Chen-Chih J. Sun

Inflammatory markers in intrauterine and fetal blood and cerebrospinal fluid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants.

Recent evidence strongly implicates the inflammatory response to intrauterine infection in the pathogenesis of neonatal brain and lung injury. We hypothesized that lung and brain injury in preterm infants occurs during a common developmental window of vulnerability as the result of an inflammatory response in different compartments. To determine whether inflammatory markers in these compartments are associated with bronchopulmonary dysplasia (BPD) or cranial ultrasound (CUS) abnormalities in infants <33 wk gestation age (GA) and <1501 g birth weight, we analyzed placental pathology and serum and cerebrospinal fluid (CSF) IL-6, IL-1β, and tumor necrosis factor-α (TNF-α) concentrations in 276 infants. Logistic regressions were performed stratified by GA. Histologic chorioamnionitis was significantly associated with BPD in infants ≤28 wk GA (OR 3.6, p = 0.027). Maternal stage of chorioamnionitis significantly correlated with severity of BPD. Presence of a fetal inflammatory response indicated by fetal vasculitis or elevated cytokines was not associated with the development of BPD. Serum IL-6 ≥17 pg/mL was associated with an abnormal CUS in infants >28 wk GA (OR 3.36, p = 0.023) but not ≤28 wk GA. CSF concentrations of IL-6 ≥6.5 pg/mL and TNF-α ≥3 pg/mL were associated with abnormal CUS in infants ≤28 wk GA (IL-6 OR 3.0; TNF-α OR 3.5; p < 0.05 each case) but not ≥28 wk GA. These data suggest that in infants ≤28 wks GA, BPD may be initiated by inflammatory mediators in amniotic fluid, but brain injury may involve variations in the systemic inflammatory response.

Inflammatory Cytokine mRNAs in Surgical Specimens of Necrotizing Enterocolitis and Normal Newborn Intestine

Coagulation necrosis, inflammation, and hemorrhage are pathologic hallmarks of necrotizing enterocolitis (NEC). Because cytokines are peptides that mediate inflammatory cell recruitment and amplify the immune response, several of the inflammatory cytokines have been implicated in NEC. We hypothesized that mRNA levels for the interrelated cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), IL-6, and the neutrophil chemotactic factor IL-8 would be increased in NEC and would be associated with the presence of inflammation. In this study, we determined the relative levels and localization of mRNA for these cytokines in surgical pathology archival intestinal tissue from 29 premature infants with acute NEC and 15 control infants with congenital intestinal malformations using a novel quantitative in situ hybridization technique. Compared with controls, there were higher IL-1 beta mRNA levels in full-thickness sections and higher TNF-alpha mRNA levels in full-thickness and mucosa sections of acute NEC samples, suggesting a potential role for these cytokines in the pathogenesis of local inflammation in NEC. IL-6 and IL-8 mRNA levels were similar in samples of control and acute NEC cases. Analysis of covariance including all subjects showed that the presence of acute inflammation was associated with increased IL-1 beta mRNA levels in mucosa (P = .035) and increased IL-8 in full-thickness sections (P = .005) and mucosa (P = .01). In four of five NEC cases in which intestinal specimens were available from reanastomosis surgery, cytokine mRNA levels decreased to low or undetectable levels. These data suggest that the inflammatory cytokines are involved in neutrophil recruitment and augmentation of the inflammatory response in neonatal intestine.

Discrepancy in Pathologic Diagnosis of Placental Lesions

CONTEXT Placentas are routinely examined by surgical pathologists, but peer review of placental diagnosis is rarely performed. OBJECTIVE To determine the frequency of discrepant placental diagnosis between general surgical pathologists and a pediatric pathologist. DESIGN One hundred fourteen placentas from infants with intrauterine growth restriction (IUGR) and 170 placentas from infants appropriate for gestational age (AGA) were reviewed for 10 lesion types using standardized criteria. The review diagnosis was compared with original reports. RESULTS The review identified 333 lesions, 168 in the IUGR group and 165 in AGA group. Discrepant diagnosis occurred in 137 lesions (41.1%). There was no significant difference in the frequency of discrepant diagnosis between the IUGR (44.7%) and AGA groups (37.6%) (P >.05). Most discrepancies (92.7%) were due to underdiagnosis (identified on review but not mentioned in original diagnosis), but a few (7.3%) were due to misdiagnosis (mentioned in original report but disagreed on review). The common underdiagnoses with their corresponding rates were as follows: hemorrhagic endovasculitis (84.6%), fetal thrombotic vasculopathy (75%), massive perivillous fibrin deposition (68.4%), maternal floor infarction (66.7%), retroplacental hemorrhage (60.6%), intervillous thrombus (57.1%), decidual angiopathy (33.3%), placental infarction (25.4%), acute chorioamnionitis (22.7%), and chronic villitis (21.7%). Misdiagnosis was found in 10 cases: 5 cases of infarction (review diagnosis was perivillous fibrin deposits in 4, intervillous thrombus in 1), 3 cases of acute chorioamnionitis, and 2 cases of decidual angiopathy. Among the 8 general surgical pathologists involved, the frequency of discrepant diagnosis ranged from 31.5% to 58.6% (P >.05). The intraobserver discrepancy rate for the reviewer was 4.8%, significantly lower than the discrepancy rate for the 8 general surgical pathologists. CONCLUSION It is common for general surgical pathologists not to recognize placental lesions, which may have clinical significance. Awareness of this deficiency, standardization of diagnostic criteria, and increased knowledge in placental pathology may improve the quality of diagnosis in this area.

