Cellular localization of the folate receptor: potential role in drug toxicity and folate homeostasis.

In the past year, gp38, a glycosyl-phosphatidylinositol linked membrane protein that is overexpressed in some malignant tissues, has been shown to be the folate receptor. Using immunohistochemical techniques with the monoclonal antibody MOv19 against gp38, we evaluated the cellular localization of folate receptors in normal human tissues, which are potential target sites for drugs that utilize this uptake mechanism. The choroid plexus was intensely positive with staining limited to the epithelium, which in some foci had a distinct bilaminar pattern limited to the luminal and basal surfaces. The epithelium of the fallopian tube, uterus, and epididymis was highly immunoreactive. The acinar cells of the breast, submandibular salivary, and bronchial glands also showed intense staining as did the trophoblastic cells of the placenta. In the kidney reactivity was localized to the proximal tubules. Lung alveolar lining including type I and II pneumocytes stained intensely. Limited but focal reactivity was noted in the vas deferens, ovary, thyroid, and pancreas. This study in conjunction with previous work showing marked overexpression of folate receptor in some malignant cells suggests that the folate receptor may be an important target for diagnostic or therapeutic exploitation and indicates sites of potential drug toxicity.

Fetal hypokinesia syndrome in the monochorionic pair of a triplet pregnancy secondary to severe disruptive cerebral injury.

We report a set of triplets, two of whom were monochorionic diamnionic and demonstrated cerebellar hypoplasia and progressive arthrogryposis on an antenatal sonogram. At delivery the infants exhibited a Pena-Shokier phenotype. At autopsy, the twins were concordant for severe disruptive lesions of the cerebrum. The mechanism resulting in the devastating symmetric lesions may have been a transient cerebral vascular compromise associated with placenta vascular anastomoses characteristic of monochorionic twinning. This report accentuates the vulnerability of the monochorionic twin for ischemic cerebral injury.

Fatal Haemophilus influenzae endocarditis diagnosed by echocardiography in an infant.

A 1-year-old boy was admitted to the hospital with Haemophilus influenzae meningitis. On the second hospital day a heart murmur heard on admission seemed louder. No signs of congestive heart failure were present. An echocardiogram demonstrated a persistent echo-dense mass behind the anterior leaflet of the mitral valve. A presumptive diagnosis of endocarditis was made. After ten days of antibiotic treatment the child was considerably improved. Treatment was continued for endocarditis. Over the next several days the infant's condition deteriorated. On the 16th hospital day he died. Autopsy examination showed a large vegetation attached to the posterior mitral valve leaflet. Bacterial endocarditis caused by H influenzae is uncommon at any age and rare in children. Echocardiography provided a definitive diagnosis early in the hospital course of this patient.

Juvenile chronic myelogenous leukemia: surface antigen phenotyping by monoclonal antibodies and cytogenetic studies.

Cells from three children with juvenile chronic myelogenous leukemia were studied using culture in semisolid media, cytogenetic analysis, and surface staining with the monocyte-specific monoclonal antibodies 61D3 and 63D3. The percentage of bone marrow mononuclear cells that were 61D3- and 63D3-positive was markedly increased in all three patients. Bone marrow and peripheral blood mononuclear cells exhibited exceptionally bright immunofluorescence with these antibodies. The presence of monocyte-specific antigens on the surface of juvenile chronic myelogenous leukemia cells suggests that they are derived from a precursor with monocytic characteristics. A specific chromosomal abnormality (47,XY+21) was present in fresh bone marrow cells from one patient; in contrast, 50 metaphases from phytohemagglutinin-stimulated peripheral blood contained a normal karyotype. The chromosomal abnormality was also identified in myeloid colonies grown in vitro from this patient. Granulocytic elements were demonstrated in tissue sections and in cultured myeloid colonies from this child. Our data suggest that malignant transformation in juvenile chronic myelogenous leukemia involves a myeloid progenitor population capable of differentiation in vitro to cells with monocytic or granulocytic characteristics.

Keratitis, hepatitis, ichthyosis, and deafness: report and review of KID syndrome.

A 14-year-old girl with ichthyosis and severe liver disease is compared to 35 reported cases of KID or Senter syndrome. Common manifestations such as ichthyosis (35/35 patients), sensorineural deafness (33/34), "ectodermal dysplasia" (25/28), corneal abnormality (26/31) were present in the proposita, while less common manifestations such as chronic infections (15/20) and neuromuscular disease (12/35) were absent. Two families with vertical transmission and 28 sporadic cases are compatible with an autosomal dominant form of KID syndrome, while one inbred sibship with liver disease suggests the existence of an autosomal recessive form. The proposita was similar to the latter patients in having progressive cirrhosis necessitating liver transplantation; she also had short stature (10/35 patients) and mental retardation (3/35). Hepatic findings included micronodular cirrhosis, cholestasis, hyperplastic Kupffer cells, abundant Mallory's hyaline, copper accumulation without steatosis, and normal peroxisomes.

