Eduardo J. Yunis

Demonstration of respiratory syncytial virus in an autopsy series.

Respiratory syncytial virus (RSV) antigen was demonstrated in formalin-fixed, paraffin-embedded autopsy tissue using an immunoperoxidase technique. Eighteen autopsy cases were selected on the basis of one of the following criteria: a positive culture for RSV, antemortem or postmortem; positive ELISA test for RSV, antemortem or postmortem; or postmortem histology suggestive of paramyxovirus infection. Controls included three cases from which parainfluenza or influenza virus had been cultured and a case in which the clinical diagnosis of measles was firmly established. Sections of formalin-fixed, paraffin-embedded tissue were stained with a rabbit anti-RSV antibody (Dako) using an immunoperoxidase technique. Staining was achieved in 12 cases. This included 6 of 7 cases selected because of positive cultures or ELISA tests for RSV. The other 6 cases in which RSV was identified by the described technique lacked culture or ELISA confirmation. Granular and globular staining was seen in the cytoplasm of respiratory epithelial cells and syncytial giant cells. None of the control cases stained for RSV. The histology of RSV lungs was consistent with changes described in the literature for RSV infection, although pneumonic consolidation and syncytial giant cells were more prominent in this series.

Epstein-Barr virus infections in children after transplantation of the small intestine

Epstein-Barr virus (EBV) infection in association with immunosuppressive drugs used for solid organ transplantation can produce a spectrum of illnesses. Forty-one children who ranged in age from 6 months to 18.5 years received small intestinal transplants alone or in combination with other organs while undergoing primary tacrolimus (FK506) immunosuppression between July 1990 and June 1995. We reviewed hematoxylin and eosin-stained sections from all biopsy, surgical, and autopsy material from these children to determine the incidence and morphology of EBV-associated disease. Nuclear staining with in situ hybridization for EBV early RNA transcript (EBER) using the EBER-1 probe confirmed the presence of EBV. The EBV lymphoproliferations were graded as 1 to 4 according to histopathology and EBV quantitation determined in the area of greatest positivity. Twenty-one patients (51%) had EBV documented histologically on one or more occasions; only 8 (38%) are alive; 5 of these had the highest grade of 2. Posttransplant lymphoproliferative disease (PTLD) developed in 13 patients. Three of 10 patients (30%) with grade 3 lesions (polymorphous PTLD) are alive with intermittent evidence of EBV infection; 6 died with PTLD. Monomorphic PTLD (grade 4) was the cause of death in the three additional patients. Thirteen of 20 patients (65%) with no histologic evidence of EBV are alive. The incidence of EBV infection in pediatric small intestinal transplant recipients is higher than reported for any other solid organ cohort. With the aid of frequent EBER staining we were able to diagnose EBV infections in 51% of 41 patients; PTLD (grade 3 or 4) developed in 32% of these children. Low-grade EBV infections often preceded the development of PTLD and were identified in gastrointestinal biopsy samples from patients with concurrent PTLD; however, results of gastrointestinal biopsy samples may be negative for EBV in some patients with PTLD and, thus, underestimate systemic EBV-associated lymphoproliferations. Rejection and EBV infection can occur simultaneously, therefore, attention to low-grade infection may be useful to patient management.

Sacrococcygeal teratomas: A review of 68 cases

Sixty‐eight cases of sacrococcygeal teratoma were reviewed and graded according to the quantity of immature tissue present. Seventy‐five percent were benign (grade 0), 11.8% immature (Grades 1–3), and 13.2% malignant. Although the immature component in most tumors was neuroepithelial, in two cases it was exclusively renal. There were no instances of local recurrence or metastasis of immature elements. The malignant lesions were all endodermal sinus tumor, stained positively for alpha‐fetoprotein and were uniformly fatal, with an average duration of survival of 8.9 months. Early adequate treatment of sacrococcygeal teratomas results in a favorable prognosis. This experience is different from that reported for immature ovarian teratomas. Immature metanephric tissue in sacrococcygeal teratomas should be interpreted the same way as immature neuroepithelial elements. Immature sacrococcygeal teratomas should be separated from tumors containing malignant elements because of their vastly different prognoses.

