Identical genetic changes in different histologic components of Wilms' tumors.

BACKGROUND: In young children and infants, Wilms' tumor is the most common cancer of the kidney. Wilms' tumor exhibits heterogeneous histopathologic features, consisting of rapidly proliferating blastemal and epithelial cells and a stromal component that has heterologous elements (e.g., cartilage, bone, and striated muscle). It is unclear whether the stromal and heterologous components of sporadic Wilms' tumor are neoplastic or should be considered non-neoplastic. PURPOSE: Our purpose was twofold: 1) to selectively analyze the different histologic tissue components of sporadic Wilms' tumors, including blastemal, epithelial, stromal, and heterologous elements, for loss of heterozygosity (LOH) of the WT1 gene and for expression of the WT1 gene and 2) to determine the role of WT1 gene expression in the development of these tissues. METHODS: By use of tissue microdissection techniques, various histologic elements (blastema, stroma, epithelium, and striated muscle) of sporadic Wilms' tumor were obtained from specimens taken from 18 patients. DNA was extracted from the dissected tissue fragments, and DNA solutions were amplified by use of the polymerase chain reaction and the polymorphic genomic markers D11S1392 and D11S904 to detect LOH at the WT1 gene locus (11p13). Three selected specimens with heterologous elements and LOH at 11p13 were analyzed for expression of the WT1 gene by means of the in situ reverse transcription-polymerase chain reaction. RESULTS: Nine (50%) of the 18 specimens showed LOH at the WT1 locus. Although identical WT1 gene deletion was consistently observed in all of the various histologic components of these nine specimens, WT1 gene expression was high in the blastemal and epithelial elements and low in the stromal and heterologous elements. CONCLUSIONS AND IMPLICATIONS: Identical allelic deletion at 11p13 in all components of the sporadic Wilms' tumors examined suggests that the stromal tissue components are neoplastic rather than non-neoplastic. In conjunction with variable WT1 gene expression in the different histologic components, the results raise the possibility that undifferentiated blastemal cells are the precursors of the stromal and heterologous elements. Morphologically benign stromal and heterologous elements may therefore be derived from neoplastic cells. The developmental state of the various tissue components of Wilms' tumor may be attributed to an altered residual WT1 gene that is required for the maturation of blastemal and epithelial cells but that is not required for the maturation of stromal and heterologous elements.

Value of endomyocardial biopsy in infants, children and adolescents with dilated or hypertrophic cardiomyopathy and myocarditis.

Endomyocardial biopsy was performed in 20 symptomatic pediatric patients with the following clinical diagnoses: dilated cardiomyopathy in 16, hypertrophic cardiomyopathy in 2 and myocarditis in 2. Transfemoral biopsy was performed without complications in patients aged 2 months to 16 years; 6 were less than 1 year old. An average of five right ventricular specimens were obtained for histologic and ultrastructure study from each patient. In 16 patients with the clinical diagnosis of dilated cardiomyopathy, biopsy findings were compatible with the diagnosis in 8, but changed the diagnosis as follows in the other 8: myocarditis, 4; hypertrophic cardiomyopathy, 2 and carnitine deficiency syndromes, 2. In two patients with the clinical diagnosis of hypertrophic cardiomyopathy, biopsy findings confirmed the diagnosis in one and were normal in the other who had an encapsulated cardiac fibroma at operation. In two patients with the clinical diagnosis of myocarditis, biopsy findings confirmed the diagnosis in one and suggested dilated cardiomyopathy in the other. In the entire series, 25% had biopsy evidence of inflammatory disease. Biopsy findings were confirmed at subsequent autopsy in five cases.

Evidence for neural origin and PAS-positive variants of the malignant small cell tumor of thoracopulmonary region ("Askin tumor").

