Demonstration of Epstein-Barr virus in immunoblastic sarcoma of B-cells arising in a child with primary immunodeficiency disease.

The subject of this investigation was an 11-month-old infant girl who presented with a pathological fracture of the right femur due to a metastasis from an abdominal immunoblastic sarcoma. Her past history included recurrent, intractable bacterial and fungal infections. Investigations of her immune status revealed low numbers of T-lymphocytes, a reversed T-helper (TH)/T-suppressor (TS) cell ratio, no response of her peripheral blood lymphocytes to pokeweed mitogen, phytohemagglutinin, concanavalin A, and Candida albicans, and an inability of her cells to react in a mixed lymphocyte culture. Serum levels of IgG, IgM, and IgA were all below normal. No thymic shadow was visible on the chest radiograph. There was no evidence of adenosine deaminase or nucleoside phosphorylase deficiencies. The tumor cells exhibited both surface IgM and IgG, and many of the cells contained large amounts of cytoplasmic IgM. Light chain specificity was restricted to lambda chain for both surface and cytoplasmic immunoglobulin. Ultrastructural study of the tumor cells revealed the presence of both intranuclear and cytoplasmic virions in roughly 1% of the tumor cells. These viral particles strongly resembled herpes viruses. DNA-hybridization studies on the neoplasm revealed the presence of 7-10 genome equivalents of Epstein-Barr virus-DNA per tumor cell.

Choline acetyltransferase (ChAT) immunoreactivity in paraffin sections of normal and diseased intestines.

There is increasing interest in localizing nerves in the intestine, especially specific populations of nerves. At present, the usual histochemical marker for cholinergic nerves in tissue sections is acetylcholinesterase activity. However, such techniques are applicable only to frozen sections and have uncertain specificity. Choline acetyltransferase (ChAT) is also present in cholinergic nerves, and we therefore aimed to establish a paraffin section immunocytochemical technique using an anti-ChAT antibody. Monoclonal anti-choline acetyltransferase (1.B3.9B3) and a biotin-streptavidin detection system were used to study the distribution of ChAT immunoreactivity (ChAT IR) in paraffin-embedded normal and diseased gastrointestinal tracts from both rats and humans. Optimal staining was seen after 6-24 hr of fixation in neutral buffered formalin and overnight incubation in 1 microgram/ml of 1.B3.9B3, with a similar distribution to that seen in frozen sections. In the rat diaphragm (used as a positive control), axons and motor endplates were ChAT IR. Proportions of ganglion cells and nerve fibers in the intramural plexi of both human and rat gastrointestinal tracts were also ChAT IR, as well as extrinsic nerve bundles in aganglionic segments of Hirschsprung's disease. Mucosal cholinergic nerves, however, were not visualized. In addition, non-neuronal cells such as endothelium, epithelium, and inflammatory cells were ChAT IR. We were able to localize ChAT to nerves in formalin-fixed, paraffin-embedded sections. The presence of ChAT IR in non-neuronal cells indicates that this method should be used in conjunction with other antibodies. Nevertheless, it proves to be a useful technique for studying cholinergic neuronal distinction in normal tissues and pathological disorders.

45,X/46,XX mosaicism in discordant monozygotic twins.

Monozygotic twins discordant for Turner's syndrome were both mosaic for 45,X/46,XX in the blood with the same low frequency of 2% to 3% 45,X cells. However, the fibroblasts of the abnormal girl were all uniformly 45,X whereas her normal twin had only 46,XX cells. Monozygosity was confirmed by genetic markers, chromosome variants, and a single monochorionic placenta with a shared vascular circulation. The mechanism by which this disparate pair developed from a single zygote is suggested.

A new autosomal recessive lethal chondrodystrophy with congenital hydrops.