Placental lesion multiplicity: risk factor for IUGR and neonatal cranial ultrasound abnormalities

OBJECTIVE To determine whether placental lesions are risk factors for neurologic morbidities in intrauterine growth restricted (IUGR) infants, we compared the incidence of cranial ultrasound (CUS) abnormalities and the number and type of placental lesions in IUGR cases and gestational age-matched appropriate for gestational age (AGA) controls. STUDY DESIGN Retrospective case-control study of 94 singleton IUGR and 145 AGA infants. Medical records, CUS reports, and placental histology were reviewed. Analyses included chi2, t-test, analysis of variance and logistic regressions to identify those variables significantly associated with IUGR and those associated with CUS abnormalities. RESULTS The incidence of CUS abnormalities was 1.7-fold higher in IUGR cases (50%) than controls (29.7%) (p<0.05). A total placental lesion score of > or =3 was associated with an increased risk for IUGR (OR 14.18, 3.41-58.99; p<0.001) and increased risk for CUS abnormality (OR 12.571, 3.33-47.416; p<0.05). In a logistic regression model only > or =2 placental lesions, IUGR and gestational age <30 weeks were significant independent predictors of CUS abnormalities. CONCLUSIONS The severity of placental abnormalities expressed as the cumulative number of placental lesions is a significant risk factor for IUGR and perinatal brain injury. These results suggest that abnormal uteroplacental or fetoplacental blood flow may adversely affect intrauterine growth and increase the risk for brain injury.

Necrotizing Enterocolitis Is Associated With Ureaplasma Colonization in Preterm Infants

The study objective was to determine whether Ureaplasma respiratory tract colonization of preterm infants <33 wk gestation is associated with an increased risk for necrotizing enterocolitis (NEC). One or more tracheal or nasopharyngeal aspirates for Ureaplasma culture and PCR were obtained during the first week of life from 368 infants <33 wk gestation enrolled from 1999 to 2003 or from 2007 to 2009. NEC Bell stage ≥2 was confirmed by radiological criteria, and pathology, if available. Cord serum samples were analyzed for IL-6 and IL-1β concentrations, and placentas were reviewed for histological chorioamnionitis in the first cohort. NEC was confirmed in 29 of 368 (7.9%) of the combined cohorts. The incidence of NEC was 2.2-fold higher in Ureaplasma-positive (12.3%) than Ureaplasma-negative (5.5%) infants <33 wk (OR, 2.43; 95% CI, 1.13–5.2; p = 0.023) and 3.3-fold higher in Ureaplasma-positive (14.6%) than Ureaplasma-negative (4.4%) infants ≤28 wk (OR, 3.67; 95% CI, 1.36–9.93; p = 0.01). Age of onset, hematologic parameters at onset, and NEC severity were similar between Ureaplasma-positive and negative infants. Cord serum IL-6 and IL-1β concentrations were significantly higher in Ureaplasma-positive than in Ureaplasma-negative NEC-affected infants. Ureaplasma may be a factor in NEC pathogenesis in preterm infants by contributing to intestinal mucosal injury and/or altering systemic or local immune responses.

Disordered Pulmonary Myofibroblast Distribution and Elastin Expression in Preterm Infants with Ureaplasma urealyticum Pneumonitis

Respiratory colonization of preterm infants with Ureaplasma urealyticum is a significant risk factor for bronchopulmonary dysplasia, a chronic lung disease characterized by arrest of alveolar development, variable interstitial fibrosis, and disordered elastic fibers in the distal airspaces. As indicated in previous studies, moderate to severe fibrosis is a hallmark of pathology in the Ureaplasma-infected preterm lung. To further characterize the preterm lungs response to Ureaplasma, lung specimens from 4 gestational controls (GC), 12 other pneumonia and 5 Ureaplasma-infected infants were analyzed by immunohistochemistry for α-smooth muscle actin (αSMA) and transforming growth factor β1 (TGFβ1), Harts elastin staining, and in situ hybridization for tropoelastin (TE) expression. Cells positive for αSMA were observed in thickened, extensive bundles surrounding terminal airspaces in Ureaplasma and other pneumonia cases compared to individual myofibroblasts in GC. The myofibroblast pattern correlated with the severity of fibrosis, but not duration of ventilation. Transforming growth factor β1 immunostaining was primarily localized to alveolar macrophages and was increased in Ureaplasma more than in other pneumonia cases. Elastic fibers and TE-expressing cells were spatially limited to emerging septal tips in GC. In pneumonia cases, increased deposition of elastic fibers was observed surrounding terminal airspaces, but TE expression was similar to GC. In Ureaplasma specimens, accumulation of elastic fibers correlated with duration of ventilation, and TE expression was extensive throughout the walls of terminal airspaces. These findings suggest that Ureaplasma is associated with alveolar macrophage TGFβ1 immunostaining and myofibroblast proliferation contributing to abnormal septation, interstitial fibrosis, and a prolonged and strong elastogenic response in the preterm lung.