Renal-hepatic-pancreatic dysplasia: a syndrome reconsidered.

Five infants, three dying neonatally and two later in the first year of life, had renal, hepatic, and pancreatic dysplasia, a combination of abnormalities first described by Ivemark et al [1959]. The renal malformation consisted of cystic dysplasia, with abnormally differentiated ducts, deficient nephron differentiation, and glomerular cysts. The hepatic abnormality consisted of enlarged portal areas containing numerous elongated biliary "profiles," with a tendency to perilobular fibrosis. Serial liver biopsies in one child with cholestasis from birth showed a progression from bile duct paucity at 1 1/2 wk to typical biliary "dysgenesis" at 7 mo. Four of the five children had intrahepatic ductal dilatation, diagnosed ante mortem in the two older children as Caroli disease. The pancreatic abnormality consisted of fibrosis and cysts, with a diminution of parenchymal tissue. The clinical and functional reflection of these abnormalities in the two children surviving the newborn period included renal insufficiency, chronic jaundice, and insulin-dependent diabetes mellitus. Similar renal, hepatic, and pancreatic abnormalities occur in other syndromes, including trisomy 9, Meckel syndrome, Jeune, Saldino-Noonan, and Elejalde types of chondrodysplasia, and glutaric aciduria II. After exclusion of identifiable syndromes, the remaining cases of renal-hepatic-pancreatic dysplasia do not necessarily constitute a homogeneous group.

Primary hepatic tumors of childhood.

A clinicopathologic review of 73 cases of primary liver tumors at Texas Children's Hospital, Houston, and Children's Medical Center, Dallas, has documented important prognostic and therapeutic implications for the histologic classification of hepatoblastoma. The pure "fetal" pattern was associated with cure in every instance that surgical excision was achieved (six of six patients), whereas only two of 19 patients with "embryonal" or other undifferentiated patterns of growth survived five years. The relationship of hepatoblastoma and hepatocarcinoma in childhood to antecedent conditions is discussed in detail. The uncommon liver sarcomas are also reviewed in the light of experience at these two institutions.

Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children.

An unusual and highly malignant childhood renal tumor has been noted among the specimens of the National Wilms' Tumor Study. Prominent nucleoli, PAS positive cytoplasmic inclusions, and light microscopic features suggestive of rhabdomyoblastic differentiation are hallmarks of this tumor. Ultrastructural examination of 11 specimens revealed the filamentous.

Molecular abnormalities associated with secretory carcinomas of the breast.

Secretory carcinomas (SCAs) represent a unique histological variant of invasive breast carcinomas, occurring predominantly in patients younger than 30 years of age. Data from limited series have shown SCAs to have a favorable prognosis in patients younger than 20 years of age, whereas the clinical course tends to parallel the more common in filtrating ductal carcinomas (IDCs) in patients older than 20 years. There are no reports on the molecular abnormalities associated with this unusual tumor. Microdissected archival formalin-fixed tissue from 10 SCAs collected from 2 institutions were used to determine the frequencies of allelic loss at 13 chromosomal regions with 19 microsatellite markers, using multiplex polymerase chain reaction (PCR)-based techniques. The results of loss of heterozygosity (LOH) and microsatellite alterations (MAs) analyses were compared with 20 cases of IDCs. P53 gene mutation analysis was also performed on the 10 SCAs using single-strand conformation polymorphism (SSCP) analysis, followed by sequencing of abnormal bands. LOH at multiple regions of chromosome 3p were the most common abnormality in both SCAs (55%) and IDCs (50%), followed by LOH at 17q21 (BRCA1 locus), 13q14 (retinoblastoma gene locus), and 8p21-23. No significant differences were seen in the frequencies of LOH at any chromosomal region except for 17p13 (p53 gene locus), where allelic losses were absent in SCAs, but evident in 46% of IDCs (P < .05). The 2 histological entities were similar in the fractional regional loss (FRL) index (0.26 v 0.24), fractional allelic loss (FAL) index (0.23 v 0.27), as well as in the frequency of MAs (0.015 v 0.005), P > .05. P53 gene missense mutation (G:C::A:T) was detected in 1 of 10(10%) SCAs. Based on the considerable similarities in the molecular abnormalities associated with both tumors, the formation of secondary lumina in both the in situ and the invasive components, as well as suggestions from limited series that the clinical behavior in adult patients parallels that of IDCs, SCA most likely reflects a secretory variant of IDCs.

Urine screen for bacteriuria in symptomatic pediatric outpatients.