Two sibs, the offspring of consanguineous parents, presented with severe short-limb dwarfism and distinct chondro-osseous, radiologic, and histologic appearance. The first sib presented at 30 wk with severe hydrops following fetal death; the second was detected by ultrasonography at 20 wk. Radiologic abnormalities included an unusual "moth-eaten" appearance of the markedly short long bones, bizzare ectopic ossification centers, and marked platyspondyly with unusual ossification centers. Marked extramedullary erythropoiesis was present in both fetuses, and chondro-osseous histology was characterized by marked disorganization of tissue with interspersed masses of cartilage, bone, and mesenchymal tissue. These sibs appear to have a distinct previously unreported autosomal recessive skeletal dysplasia, which can present as hydrops fetalis.

The inflammatory response in candidal chorioamnionitis.

Fetal infection with Candida organisms has not commonly been reported. Umbilical cords and placentas from 23 cases of chorioamnionitis collected over a nine-year period were examined by electron microscopy and immunoperoxidase staining. Gross features, especially of the umbilical cord, were distinctive and included the pale yellow plaques pathognomonic of candidal funisitis. Histopathologically, the lesions were found to be focal and subamniotic and were often embedded in a "fibrinoid" exudate and surrounded by inflammatory cells. In some cases the exudate and inflammatory cells were deposited in dense bands. Immunoperoxidase staining showed the lesions to contain IgG, IgM, and IgA, which probably originated in dense-staining plasmacytoid and immunoblastic cells in the inflammatory infiltrates. Additional findings in two fetal cases of giant cell pneumonitis suggested that the fetus can mount a brisk inflammatory and immune response to Candida organisms as early as 18 weeks' gestation and that mucosal exposure to this antigen can result in production of IgA by the lung.

Congenital stenosis and atresia of the jejunum and ileum.

The macroscopic and microscopic findings in 12 cases of stenosis and/or atresia of the jejunum and ileum are presented. There was considerable uniformity within the series with overlapping of cases of atresia, stenosis, and gut infarction. An analysis of associated lesions in cases coming to necropsy suggests that the infants were suffering from shock. In nine out of the 12 cases there was evidence of intrapartum asphyxia and in eight cases evidence of retardation of intrauterine growth. It is argued that, since many of the associated complications of pregnancy are known to be of importance in the aetiology of gut infarction in the neonatal period, they are likely to be of aetiological significance in the development of atresia and stenosis of the gut. A review of perinatal deaths shows that gut ischaemia of varying degrees of severity is a common finding at necropsy, being noted in 19 out of 56 cases studied. It is suggested that stenosis and atresia are sequelae of previous gut ischaemia.

Benign oesophageal papillomatosis. A case report with a review of the literature.

An 18-year-old boy presented with a four-year history of dysphagia which had been treated repeatedly by endoscopic removal of papillomata of the oesophagus. Eventually, due to increasing dysphagia and repeated recurrences of the papillomata, resection of the affected lower third of the oesophagus was deemed necessary. The resected segment of the oesophagus was carpeted with numerous benign squamous papillomata. The clinical features, radiographic appearances, and pathology of this extremely rare tumour are presented. Only two acceptable cases of oesophageal papillomata can be found in the literature, making this the third case, and apparently the only one with multiple lesions.

Adriamycin cardiotoxicity: report of an unusual case with features resembling endomyocardial fibrosis.

We report on a case of adriamycin cardiotoxicity occurring in a five-year-old boy treated for rhabdomyosarcoma. In addition to the usual features of myofibrillary degeneration associated with adriamycin, extreme endocardial fibrosis and mural thrombosis affecting the apical segments of both ventricles but particularly the left ventricle was seen at necropsy. The changes resembled classical endomyocardial fibrosis.

Placental involvement in congenital neuroblastoma.

We describe two cases of congenital neuroblastoma involving the placenta and review previously reported cases. The placentae in congenital neuroblastoma have a bulky, hydropic appearance, and contain tumour cells which are confined to the fetal circulation. The tumour emboli are not macroscopically identifiable. Pathophysiological mechanisms of placental involvement by fetal and maternal malignancies are considered. The rarity of this lesion may be artefactual, and may result from failure to examine grossly enlarged placentae in cases of stillbirth and hydrops fetalis. Congenital malignancy must be considered in the differential diagnosis of an abnormally large placenta.