A study of gata3 and phox2b expression in tumors of the autonomic nervous system.

Autonomic neurons and chromaffin cells, which constitute the autonomic nervous system, are derived from a common progenitor from the neural crest, and its development is controlled by a network of transcription factors, including the master regulator, Phox2b, and its downstream, Gata3. Anti-Phox2b and anti-Gata3 antibodies were applied to a total of 77 autonomic nervous system tumors, including 35 paragangliomas, 21 pheochromocytomas, 9 neuroblastomas, 4 ganglioneuroblastomas, and 8 ganglioneuromas, as well as their potential morphologic mimics, including tumors of the small round cell tumor group, neuroendocrine carcinomas of lung and gastrointestinal tract (carcinoid tumors/neuroendocrine tumors, large cell neuroendocrine carcinomas, and small cell carcinomas), Merkel cell carcinomas, benign and malignant tumors of thyroid, parathyroid, and adrenal cortex, and malignant melanomas. A variety of nonendocrine/neuroendocrine carcinomas were also studied. Gata3 expression was seen in 89% of paragangliomas, 95% of pheochromocytomas, and all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas, as well as in all parathyroid tumors, a majority of urothelial and mammary carcinomas, and a subset of squamous cell carcinomas, but all other tumors were negative. Phox2b expression was seen in all neuroblastomas, ganglioneuroblastomas, and ganglioneuromas and in 40% of paragangliomas, but pheochromocytomas and all other tumors were negative. Gata3 is a highly reliable marker for paragangliomas, pheochromocytomas, and neuroblastic tumors to distinguish from their simulators. This is an additional utility for this marker, which is used for the diagnosis of urothelial and mammary carcinomas. Phox2b is also highly specific, but its low sensitivity to paragangliomas and pheochromocytomas would limit the utility only to neuroblastic tumors.

Congenital Fibrosarcoma with Metastasis in a Fetus

It is well known that congenital or infantile fibrosarcoma has a much less aggressive behavior than fibrosarcoma in adults, and it rarely metastasizes. We report a case of congenital fibrosarcoma in a 26-wk-old fetus, the diagnosis of which was made by an in utero needle core biopsy. Metastatic tumors were identified at autopsy when the pregnancy was terminated 3 wk later. English literature of metastatic congenital fibrosarcoma was also reviewed.

Alimentary Duplication Presenting as an Hepatic Cyst in a Neonate

A large hepatic cyst was excised from an infant who presented on the first day of life with an abdominal mass. Intraoperative, gross, and microscopic observations indicated that this was a cystic duplication of the ileum that extended into the liver. The cyst had a gastric mucosal lining, and there was evidence of ulceration. The occurrence of an alimentary duplication within the liver has been described in only one previous report.

Antenatal factors modulate hearing screen failure risk in preterm infants

Objective The objective of this study was to characterise the effects of antenatal inflammatory factors and maternal therapies on neonatal hearing screen outcomes in very low birthweight infants. Methods We conducted a retrospective study of a cohort of infants <33 weeks’ gestational age and <1501 g birth weight prospectively enrolled between 1999 and 2003 for whom placental pathology, cord blood interleukin (IL) 6, IL-1ß, tumour necrosis factor-α and neonatal hearing screen results were available. Results Of 289 infants with documented hearing screen results, 244 (84%) passed and 45 (16%) failed the hearing screen (unilateral, N=25 (56%); bilateral, N=20 (44%)). In the final logistic model, the fetal inflammatory response syndrome defined as the presence of fetal vasculitis and/or cord serum IL-6>18.2 pg/mL was the factor with greatest risk for hearing screen failure (OR 3.62, 95% CI 1.38 to 9.5). A patent ductus arteriosus treated with indomethacin significantly increased the risk (OR 3.3, 95% CI 1.3 to 8.26), while combined maternal steroid and magnesium sulfate exposure (0.37, 95% CI 0.11 to 0.81) reduced the risk for hearing screen failure. Conclusions Intrauterine infection with a fetal inflammatory response is a risk factor for neonatal hearing loss while maternal therapies significantly reduced the risk of neonatal hearing loss in very low birthweight infants.