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Background/rationale Biliary atresia (BA) is a cholangiopathy characterized by bile flow obstruction due to destruction of the biliary tree. Without surgical correction with Kasai portoenterostomy (KPE), BA leads to death or liver transplant (LTx). Early-onset, progressive liver fibrosis is a defining characteristic of BA. Collagen hybridizing peptide (CHP) is a synthetic peptide which binds to denatured collagen strands allowing quantification of fibrosis. This technique has not been used on human liver tissue. The aim of this pilot study was to evaluate the utility of CHP as a measurement of quantitative fibrosis to allow earlier survival with native liver prognostication. Results We identified 21 patients with wedge liver biopsies available, of which 14 required LTx. No deaths occurred. Patients requiring LTx tended to be girls with a significantly different mean bilirubin (P = 0.002), albumin (P = 0.001), and alanine aminotransferase (P = 0.03) at 3 months post-KPE. By 1 year post-KPE, 50% of patients in the high CHP intensity group required LTx versus 27% in the low CHP. Overall, fibrosis as quantified by CHP at time of KPE was associated with more than 3 times the risk of requiring LTx by 4 years of age (hazard ratio 3.6, 95% confidence interval 1.15-10.93, P = 0.03). When controlling for sex and total bilirubin >2 mg/dL and albumin at 3 months post-KPE, it predicted nearly 7 times the risk of LTx (hazard ratio 6.89, 95% confidence interval 1.38-34.32, P = 0.02). Conclusion Our results suggest that quantitative assessment of fibrosis at the time of KPE holds promise as an earlier predictor of LTx requirement in BA. A larger study is justified to assess quantitative fibrosis as a BA prognostic tool.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition that is becoming more widely recognized in children. Recent EoE practice guidelines provide clear recommendations on adequate biopsy sampling at diagnostic endoscopy and necessity of close follow-up endoscopy with biopsy to ensure mucosal healing with therapy.1 Despite these recommendations, adherence to biopsy guidelines, time to first follow-up endoscopy, and overall surveillance endoscopy rates have not been robustly studied. Using a population-based cohort of children diagnosed with EoE in Utah, we assessed adherence to guidelines across multiple provider types, including academic pediatric gastroenterologists (PGIs), private practice PGIs, and adult-trained providers performing endoscopy in children.

Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment.Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and85 for χThere were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age.Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions.Clinicaltrials.gov: NCT00061828 and NCT00294684.

Background & Aims Eosinophilic esophagitis is usually triggered by foods, by unclear mechanisms. We evaluated the roles of IgE and IgG4 in the development of eosinophilic esophagitis. Methods We performed a prospective, randomized, double-blind, placebo-controlled trial of adults with eosinophilic esophagitis given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2–4 weeks for 16 weeks, based on weight and serum level of IgE. Endoscopy was performed, esophageal biopsy specimens were collected, and symptoms were assessed at baseline and at 16 weeks. Maximum numbers of eosinophils/high-power field were determined. Homogenates of esophageal biopsy specimens from 11 subjects with eosinophilic esophagitis and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses. In a retrospective analysis, we performed immunofluorescence analysis of IgG4 in fixed esophageal tissues from 2 patients with eosinophilic esophagitis who underwent esophagectomy and 47 consecutive autopsies (controls). We also performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsy specimens from 24 subjects with eosinophilic esophagitis and 9 without (controls). Finally, sera were collected from 15 subjects with eosinophilic esophagitis and from 41 without (controls), and assayed for total and food-reactive IgG4. Results Omalizumab did not alter symptoms of eosinophilic esophagitis or eosinophil counts in biopsy samples compared with placebo. Homogenates of esophageal tissues from patients with eosinophilic esophagitis had a 45-fold increase in IgG4 compared with controls ( P -5 ), but no significant increases in other IgG subclasses, IgM, or IgA. Sparse stromal deposits resembling immune complexes were found in 2 of 5 eosinophilic esophagitis biopsy specimens based on ultrastructural analysis. Esophagectomy samples from 2 patients with eosinophilic esophagitis contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than in tissues from controls. Fibrosis essentially was exclusive to the lamina propria. Granular extracellular IgG4 was detected in biopsy specimens from 21 of 24 patients with eosinophilic esophagitis, but in none of the specimens from 9 controls ( P = 6 × 10 -6 ). The total serum level of IgG4 increased only slightly in patients with eosinophilic esophagitis, compared with controls. Subjects with eosinophilic esophagitis had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts—the 4 foods that most commonly trigger this condition ( P ≤ 3 × 10 -4 for each food). Conclusions In a prospective trial, omalizumab did not reduce symptoms of eosinophilic esophagitis or tissue eosinophil counts compared with placebo. This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods, indicate that, in adults, eosinophilic esophagitis is IgG4-associated, and not an IgE-induced allergy. ClinicalTrials.gov number: NCT 00123630.