Congenital ependymoblastoma presenting as a sacrococcygeal mass in a newborn: an immunohistochemical, light and electron microscopic study.

We describe a case of congenital ependymoblastoma presenting as a subcutaneous mass in the sacrococcygeal area of a newborn male. The tumor was composed of primitive cells disposed in compact sheets and cords and exhibiting focal ependymal differentiation. No other line of cellular differentiation was identified by either immunohistochemistry or ultrastructural study. Elevated serum alpha-fetoprotein was found, which decreased following surgical extirpation of the tumor. We propose that this tumor had its origin in the ependymal medullary vestige, similar to other sacrococcygeal ependymomas.

Isolated myocarditis as a cause of sudden death in the first year of life.

A series of three cases of isolated myocarditis, presenting as sudden death in infancy, occurred over a period of 3 months. This prompted a review of the autopsy records of the Children's Hospital of Winnipeg. Over a period of 40 years, 24 cases of isolated myocarditis were traced from 3196 autopsies. Most (21 of 24) cases of isolated myocarditis occurred in infants less than 12 months of age. In 16 of the infants there were either no antecedent clinical signs (sudden deaths), or a short clinical history of less than 24 h duration. Heart weights, however, were greater than the 99th percentile of published normals in three infants and above the 95th percentile in a further 16 infants. Areas of hypertrophied fibres were seen even in infants with a short history. These latter findings suggest that a latent phase of myocarditis may exist. The responsible pathogens were identified very rarely, due to a lack of suspicion of the existence of myocarditis, and it is suggested that samples of myocardium should be submitted for virologic examination in all cases of sudden death in the first year of life.

Mucosal metaplasia and chronic inflammation in the middle ear of infants receiving intensive care in the neonatal period.

The histological findings in the middle ear cavity of 72 infants of varying gestations, birthweights, and ages are presented. All infants died after receiving ventilatory support and oxygen for longer than 14 days. In 5 infants there was no detectable histological abnormality. In the remainder, a wide range of lesions was seen including glandular metaplasia, retained squamous debris, squamous polyps, otitis media, and destruction of ossicles. None of the cases of otitis media was diagnosed before necropsy; all were associated with pneumonia. No single specific infectious agent predominated. Several factors could contribute to the spectrum of lesions, and these include persistent amniotic squamous debris, infection, and the effects of oxygen and a nasal airway. The possible implications of these findings are discussed, and it is argued that similar changes of lesser severity could be present in survivors in whom otitis media and conduction hearing defects could be expected.

Isolated myocarditis in the first year.

Over a period of nearly 40 years, 20 cases of isolated myocarditis were traced from 3086 necropsies. Seventeen occurred in infants less than 12 months of age, often with no antecedent clinical signs (sudden deaths) or with a short clinical history of less than 24 hours' duration.

The spectrum of ischemic bowel disease in the newborn.

In this review the author's opinion regarding the etiology of most cases of perinatal and neonatal bowel ischemia has been stated. It is recognized that the changes brough about by hypoxia (splanchnic shutdown, bowel ischemia) represent the "soil" on which other "seeds" can prosper. In its simplest form following acute ischemia, the processes of repair take over, leading to functional recovery and a presumably normal bowel. In those patients with more extensive initial damage, degrees of stenosis and even atresia may be expected as a result of the healing of the bowel. Rapidly evolving ischemia may produce perforations; these may be restricted and involve only very small areas of bowel or may be part of a more generalized involvement, possibly even with multiple perforations. In other infants, alterations of bacterial flora could contribute to the clinical picture of "necrotizing enterocolitis," and gas may or may not be present in the bowel wall. If the process of ischemia has been relatively mild, or bacterial overgrowth not particularly marked, some of the more obscure functional syndromes may be noted. The persistence of these obscure syndromes may in turn be related to incomplete phases of regeneration of the bowel that fall short of producing stenosis but lead to a mucosa that is not optimally functional.

Follicular ovarian cysts in stillbirths and neonates.

