic features relevant to preterm birth.

OBJECTIVE: Many previous studies of agreement in identifying placental histopathologic lesions have been based on small sample sizes, and none has examined whether individual histologic features cluster robustly together within and between observers. STUDY DESIGN: We studied 767 placental specimens from case-control studies of preterm birth and preeclampsia nested within a prospective cohort of pregnant women recruited from 4 large Montreal maternity hospitals. The specimens were fixed, embedded, stained, and examined using a standardized protocol; a 10% random sample (n = 81) was then blindly reexamined at least 6 months later by the same pathologist and a second pathologist. RESULTS: Intra- and interobserver agreement were high (kappa > or = 0.50) for membrane inflammation, funisitis, and umbilical cord vasculitis, and these 3 features were robustly clustered statistically, consistent with an underlying mechanism of ascending infection. Agreement and clustering were also high or moderate for features of placental underperfusion: infarction, decidual vasculopathy, and syncytial knotting. CONCLUSION: Our results should help researchers to interpret future findings relating placental histopathology to preterm birth, preeclampsia, and other adverse pregnancy outcomes, and to their etiologic determinants and causal pathways.

Nerve fibers in ovarian dermoid cysts and endometriomas.

No nerve fibers are found in endometriomas or in the endometrioma-containing ovaries. These findings are consistent with our previous report that no correlation exists between the presence of nerve fibers and endometriosis.

Muscle, adipose, and connective tissue variations in intrinsic musculature of the adult human tongue.

The purpose of this investigation was to identify the composition and organization of lingual tissues underlying the histostructural and biomechanical functions of the adult human tongue. The small-scale structures of three intrinsic muscle regions, their principal cells, structural complexities, and differences in underlying tissue composition were compared to other skeletal muscle systems and the results discussed in relation to lingual morphology. Analysis of pixel color distributions determined the percent area concentration of each stained tissue component. Results indicated that muscle content increased from anterior to posterior (p <.0001). Greater adipose (p =.005) and connective tissue (p <.002) concentrations occurred in anterior regions. Dense collagen sheaths and elastic fibers found anteriorly occurred with less magnitude in medial and posterior sites. The unique elastin, collagen, and adipose connective tissue distributions found in intrinsic sampling sites are discussed in terms of understanding lingual biomechanics in both normal and pathologic states.