Fibrosarcoma in infants and children: application of new techniques

Fibrosarcomas occurring in infants and young children are intriguing tumors. Although biologically more benign than their counterparts occurring in old patients, they are histologically similar. Microscopically, they fit in one end of a spectrum of fibrous proliferations occurring in the pediatric population. Prompted by recent karyotypic reports of nonrandom gains of chromosomes 8, 11, 17, and 20 in infantile fibrosarcomas, we retrospectively analyzed 12 infantile fibrosarcomas utilizing fluorescence in-situ hybridization (FISH) with chromosome 8-, 11-, 17-, and 20-specific probes. Parallel studies were performed on fibrosarcomas occurring in older children and young adults and also on cellular fibromatoses, myofibroma-toses, and fibromatoses. Gains of chromosomes 8, 11, 17, and 20 (in various combinations) were observed in 11 of 12 fibrosarcomas occurring in infants <2 years of age. Extra copies of chromosomes 17 and 20 were observed in a fibrosarcoma occurring in a 5-year-old child but no abnormalities were detected by FISH in four additional fibrosarcomas occurring in patients aged 6–17 years. One of three cellular fibromatoses was characterized by extra copies of chromosome 8, 11, 17, and 20. Similar findings were not observed in any of the noncellular fibromatoses or in myofibromatoses.

Prognostic factors in osteosarcoma: A review of 20 years' experience at the university of pittsburgh health center hospitals

The histologic and clinical characteristics of 54 patients with osteosarcoma are reviewed. The association of rapid linear bone growth with the occurrence of this tumor is confirmed, and evidence for increased growth in these adolescent patients is presented. A significant increase in female survival is seen in this study, and the literature relevant to gender and survival is reviewed. A histologic characterization of six predominant tumor patterns is presented with correlation to survival. Increased survival is seen with two specific histologic patterns, but there is great variability in the histology and sampling of osteosarcomas, and the series is small.The histologic and clinical characteristics of 54 patients with osteosarcoma are reviewed. The association of rapid linear bone growth with the occurrence of this tumor is confirmed, and evidence for increased growth in these adolescent patients is presented. A significant increase in female survival is seen in this study, and the literature relevant to gender and survival is reviewed. A histologic characterization of six predominant tumor patterns is presented with correlation to survival. Increased survival is seen with two specific histologic patterns, but there is great variability in the histology and sampling of osteosarcomas, and the series is small.

Recurrent Epstein-Barr virus-associated lesions in organ transplant recipients☆

Posttransplant lymphoproliferative disorders (PTLD) are related to Epstein-Barr virus (EBV) and range from lymphoid hyperplasias to lymphomas. The authors report 11 transplant recipients with recurrent EBV-associated lesions. Four patients presented with EBV-positive mononucleosis-like lymphadenitis. One had recurrence of a similar lesion and the other three developed polymorphic PTLDs. Matched clonal studies in one patient showed clonal lymphoid and EB viral populations in the recurrent lesion, but not in the initial lesion. Six patients presented with polymorphic PTLDs. Five later developed histologically dissimilar tumors that resembled non-Hodgkins lymphoma (two B-cell and one T-cell origin), Hodgkins disease (one patient), or smooth muscle tumor (one patient). Matched clonal studies were available from one patient and showed that the primary and recurrent lesions were clonally distinct. The sixth patient had recurrence of histologically and clonally identical polymorphic PTLD. One patient presented with monomorphic PTLD and developed recurrence of a clonally identical tumor after a 6-month remission. This study shows that a few patients with EBV-associated lesions have clinical recurrence, which may be either a relapse of the original process or a new EBV-associated lesion. In some patients, the new lesion appeared to represent a more fully developed malignancy that did the antecedent lesion.

Intestinal Neuronal Dysplasia

Summary Four hundred ninety-eight acetylcholinesterase-stained suction rectal biopsies from 456 children were examined to assess the occurrence of “isolated” or “primary” intestinal neuronal dysplasia at Childrens Hospital of Pittsburgh. Cases of proven Hirschsprungs disease were excluded. In 38 biopsies from 38 patients, we found a mild to moderate increase in mucosal acetyl-cholinesterase staining and abundant submucosal ganglion cells (large, irregular ganglia or at least five ganglia per HPF). This group was clinically heterogeneous with a frequent history of prematurity and small left colon/meconium plug syndrome, protein/formula intolerance, or obstructive anatomic gastrointestinal abnormalities. We feel that isolated “intestinal neuronal dysplasia,” as diagnosed by suction rectal biopsy and the above criteria, is a descriptive biopsy appearance. Rather than characterizing a unique disease entity, it is encountered in a variety of clinical situations. Based on our observations and review of the literature, we therefore conclude that “intestinal neuronal dysplasia” not associated with Hirschsprungs disease, neurofibromatosis, or multiple endocrine neoplasia syndrome has yet to be well defined in clinical and histopathologic terms. The histologic diagnosis, at this time, should be reserved for those rare, florid cases of parasympathetic hyperganglionosis that are documented by adequate tissue sampling.