Background & Aims Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. Methods Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. Results We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. Conclusion In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah’s searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.

The Stillbirth Collaborative Research Network (SCRN) was organized to study the scope and causes of stillbirth (SB) in the United States. The objective of this report is to describe the approach used for the placental examination performed as part of the study. The SCRN consists of a multidisciplinary team of investigators from five clinical sites, the National Institute of Child Health and Human Development, and the Data Coordination and Analysis Center. The study is a population-based cohort and nested case-control study, with prospective enrollment of women with SB and live births (LB) at the time of delivery. Detailed and standardized postmortem examination was performed on SB and placental examination in both groups. A total of 663 women with SB and 1932 women with LB were enrolled into the case-control study. In the SB group, there were 707 fetuses. Of these cases, 654 (98.6%) had placental examination. Of these LB controls, 1804 (93.4%) had placental examination. This is the largest prospective study to include population-based SB and LB, using standardized postmortem and placental examination, medical record review, maternal interview, collection of samples, and a multidisciplinary team of investigators collaborating in the analyses. Thus it has the potential to provide high-level evidence regarding the contribution of placental abnormalities to stillbirth.

Context.—Intraoperative consultations, including frozen sections (FSs), are essential for patient care and are a key quality component in anatomic pathology. Little data exists about the use, frequency, and type of discrepancies and deferral rates of FS diagnoses in pediatric and adolescent surgical pathology. Objective.—The purpose of this study was to analyze indications, discrepancies, and deferrals for all FSs performed at a children's hospital during a 10-year period. Design.—All FSs for 1995–2004 were reviewed for indications, discrepancies, deferred diagnoses, and turnaround time. Discrepancies were categorized into major and minor subtypes according to potential impact on patient care. Results.—A total of 35 611 surgical pathology cases were accessioned, with 2839 intraoperative consultations, which included 2783 FSs and 56 nonmicroscopic consultations. Most frequent indications included questions related to neoplasms (tumor detection, specimen adequacy, triage, classification, and margins) and suspected Hirschsprung disease. In these consultations, 115 discrepancies (4%) were identified, of which 7 (0.2%) were major, with potentially significant clinical impact, and 108 (3.9%) were minor. The major discrepancies included tumor, ganglion cell, or organism detection. The minor discrepancies involved sampling error, reclassification of benign or malignant neoplasms without clinical consequences, tumor typing or grading, and ganglion cell identification without clinical impact. Deferrals in 718 FSs (25% deferral rate) included tumor classification from generic to specific, identification of organisms, and evaluation of lymph node biopsies for lymphoma. Turnaround time exceeded 20 minutes in 403 cases (14%). Conclusions.—The FS rate of 7.8% overall and 5% of surgical pathology cases is similar in children's and general hospitals. The major discrepancy (discordance) rate is lower, which may reflect the different indications for FS in children and adolescents. Evaluation of colonic biopsies for ganglion cells is a diagnostic pitfall. The deferral rate of 25% reflects the definition of a deferred diagnosis. Traditional definitions of deferred and discordant FS diagnoses should be refined to reflect the increasing use of adjunct techniques, especially in tumor classification. These findings emphasize that, in children and adolescents, most FSs are performed for tumor classification, triage, detection, and specimen adequacy, and for possible Hirschsprung disease. In children and adolescents, FSs are used infrequently to identify normal or unknown tissue, to analyze a lesion in a radiographically directed specimen, or to detect lymph node metastases. The differences in pediatric and adolescent FS indications and use underscore the importance of focused education in pediatric surgical pathology.