The differential diagnoses of childhood and adolescent tumors composed of small round cells include a distinctive clinicopathological entity called malignant small cell tumor (MSCT) of the thoracopulmonary region in childhood. In the present study, 15 such tumors that fulfilled the criteria by Askin et al. were examined for features of possible neural differentiation by light and electron microscopy (EM). With hematoxylin-eosin stain (H&E) the tumors were made up of small undifferentiated cells; rosette formation was noticed in four cases. By immunohistochemistry all 15 tumors were positive for neuron/specific enolase (NSE), which is a specific marker for neural elements and their tumors including neuroblastomas. Ten of 15 MSCT had positive PAS staining. Ultrastructurally dense core (neurosecretory) granules and cell processes indicative of neuronal differentiation could be recognized in 10 of 14 tumors. The dense core granules were often atypical. Filamentous cytoskeleton, never observed in Ewing's sarcoma, was often present. Based on the current results, MSCT of the thoracopulmonary region can be considered a peripheral neuroectodermal tumor with the possible origin in intercostal nerves. MSCTs are generally misdiagnosed as Ewing's sarcoma due to their primitive appearance in H&E sections and their periodic acid-Schiff positivity. NSE immunostaining, preferably augmented by electron microscopy, is necessary for their correct diagnosis.

Testicular histology in the adolescent with a varicocele.

A varicocele is a common cause of adult male infertility, and surgical ligation is a generally accepted mode of therapy. However, the guidelines for management of the adolescent with a varicocele are not clearly defined. Herein, we describe histologic abnormalities noted on testis biopsy in nine of 24 boys with moderate to large varicoceles. Surgical ligation of the varicocele is recommended when there is volume loss of the testis ipsilateral to the varicocele. All others should be reexamined periodically, and an attempt should be made to obtain a baseline semen analysis.

Aortic valve atresia: a new classification based on necropsy study of 73 cases.

Certain clinical and morphologic observations are described in 73 necropsy patients with aortic valve atresia. The mean age at death was 5 days; 80 percent died during the first week of life, and 70 percent were boys. Of the 73 patients, 69 (95 percent) had a hypoplastic left ventricle with intact ventricular septum and either an atretic (25 patients) or hypoplastic (44 patients) mitral valve. The other four patients had a well developed left ventricle with one or more defects in the ventricular septum and either an atretic (one patient) or well developed (three patients) mitral valve. Review of previous reports on aortic valve atresia disclosed that a well developed left ventricle or ventricular septal defect in association with absence of the aortic valve was extremely rare. A new classification for aortic valve atresia is presented based on the status of the ventricular septum, which in turn appears to determine the size of the left ventricular cavity. The predilection for male subjects for all types of aortic valve disease, including atresia, is emphasized.

PHAVER syndrome: an autosomal recessive syndrome of limb pterygia, congenital heart anomalies, vertebral defects, ear anomalies, and radial defects.

We have studied 2 sibs with vertebral, radial, congenital heart, and ear defects. The second patient also had limb pterygia and meningomyelocele. The abnormalities in these two sibs are seen in the VATER association; however, distinguishing these cases from the VATER association are the findings of pterygia, meningomyelocele, and probable autosomal recessive inheritance. We propose the acronym PHAVER syndrome for limb pterygia, heart defects, autosomal recessive inheritance, vertebral defects, ear anomalies and radial defects. This represents a new autosomal recessive disorder with phenotypic variability.

Human immunodeficiency virus (HIV)-associated nephropathy in children from the Washington, D.C. area: 12 years' experience.

Human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is a clinicopathologic entity that includes proteinuria, azotemia, focal segmental glomerulosclerosis or mesangial hyperplasia, and tubulointerstitial disease. The incidence of HIVAN is increased in black patients and variable depending on the age and geographic area. The objective of this study was to describe relevant clinical and pathological findings in 30 children with HIVAN followed at the Children's National Medical Center in Washington, D.C. Our experience of the last 12 years showed a spectrum of HIVAN that seems to be coincident with the degree of acquired immunodeficiency syndrome (AIDS) symptomatology. By renal sonograms and frequent urinalysis, we identified children undergoing the early stages of HIVAN with enlarged echogenic kidneys, proteinuria, and "urine microcysts". HIVAN did not necessarily progress rapidly to end-stage renal disease. Nephrotic syndrome or chronic renal insufficiency were late manifestations of HIVAN. Children with HIVAN were likely to develop transient electrolyte disorders, heavy proteinuria, and acute renal failure due to systemic infectious episodes or nephrotoxic drugs. HIVAN was associated with other HIV-induced illnesses and high mortality rates. Early detection and careful clinical follow-up of children with HIVAN may reduce the incidence of renal-cardiovascular complications and improve their quality of life.

