Margaret H. Collins

The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome

OBJECTIVESnThe purpose of this study was to investigate the outcome in infants with hypoplastic left heart syndrome and intact atrial septum and to evaluate the relationship of atrial morphology, left atrial decompression pathway and lung histopathology to outcome.nnnBACKGROUNDnIn the hypoplastic left heart syndrome, severe restriction at the atrial level results in marked systemic hypoxemia after birth. Infants with intact atrial septum may be at high risk for mortality after Norwood operation.nnnMETHODSnOf 316 infants with hypoplastic left heart syndrome seen at our center over a 6.5-year period, 18 (5.7%) had intact atrial septum. Medical records and echocardiograms were reviewed.nnnRESULTSnOn echocardiography, three types of intact atrial septal morphology were identified: 1) large left atrium, thick prominent septum secondary with thin septum primary adherent (type A, n = 12); 2) small left atrium with thick, muscular atrial septum (type B, n = 4), and 3) giant left atrium, thin atrial septum with severe mitral regurgitation (type C, n = 2). Seven infants had left atrial decompression pathways that were severely obstructed (3/12 type A, 4/4 type B). Norwood operation was performed in 17 infants; one underwent emergency balloon atrial septostomy and died. Of six early survivors, all with type A atrial morphology and unobstructed decompression pathway, three died after subsequent cavopulmonary surgery. Lung histopathology revealed severely dilated lymphatics and arterialization of the pulmonary veins in those with the severest degree of obstruction to left atrial egress (type B atrial morphology).nnnCONCLUSIONSnDespite aggressive intervention, outcome for infants born with hypoplastic left heart syndrome and intact atrial septum is poor. Maldevelopment of the pulmonary vasculature contributes to the high mortality seen. Atrial morphology can be used as a marker for the severity of pulmonary vascular disease.

Long-term outcome of infants with single ventricle and total anomalous pulmonary venous connection.

BACKGROUND AND METHODSnBetween January 1, 1984, and December 1, 1997, 73 infants with functional single ventricle and total anomalous pulmonary venous connection were admitted to our institution. A retrospective review was undertaken to determine factors influencing survival.nnnRESULTSnHeterotaxy syndrome was present in 52 patients and hypoplastic left heart syndrome in 14. Obstructed total anomalous pulmonary venous connection was present in 21 patients. The pulmonary venous connection was supracardiac in 32 patients, cardiac in 21 patients, infracardiac in 13, and mixed in 7. Twelve patients died before the operation. The remaining 61 patients underwent surgery at a median age of 5 days (range 1 day-2. 5 years). Overall survival was 45% at 6 months of age, 37% at 1 year, and 19% at 5 years. Survival for patients undergoing surgery was 54% at 6 months of age, 44% at 1 year, and 23% at 5 years. By univariate analysis with the Cox proportional hazards model, younger age at the time of the initial operation and repair of total anomalous pulmonary venous connection were predictors of mortality. Lung tissue from 14 patients was available for histologic examination. The pulmonary veins were dilated and wall thickness was increased. Increased muscularization of the arteries was seen in 11 patients.nnnCONCLUSIONSnThe long-term prognosis for children undergoing staged reconstructive operations for single ventricle and total anomalous pulmonary venous connection is poor. Early mortality is high and late death is a continuing risk. Development of the pulmonary vasculature, especially the pulmonary veins, is abnormal, even in children without clinical evidence of pulmonary venous obstruction.

Post-transplant lymphoproliferative disease in children

Abstract: Epstein–Barr virus (EBV)‐driven post‐transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following transplantation, and it occurs more frequently in children than in adults. Of 22 (5%) children at our institution who developed tissue‐proven PTLD 1–60u2003months (mean 16.5u2003months) following organ transplant, 11 died: nine of these 22 patients developed PTLD between 1989 and 1993, and seven (78%) died; the remaining 13 developed PTLD between 1994 and 1998, and four (31%) died (p =u200a0.08). All nine patients who developed PTLD <u20036u2003months after transplant died, but 11 of 13 patients who manifested disease ≥u200a6u2003months after transplant survived (p =u200a0.0002). Ten of 11 (91%) survivors, but only two of eight (25%) children who died, had serologic evidence of EBV infection at the time of PTLD diagnosis (pu2003=u20030.04). EBV seroconversion identified patients at risk for developing PTLD, but also characterized patients with sufficient immune function to survive EBV‐related lymphoid proliferation. In situ hybridization for EBER1 mRNA was diagnostically helpful because it detected EBV in tissue sections of all 20 patients with B‐cell PTLD, including those with negative serology.