A 17-year-old boy with juvenile rheumatoid arthritis presented with jaundice, confusion, hemolytic anemia, thrombocytopenia, and acute renal failure secondary to titer-confirmed acute Epstein-Barr virus (EBV). Renal biopsy specimen revealed interstitial nephritis with an inflammatory infiltrate composed of cytotoxic/suppressor T cells, and interstitial mononuclear cell nuclei expressed EBV encoded RNA-1 (EBER-1) mRNA. Methylprednisolone treatment resulted in rapid improvement.

We report two cases of lipoblastoma with chromosome 8-related aberrations, ie, a 92,XXYY,t(7;8Xp22;q11.2)x2 [8]/46,XY[16] in Case 1 and a 46,XY,-8,-13,add(16) (q22),+mar, +r [cp13]/46,XY[7] in Case 2. Using spectral karyotyping and fluorescence in situ hybridization techniques, the karyotype of Case 2 was redesignated as 46,XY, r(8), del(13)(q12), der(16)ins(16;8)(q22; q24q11.2)[cp13]/46,XY[7]. This report delineates a new chromosome rearrangement, ie, der(16)ins(16;8)(q22; q24q11.2) in lipoblastoma, and also confirms the t(7; 8)(p22;q11.2), reported only once previously, as a recurrent translocation involved in such a tumor. These findings provide valuable information for clinical molecular cytogenetic diagnosis of lipoblastoma. Furthermore, this report highlights the value of cytogenetic and molecular cytogenetic analysis in differential diagnosis of childhood adipose tissue tumors and adds to the number of lipoblastomas reported with chromosomal abnormalities at 8q11.2.

Timely communication of significant or unexpected findings in surgical pathology can significantly improve patient care. Although surgical pathology critical values have been published, no systematic assessment in pediatric surgical pathology has been published. We surveyed pediatric pathologists and pediatric subspecialists to develop pediatric surgical pathology critical values for verbal reporting before the final pathology report. A policy and process for reporting and documentation was implemented, with retrospective and prospective quality review. Critical values cases constituted 9.4% of surgical pathology accessions. Retrospective analysis revealed that 80% (73/91) had been reported and documented before policy implementation. Following implementation, 97.3% (402/413) were verbally reported and documented. A multidisciplinary group provided valuable information about critical values that might not have been obvious to pediatric pathologists but are important for patient care. Although the term critical values has become embedded in the surgical pathology literature, we would propose an alternative term for significant or unexpected findings that require timely communication and documentation.

Dramatic improvements in survival for children with cancer have led to increased numbers of posttreatment pathologic specimens, particularly in bone and soft tissue sarcomas. Current therapeutic protocols in North America require specific pathologic classification and stratify patients based on clinical, biologic, and pathologic features. For osteosarcoma, the pathologic response to therapy predicts prognosis and modifies the treatment regimen. Ongoing studies aim to assess the response to therapy and outcome in other types of soft tissue and bone tumors. The pathologic evaluation of pretreatment and posttreatment specimens is critical for therapeutic decisions and prognostic assessment. A standardized approach to posttherapy pathologic specimens, with attention to appropriate use of ancillary tests, and assessment of clinical and biologic significance of therapy-induced pathologic changes has significance for patient management and treatment protocols.