Neuron-specific enolase in the diagnosis of neuroblastoma and other small, round-cell tumors in children.

Immunocytochemical staining for neuron-specific enolase (NSE) was performed in 44 round-cell tumors from children by the improved immunoglobulin-enzyme bridge method with antiserum against NSE. The tumors studied consisted of 15 neuroblastomas showing various degrees of histologic differentiation, 13 Ewing's sarcomas, ten soft tissue sarcomas of diverse origin, and six lymphomas of bone and soft tissues. Neuron-specific enolase was detected in all neuroblastomas, irrespective of the degree of histologic differentiation. None of the other round-cell tumors was positive for NSE, except one embryonal rhabdomyosarcoma that contained differentiated myoblasts. The primitive cells of this tumor were negative as well. It is concluded that immunocytochemical staining with antibodies to NSE is a practical and reliable method for distinguishing neuroblastomas from other nonneural round-cell tumors in children. This is true even for the most primitive forms of neuroblastomas, in which morphologic techniques are less reliable. Neuron-specific enolase may also be useful in delineating the neural histogenesis of other ill-defined tumors.

Vasculopathy of small muscular arteries in pediatric patients after bone marrow transplantation.

Bone Marrow Transplant (BMT) is a critical therapeutic intervention for a variety of diseases occurring in the pediatric patient. Complications of allogeneic BMT include graft-versus-host disease (GVHD), infection, drug toxicity, thrombotic microangiopathy, and veno-occlusive disease. With solid organ transplantation, chronic vascular rejection has emerged as a major factor limiting long-term survival of the graft. We present a vasculopathy of small muscular arteries in 6 patients after allogeneic BMT. Cases include 4 boys and 2 girls ranging in age from 4 months to 13 years with full or partial human leukocyte antigen matching. Five of the 6 transplants were from related donors. The vasculopathy occurred 13 to 418 days after transplant and was noted in surgical specimens (2) and at autopsy (4). It was seen in the gastrointestinal tract and lung in 3 cases each. Vascular changes in small muscular arteries include concentric intimal or medial hyperplasia with luminal narrowing, prominent myxoid change, extravasated red blood cells, and presence of some foamy histiocytes with no evidence of thrombotic microangiopathy. Vasculopathy contributed to intestinal compromise requiring surgical intervention 3 times in 1 patient, and diffuse alveolar damage with hemorrhage in another. All 6 patients are dead. The cause of this unusual vasculopathy present in patients after BMT is likely to be multifactorial, involving effects of irradiation, chemotherapy, cyclosporine, and GVHD. Together these may create a negative synergy which produces an obliterative arteriopathy that should be recognized as a pathological entity and may be a harbinger of a poor prognosis.

Tumoral multiple sclerosis of the cerebellum in a child.

We present a case of cerebellar tumoral multiple sclerosis in an 11-year-old girl and emphasize these two features: (1) Tumoral multiple sclerosis can occur within the posterior fossa and should be strongly considered in the differential diagnosis of mass lesions of the posterior fossa when typical white matter lesions are seen on T2-weighted images. (2) Tumoral multiple sclerosis can demonstrate ring enhancement on MR.

CT and MR evaluation of intracranial involvement in pediatric HIV infection: a clinical-imaging correlation.