Matrix metalloproteinase‐9 (MMP‐9) expression in childhood osseous osteosarcoma

BACKGROUNDnOver 80% of patients with osteosarcoma treated with excision alone develop pulmonary metastases, suggesting that the majority of patients with this disease harbor micrometastases at diagnosis. There are no histologic or molecular variables which can predict the presence or absence of micrometastasis. Matrix metalloproteinases (MMPs) are a class of matrix- and basement membrane-degrading enzymes whose expression is associated with tumor cell invasive and metastatic behavior. One of these enzymes, MMP-9 or gelatinase B, is expressed in developing and remodeling bone and in osteosarcoma cell lines. We speculated that MMP-9 expression might be associated with the micrometastatic behavior of osteosarcoma.nnnPROCEDUREnWe examined a series of pediatric primary osseous osteosarcomas and metastases for the expression of MMP-9, using a monoclonal antibody.nnnRESULTSnWe found intense MMP-9 immunostaining in most tumor cells in all samples of pretreatment osteosarcomas. In all postchemotherapy resection samples, tumor cells stained similarly, but there were fewer positively staining cells overall. In 4 of 5 metastastic lesions examined, intense immunostaining for MMP-9 was detected.nnnCONCLUSIONSnThese results suggest that MMP-9 expression is common in osteosarcoma, and that further study of the role of MMP-9 in pediatric osteosarcoma behavior is warranted.

Very Low Birthweight Infant’s Placenta and Its Relation to Pregnancy and Fetal Characteristics

Our objective was to relate pathology of the very low birthweight (VLBW) infant’s placenta to pregnancy and fetal characteristics. We correlated the pathologic features of 1146 placentas from infants with birth weights of 500–1500 g who were born between 1/1/91 and 12/31/93 to the number of gestations per pregnancy, initiator of preterm delivery, gestational age, birth weight Z score, and duration of rupture of membrane (ROM). Placental correlates of acute inflammation and villous edema were associated with preterm labor (PTL), prelabor premature rupture of membranes (PROM), lower gestational age, and higher birth weight Z score. In PTL pregnancies delivered within 1 h of membrane rupture, 61% of placentas already had membrane inflammation. Placental correlates of pregnancy-induced hypertension (PIH) were seen more commonly with PIH pregnancies, older gestational age, and lower birth weight Z score. We found a more prominent histopathologic signature for singleton than for multiple gestation placentas. The placental pathologic findings associated with the clinical diagnoses of infection, PIH, and low–birth weight Z scores in our VLBW/preterm population are similar to those in the literature regarding term pregnancies. The presence of multiple histologic findings consistent with inflammation in placentas of PTL pregnancies with duration of ROM lasting <1 h suggests that some cases of PTL are precipitated by a more long-standing infection than that previously suspected. Morphologic placental features appear to be correlates of the phenomena leading to premature delivery. Examination of the VLBW infant’s placenta provides insight into the etiology and management of VLBW/preterm deliveries.

Very Low Birthweight Placenta: Clustering of Morphologic Characteristics

Our objective was to use factor analysis as a data reduction tool to organize a large number of placental pathologic features into useful aggregates. We examined 1146 placentas of live-born infants with a birth weight of 500–1500 g. We then conducted analyses of pairs of characteristics and multiple characteristics to identify “associated groups” and “factors,” respectively. We found an associated group and factor that had placental features associated with acute inflammation and another associated group and factor that had features associated with vasculopathy. Acute umbilical vasculitis had the strongest correlation with other features of the acute inflammation associated group and factor. Gross evidence of acute inflammation (opacification and green appearance of membrane) was eliminated in the reduction from associated group to factor. Infarcts and syncytial knots were strongly dissociated with features of acute inflammation. The multiple pathologic features of the very low birthweight placenta can be aggregated into two associated groups or two factors. Lack of membrane opacification cannot be used as a criterion for declining microscopic examination. The absence of infarcts and syncytial knots should prompt a search for features of acute inflammation. If a placenta has two or more findings from the acute inflammation factor or the vasculopathy factor, it is unlikely to demonstrate features from the other factor.

Forehead Lipoblastoma Mimicking a Hemangioma

A case of forehead lipoblastoma simulating a hemangioma in a male infant is reported, to alert pediatricians to this rare tumor and to increase the index of suspicion in atypical hemangiomas. A 2-month-old male infant developed a protruding forehead mass with increased vascularity. It demonstrated progressive and accelerated growth over the subsequent 6 months, unresponsive to steroid therapy. A magnetic resonance imaging scan supported the diagnosis of hemangioma because of the hypervascular nature of the lesion. Surgical excision was performed because of visual obstruction. Pathologic examination of the specimen was consistent with a very primitive lipoblastoma. This tumor is a rare, benign lesion of immature fat cells that is found almost exclusively in the pediatric population. Lipoblastomas are more common in males than females and frequently present as asymptomatic, rapidly enlarging, soft lobular masses on the extremities. Complete surgical excision is the definitive treatment. In the vast majority of reported cases, however, the preoperative diagnosis was incorrect, underscoring the diagnostic dilemma presented by these rare tumors.