Context.—Although autopsy rates have declined significantly in recent decades, studies continue to validate the autopsy as an important source of clinically relevant information, a teaching tool, and a quality assurance measure. A recent review of autopsy series showed a decline in the number of serious errors likely to have affected clinical outcome detected at autopsy during the past 46 years, with a current major error rate of 8.4% to 24.4%.Objective.—Our hypothesis was that the pediatric autopsy would uncover a significant number of major unexpected findings at the high end of the spectrum predicted by a recent review. This study assesses the unexpected findings at a pediatric hospital whose autopsy service handles both in-house (tertiary care) and referral (mostly perinatal) cases for a vertically integrated health care system.Design.—Data were analyzed from an autopsy effectiveness report completed for all autopsies performed in 2000. The data from this series include concordance of premortem and postmortem diagnoses, with the autopsy considered the criterion standard. The autopsy effectiveness report also provided logistic information, such as problems with consents, medical records, specimen identification, and prosection.Setting.—Pediatric autopsies were performed by members of the Pediatric Pathology Division in a freestanding children's hospital in the Intermountain West of the United States with a large rural catchment area. This hospital is part of a large health maintenance organization serving the surrounding urban and rural areas.Patients.—A sample of all in-house and referral autopsies for the year 2000 was examined.Main Outcome Measure.—The percentage of cases with a major or minor diagnostic discrepancy or unexpected pathologic finding using the autopsy as the criterion standard.Results.—The overall autopsy rate was 40% (39 hospital autopsies and 15 forensic autopsies per 135 total deaths) and was 32% excluding forensic cases. Twenty-two additional referral autopsies from outside institutions were performed. Of 61 autopsies, 12 (20%) revealed a major diagnostic discrepancy or unexpected pathologic finding, 17 (28%) had a minor unexpected finding or additional diagnosis, 41 (67%) clarified the differential diagnosis, 46 (75%) confirmed or verified a major diagnosis, and 21 (34%) provided information regarding treatment effects. Additionally, 3 (5%) had problems with identification, and 12 (20%) had problems with consent, all of which were resolved prior to initiation of the autopsy.Conclusions.—These data confirm the value of the pediatric autopsy in a children's hospital and a vertically integrated health care system. It is an important medical and quality assurance procedure for assessing the accuracy of diagnoses, clarifying differential diagnoses, yielding unexpected findings, and providing feedback regarding therapeutic outcomes.

Granulomatous interstitial nephritis (GIN) is an uncommon disorder, previously documented in the literature in asso-ciation with sarcoidosis, multiple medications, and infection. The coexistence of GIN and Crohn's disease has rarely been reported, and its true incidence is unknown. We describe a young female with Crohn's disease who was found to have an elevated serum creatinine with a normal urinalysis and autoimmune work-up. Kidney biopsy revealed granulomatous interstitial nephritis. She was treated with corticosteroids, cyclophosphamide, and mycophenolate mofetil. Her kidney function remains stable 2 years after diagnosis. This case report highlights the diagnosis and explores a novel treatment regimen.

An 11-month-old infant presented with cranial nerve palsy and ataxia. MR revealed a large, enhancing pontine mass and small, nonenhancing parafalcial lesions; no organisms were seen in cerebrospinal fluid. After empiric treatment for brain stem glioma, the patient died. Autopsy revealed meningoencephalitis caused by leptomyxid amebae.

Snakes representing the genera Agkistrodon, Nerodia, Elaphe, Coluber, Lampropeltis, Farancia, Crotalus, Thamnophis, and Heterodon were captured over a 22-yr period from 2 swamps in southeastern Louisiana, tail-clipped, and thin blood smears made prior to release. A low prevalence (13%, n = 7) was observed only for the mud snake (F. abacura reinwardtii). Prevalence and levels of parasitemia for 322 cottonmouths (A. piscivorus leucostoma), 219 from Sarpy Swamp in St. Charles Parish and 103 from Hebert Center in Plaquemines Parish, were recorded. A short and long gamont form were commonly seen in cottonmouths and other species from both localities; prevalence patterns and results of experimental transmission suggest that these forms represent different species. Congenital infection was observed in 1 brood of banded water snakes (N. fasciata confluens). Preliminary mark-recapture experiments suggest that snakes may retain constant parasitemia levels for 11 mo or longer.