A review of the histology of 332 ovaries from stillbirths and neonatal deaths within the first 28 days of life showed that follicular cysts, lined by granulosa epithelium and having a diameter greater than 1 mm on a microscopical section, were present in 113 infants. In 48 cases multiple cysts were present, while in 65 only a single cyst satisfying the criteria was found. There was an excess number of infants of low birthweight score among those with multiple cysts and the results were highly significant. Cysts, whether single or multiple in distribution, were commoner with increasing gestation, and possibly occurred more commonly in the infants of diabetic mothers and in infants where pregnancy had been complicated by rhesus isoimmunization. The nature of the changes seen in the granulosa lining and theca internal layer surrounding the cysts suggested that these cysts were not some degenerative phenomenon but occured in response to stimulation. It is suggested that homologous changes may occur in the testis of the dysmature male. The possible significance of these findings with regard to hormonal imbalance in the growth-retarded infant is considered, and the need for closer attention to endocrine function in these infants stressed.

Myocardial changes in immature infants requiring prolonged ventilation.

Fourteen infants who had required prolonged ventilation with high concentrations of oxygen for 14 days or more, were studied at necropsy. 11 infants of immature gestation at birth had gross cardiac hypertrophy, defined as a heart weight greater than 2 SD above the mean for their age. No congenital malformation of valves or septum was found, and in the 7 youngest infants with hypertrophy, the ductus arteriosus was anatomically patent. 3 of these 7 infants had an accompanying nurmur. All 11 infants had severe bronchopulmonary dysplasia. The cardiac hypertrophy affected both ventricles and septum in an irregular fashion and was associated with areas of necrosis, progressing to coarse fibroelastotic scars. The intramural vessels showed marked intimal thickening but the main coronary vessels were normal. The 2 youngest infants with cardiac hypertrophy showed the presence of intravascular and endocardial platelet thrombi. In the 3 infants without cardiac hypertrophy less severe zones of necrosis and scarring were present, and only occasional bundles of hypertrophied muscle fibres were seen. In an attempt to understand these hitherto undescribed lesions, a group of 50 fresh stillbirths and 50 first-week neonatal deaths of comparable gestational age were studied. In 19 of these infants foci of myocardial fibre necrosis were present. It is suggested that the lesions in the older infants represent a more advanced and continuing stage of that seen in the younger infants, and that the foci of necrosis are the result of continuing hypoxia and related problems to a failing coronary circulation. The possibility of myocardial damage represents a serious hazard to the successful therapy of the immature asphyxiated infants.

Polypoidal organization of aspirated amniotic squamous debris(amnion nodosum) in middle-ear cavity of newborn infants.

The development of polypoidal structures, derived from organization of amniotic squamous debris, in the middle-ear cavity of 3 infants is described. The lesions mimicked the development of amnion nodosum lesions of the placenta and were attached to either the tympanic membrane or the head of the stapes. They were accompained by atypical metaplastic changes in the middle-ear epithelium. While the clinical significance of the structural changes is uncertain, they strengthen the case for histopathological examination of the middle ear in infant necropsies.

Intrauterine infections with group B beta-haemolytic streptococci.

The case records of 15 infants with intrauterine infections due to group B beta-haemolytic streptococci were traced from the records of two geographically separate centres over a 4-year period (1979-1982). Six infants were stillborn and the other nine died within the first 6 h. All the infants weighed less than 1000 g and were less than 28 weeks gestation. Placental examination in 14 of the 15 infants showed the presence of chorioamnionitis and funisitis. The infants also showed evidence of pneumonitis. Four infants had evidence of otitis media, two had evidence of an early meningitis. A history of antepartum bleeding was present in six infants and abundant retroplacental clot was noted in four of them. The membranes had been ruptured for greater than 24 h in only three infants. In six of the infants the membranes were intact at the time of delivery. A history of intact membranes at the time of delivery does not exclude a diagnosis of an intrauterine infection with this organism, and this series of infants highlights the importance of routine bacteriologic studies of all perinatal deaths.