PURPOSE: To review the cranial CT and MR examinations of 29 children with perinatally transmitted HIV infection and correlate the imaging findings with clinical and pathologic data. METHODS: 28 children were examined with CT, four with MR. RESULTS: CT abnormalities were seen in 25 children studied (89%), including cerebral atrophy (25 children), basal ganglia calcification (10 children), periventricular frontal white matter calcification (four children), cerebellar calcification (one child), white matter low attenuation areas (two children), intracranial hemorrhage (three children) and cerebral infarction (one child). Intracranial calcifications were only seen in association with cerebral atrophy and were never seen prior to 1 year of age. Calcifications in the periventricular white matter or cerebellum were always associated with basal ganglia calcifications. MR abnormalities were seen in all four children studied; cerebral atrophy (four children), areas of high signal intensity in white matter (four children), loss of normal posterior pituitary high signal intensity (one child). Cerebral atrophy appeared to be a nonspecific finding that was seen in some children in the absence of neurologic signs and symptoms. All children with intracranial calcifications had developmental delay. Intracranial hemorrhage was seen in children with severe thrombocytopenia. Focal intracranial infections were unusual and neoplastic lesions were not found. CONCLUSIONS: Cerebral atrophy, basal ganglia calcifications, and focal white matter lesions were the most common abnormalities seen neuroradiologically in our series of HIV-infected children; cerebral atrophy was a nonspecific finding.

In vitro effect of intravenous immunoglobulin supplementation on serum opsonic activity in tracheostomised patients.

An in vitro study of the effect of immunoglobulins (mainly IgG) on opsonophagocytic activity of polymorphs was carried out in 17 tracheostomised patients admitted in medical intensive care unit of our hospital. The opsonic and phagocytic activities were tested against Staphylococcus aureus by modified polymorphonuclear leucocyte overlay method; and serum IgG and serum IgM levels were estimated by single radial immunodiffusion technique. As compared to healthy volunteers, opsonophagocytic activity was significantly lower in tracheostomised patients. However, this activity improved markedly after immunoglobulin supplementation (P less than 0.01). The same degree of enhancement was also observed in normal controls.

Malignant endovascular papillary angioendothelioma. Cutaneous borderline tumor.

Malignant endovascular papillary angioendothelioma, a rare but distinctive vascular tumor of childhood, was first described in 1969. It was termed malignant because of its mitotic activity, areas of necrosis, and demonstrated ability to metastasize to regional lymph nodes. Despite these features it had a uniformly good prognosis. We report an example of this lesion in a 6-year-old boy that does not show malignant histologic features. Based on its good long-term prognosis and variable histologic features, this lesion is better classified as a borderline vascular tumor.

Benign hepatocellular tumors in the young. A clinicopathologic spectrum.

Hepatic tumors unassociated with cirrhosis were encountered in seven patients aged 10 to 19 years. Four patients had received androgens for aplastic anemia. Two patients had transfusional hemosiderosis. One patient had had a renal transplant 2 1/2 years ago. Two patients are alive at 2 3/4 and 2 1/2 years after surgical resections. Nodules were found at autopsy in the others. The tumors were well differentiated and, in the androgen-related cases, differed from the others in the following features: canalicular bile retention, mild nuclear atypia, and acinar formation. No mitoses, vascular invasion, or metastatic tumor were evident. The clinical setting was variable; different factors, including iron overload and androgen therapy, played a role in the development of tumor. Although the androgen-related cases showed mild cellular atypia, biologic evidence of malignancy was lacking as in most previous reports.

Malignant rhabdoid tumor of the kidney and soft tissues. Evidence for a diverse morphological and immunocytochemical phenotype.