Multiple Vascular and Bowel Ruptures in an Adolescent Male with Sporadic Ehlers-Danlos Syndrome Type IV

ABSTRACT Ehlers-Danlos syndrome (EDS) type IV is a heritable disorder resulting from mutations in the COL3A1 gene that cause deficient production of type III collagen. Clinical manifestations of EDS type IV include hypermobility of small joints, excessive bruisability, thin translucent skin, poor wound healing, bowel rupture, and vascular rupture that is often fatal. A 14-year-old male without a family history of EDS died following multiple bowel and abdominal blood vessel ruptures. Even in areas apart from rupture sites, the bowel wall was thin because of diminished submucosa and muscularis propria. Similarly, the walls of blood vessels in bowel submucosa and elsewhere in the abdomen varied in thickness, and contained frayed and fragmented elastic tissue fibers. Fibroblasts cultured from the patients skin secreted reduced quantities of type III collagen that was explained by a point mutation in one copy of the COL3A1 gene. EDS type IV should be strongly suspected in any patient with otherwise unexplainable bowel and/or vessel rupture.

Hepatic granulomas in children : A clinicopathologic analysis of 23 cases including polymerase chain reaction for histoplasma

In a 15-year period at the Riley Hospital for Children, granulomas were found in 23 (4%) of a total of 521 liver biopsies. An etiology was identified in 87%: Histoplasma was diagnosed in 15 cases (65%) by polymerase chain reaction (PCR) on paraffin-embedded tissue, serology, and special stains; sarcoidosis was diagnosed in four cases; and schistosomiasis was diagnosed in one case. Serial liver biopsies were available from five patients; granulomas occurred in only one biopsy of the series from each patient. Extrahepatic tissue from six patients contained granulomas, and an etiology for the liver granulomas was identified in all six patients (four histoplasmosis, two sarcoidosis). The extrahepatic tissue from two patients with Histoplasma was diagnostic. We made the following conclusions: that PCR is applicable to archival material and greatly increases the yield of specific infectious diagnoses of liver granulomas compared with conventional diagnostic methods (65 versus 22%); that the infections causing liver granulomas are those that are endemic in a community (e.g., Histoplasma in Indiana); that Histoplasma can coexist with a wide variety of systemic and primary liver diseases; that the likelihood of identifying a cause of liver granulomas is increased if there are extrahepatic granulomas; and that hepatic granulomas may have a limited life span. Treatment of liver granulomas should be determined by the clinical setting and directed at the underlying cause.

Increased pulmonary blood flow produces endothelial cell dysfunction in neonatal swine

BACKGROUNDnThe mechanisms by which increased pulmonary blood flow results in pulmonary hypertension have not been determined.nnnMETHODSnTo determine if increased pulmonary blood flow produces endothelial dysfunction that precedes vascular remodeling and smooth muscle proliferation, neonatal swine (n = 12) (age, 6.1+/-0.5 days) underwent ligation of the left pulmonary artery (LPA) to increase blood flow to the right lung. At 12 weeks of age, endothelium-dependent vasodilatation was assessed by acetylcholine infusion and endothelium-independent vasodilatation by inhaled nitric oxide (NO) in the LPA group and age-matched controls (CON) (n = 11).nnnRESULTSnMean pulmonary artery pressure was 24.1+/-3.0 mm Hg in the LPA group and 20.8+/-1.9 mm Hg in the CON group (p < 0.1). Pulmonary vascular resistance was 13.2+/-2.2 Wood units in the LPA group and 5.8+/-0.8 Wood units in the CON group (p = 0.001). Acute occlusion of the left pulmonary artery in the CON group increased pulmonary vascular resistance to 6.9+/-3.9 Wood units (p = 0.04). Administration of acetylcholine in the CON group after preconstriction with the thromboxane A2 analogue U46619 resulted in a 30.6%+/-5.4% decrease in pulmonary vascular resistance. In the LPA group, acetylcholine produced paradoxical vasoconstriction and a 15.4%+/-4.1% increase in pulmonary vascular resistance (p < 0.001 versus CON) indicating loss of endothelium-dependent vasodilatation. Nitric oxide decreased pulmonary vascular resistance by 41.9%+/-3.3% in the CON group and 30.8%+/-2.7% in the LPA group (p = 0.04 versus CON), indicating preserved endothelium-independent vasodilatation in both groups. Morphometric analysis was performed in 4 animals from each group. Medial wall thickness as percent of external diameter of small arteries (<100 microm) was the same in both groups (6.4%+/-0.4% in the LPA group versus 6.6% +/-0.4% in the CON animals; p > 0.1).nnnCONCLUSIONSnIncreased pulmonary blood flow in immature animals produces endothelial cell dysfunction with loss of endothelium-dependent vasodilatation before the onset of pulmonary vascular remodeling. Subsequent smooth muscle proliferation may be mediated by endothelium-derived factors.