Tubular inclusions of systemic lupus erythematosus: Ultrastructural observations regarding their possible viral nature

Abstract The finding of tubular cytoplasmic inclusions in renal and skin endothelium of patients with SLE is confirmed. Similar inclusions were seen in a lymph node of a patient with SLE, focal and diffuse glomerulonephritis, Krabbe leukodystrophy and Coxsackie myocarditis. Although the inclusion resembles paramyxovirus nucleoprotein, definite proof of its viral nature is lacking. The hypothesis that the inclusion is a manifestation of cellular injury is supported by its occurrence in such a variety of unrelated conditions. It remains to be determined whether the prevalence of the inclusion or the frequency with which it is found in tissues from patients with SLE may be of diagnostic significance.

Liver transplantation for type IV glycogen storage disease

Type IV glycogen storage disease is a rare autosomal recessive disorder (also called Andersen’s disease1 or amylopectinosis) in which the activity of branching enzyme alpha-1, 4-glucan: alpha-1, 4-glucan 6-glucosyltransferase is deficient in the liver as well as in cultured skin fibroblasts and other tissues.2,3 This branching enzyme is responsible for creating branch points in the normal glycogen molecule. In the relative or absolute absence of this enzyme, an insoluble and irritating form of glycogen, an amylopectin-like polysaccharide that resembles plant starch, accumulates in the cells. The amylopectin-like form is less soluble than normal glycogen, with longer outer and inner chains and fewer branch points. The clinical onset of the disease is insidious, with nonspecific gastrointestinal symptoms at first, followed by progressive hepatosplenomegaly, portal hypertension, ascites, and hepatic failure. Children with this disorder usually die of hepatic cirrhosis by the age of two to four years. 4–8 In exceptional cases, cardiomyopathy,5–7,9 neurologic syndromes — including tremors, seizures, and dementia10,11 — or variable manifestations of myopathy5,12,13 have been reported. In patients with these unusual symptoms, the clinical onset is frequently later than in typical cases, and death most often results from cardiac failure. Liver transplantation for Type IV glycogen storage disease was attempted in 1972; the recipient died 110 days later after the rejection of the first liver transplant and attempted re transplantation.14 Liver transplantation was first performed successfully in September 1984 in Patient 1 of this series; since that time we have treated six more such patients. Our experience with these seven patients forms the basis of this report.

Recurrent and de novo giant cell hepatitis after orthotopic liver transplantation.

This study examines the clinical and pathologic course of seven patients who developed giant cell hepatitis (GCH) after liver transplantation. Five of these patients also had GCH as their native liver disease and experienced a particularly aggressive course because of recurrent disease, beginning 1-21 months after transplantation. Two died and another two required hepatic retransplantation because of recurrent GCH; one of them had GCH recurrence in a second liver allograft. A remaining patient with recurrent GCH is alive 6 years after transplantation. Follow-up of the two patients who developed de novo GCH between 8 and 24 months after hepatic transplantation showed active micronodular cirrhosis in one and persistent giant cell transformation in the other at 4 years. All of the patients were serologically negative for hepatitis C virus, hepatitis B virus, and human immunodeficiency virus before transplantation. One patient became positive for hepatitis C virus after transplantation. Two patients had an associated autoimmune syndrome, which could have been accounted for by the GCH. None had a history of drug exposure. Interestingly, human papilloma virus (HPV) type 6 was detected by PCR analysis of liver tissues with GCH from one of three cases before and three of four cases after transplantation. This small series shows that GCH occurs in liver allografts, but it is uncommon. Documentation of recurrent disease in five of seven patients suggests that GCH in a subgroup of patients may be related to a transmissible agent, or that a particular recipient may injure livers in a way that elicits a giant cell reaction.