Three malignant rhabdoid tumors of the kidney and two extrarenal rhabdoid tumors of soft tissues were studied by light and electron microscopy and by immunocytochemistry for the expression of keratin, vimentin, desmin, neurofilament triplet proteins, epithelial membrane antigen, myoglobin, and HNK-1 (Leu-7). Electron microscopy revealed the characteristic cytoplasmic whorled filamentous inclusions in all tumors. An epithelial phenotype (presence of cytoplasmic tonofilaments) was observed in two tumors (one renal and one extrarenal); and a focal primitive neural phenotype (cytoplasmic processes with neurosecretory granules), in a renal rhabdoid tumor. Strands of basal lamina were seen in two renal and one extrarenal rhabdoid tumors. Evaluation of basal lamina was more difficult in the third renal rhabdoid tumor, in which tissue preservation was not optimal. Primitive attachments were present in all rhabdoid tumors. Immunocytochemical staining supported a diverse phenotype, ranging from epithelial and/or mesenchymal to myogenous and/or neuroectodermal. Simultaneous expression of several of the studied antigenic determinants by the same tumor was noted. The findings suggest that both renal and extrarenal rhabdoid tumors express a diverse morphological and immunocytochemical phenotype.

Solitary thyroid nodules in 71 children and adolescents.

Seventy-one children and adolescents with a solitary nodule of the thyroid gland were seen over a 27-year period and all had their nodules removed surgically. All of the patients had preoperative thyroid scintiscans, 55 of which showed a cold nodule. The most common cause of solitary thyroid nodules was follicular adenoma. Fourteen of the 55 cold nodules were malignant (25.5%) while no malignancies were present in warm or hot nodules. Available diagnostic methods for attempting differentiation of benign from malignant solitary nodules are reviewed and recommendations to their clinical management as derived from our experience are presented.

Analysis of a clinically important interaction between phenytoin and Shankhapushpi, an Ayurvedic preparation.

During the course of routine plasma drug level monitoring an unexpected loss of seizure control and reduction in plasma phenytoin levels was noticed in two patients who were also taking 'Shankhapushpi' (SRC), an Ayurvedic preparation. Therefore, the present study was undertaken in rats to investigate any SRC-phenytoin interaction from both pharmacokinetic (serum levels) and pharmacodynamic (electroshock seizure prevention) aspects. Single dose SRC and phenytoin (oral/i.p.) coadministration did not have any effect on plasma phenytoin levels but decreased the antiepileptic activity of phenytoin significantly. On multiple-dose coadministration, SRC reduced not only the antiepileptic activity of phenytoin but also lowered plasma phenytoin levels. SRC itself showed significant antiepileptic activity compared to placebo and is worth further investigation. However, the clinical combination of SRC with phenytoin is not advised.

Compliance monitoring in epileptic patients.

Poor patient compliance is one of the major causes of non responsiveness to antiepileptic drug therapy. Compliance is mostly assessed by self reporting, pill counting and plasma drug level estimation. However, none of them is fool proof. Subtherapeutic plasma drug levels can be due to poor compliance or need for higher dosage. Therefore, in the present study, 20 adult non responsive epileptic patients showing subtherapeutic plasma phenytoin levels inspite of receiving standard phenytoin therapy and history of good compliance were admitted in the clinical pharmacology ward and received supervised drug treatment for five days after which plasma phenytoin levels in 14 patients increased to therapeutic range. All except one (i.e. 9 out of 10) patients showing phenytoin levels < 5 ug/ml inspite of phenytoin dosage of > 300 mg/d and history of good compliance were found to be noncompliant. Hence adult patient receiving greater than or equal to 300 mg/day phenytion and showing phenytoin levels less than or equal to 5 ug/ml should be investigated for possible noncompliance before altering their dosage schedules.

Translocation t(X;11)(q22;q25) in a woman with premature ovarian failure.

Genetic, autoimmune, environmental, iatrogenic, and idiopathic factors are known to cause premature ovarian failure (POF). This report describes an X;11 translocation, t(X;11)(q22;q25), in a woman diagnosed with POF. The FSH level was found to be elevated. Menstrual cycle was regular initially, and she had a spontaneous abortion at the 5th month of gestation at 16 years of age. Her mother was karyotypically normal while her father was not investigated. Male carriers of X;autosome translocations are mostly infertile, and hence the translocation is presumed to be of de novo origin. Fluorescence in situ hybridization using whole chromosome paint probes confirmed the rearrangement.