A retrospective review of 1019 symptomatic pediatric outpatients compared urine dipstick including leukocyte esterase and nitrite to semiquantitative Gram-stained smear of uncentrifuged urine for the identification of specimens that contained greater than or equal to 10(5) organisms/ml as determined by semiquantitative urine cultures. The Gram-stained smear was slightly more sensitive than the dipstick; 97.6% (any microorganisms seen or greater than or equal to 2 organisms/oil immersion field) vs. 90.2% (either leukocyte esterase- or nitrite-positive). The negative predictive value of both screening methods was excellent (99.9 and 99.6%, respectively). The predictive value of a positive screen was low for both methods although the predictive value of a positive screen of the Gram-stained smear did reach 63% when there were greater than or equal to 5 organisms/oil immersion field. Neither method of urine screen should substitute for a urine culture in the symptomatic outpatient. However, the urine dipstick test is a reasonable alternative to a Gram-stained smear for initial patient assessment.

Bilateral nephromegaly and multiple pulmonary cysts.

A newborn female infant with marked bilateral renal enlargement resulting from an absolute increase in renal parenchymal mass is described. The number of renal lobes was increased and there was persistent subcapsular glomerulogenesis. In addition, the lungs manifested delayed maturation and contained multiple small cysts. Although the renal growth disturbance resembled that sometimes found in hemihypertrophy and the Beckwith syndrome, the associated pulmonary lesions and the absence of other anomalies make this patient distinctive.

Acute megakaryoblastic leukemia simulating carcinoma.

Acute megakaryoblastic leukemia has emerged as an important subset of early childhood leukemia. It often presents a diagnostic dilemma because of its many morphologic manifestations and propensity to mimic metastatic carcinoma. An abdominal mass was identified by sonographic and computed tomographic scans in a 10-month-old girl, who had anemia and thrombocytopenia. An open biopsy of the 3-cm, peripancreatic mass showed cohesive nests and sheets of tumor cells with focal spindling and desmoplasia. Although the diagnosis of acute megakaryoblastic leukemia was established from a bone marrow aspirate using immunocytochemical techniques and karyotype analysis, a coexistent abdominal epithelial malignant neoplasm could not be excluded entirely by light microscopic examination alone. The megakaryoblastic nature of the abdominal tumor was established by immunocytochemical stains for glycoprotein IIIa on paraffin-embedded tissue.

Catecholamine fluorescence and tissue culture morphology. Technics in the diagnosis of neuroblastoma.

Neuroblastoma is often confused histologically with other small round cell tumors such as Ewing's sarcoma, acute lymphocytic leukemia, lymphoma, and oat cell carcinoma, particularly at metastatic sites. Studies were performed to evaluate glyoxylic acid-induced catecholamine fluorescence as a rapid method for identifying neuroblastoma cells in biopsy specimens. The morphology of tumor explants in tissue culture was also evaluated for use as a diagnostic aid. Eighteen neuroblastomas were stained for catecholamines; 78% showed specific catecholamine fluorescence. Two ganglioneurons and a pheochromocytoma also showed positive catecholamine fluorescence. All 20 neuroblastomas placed in tissue culture demonstrated neurite outgrowth, a property that distinguishes neuroblastoma from other small round cell neoplasms. Seventeen nonneuroblastoma tumors displayed neither specific fluorescence nor neurite outgrowth. The ability of these two technics to identify neuroblastoma was compared with routine histology, urinary vanillylmandelic acid (VMA) spot tests, quantitative urinary VMA and catecholamine assays, and electron microscopy. Only electron microscopy was as sensitive as fluorescence and morphology in culture. The fluorescence method is rapid and simple and provides a valuable tumor marker when positive. Neurite outgrowth in cell culture and electron microscopy, although more time-consuming, were the most sensitive of all the diagnostic methods evaluated.

Precursor B-cell lymphoblastic lymphoma. A study of nine cases lacking blood and bone marrow involvement and review of the literature.

We describe 9 cases of precursor B-cell lymphoblastic lymphoma (LYL) without evidence of marrow or blood involvement. Four patients had superficial nodal disease, 2 cutaneous involvement, and 1 each ovarian, retroperitoneal, or tonsillar primary tumor. Six patients had limited disease; 3 patients were stage III. Immunophenotyping revealed a terminal deoxynucleotidyl transferase (TdT)-positive, immature B-cell population with variable expression of CD10, CD20, and CD45. All patients are in complete clinical remission (median follow-up, 14 months). A literature review yielded 105 patients with a diagnosis of precursor B-cell LYL based on less than 25% marrow involvement. Of these, 64% were younger than 18 years. Skin, lymph nodes, and bone were the most common sites of disease. Mediastinal involvement was uncommon. TdT, CD19, CD79a, CD10, and HLA-DR were the most frequently expressed antigens, while CD45 and CD20 were expressed in only two thirds of the cases. Cytogenetic analysis showed additional 21q material as a recurring karyotypic abnormality. At a median follow-up of 26 months, 74% of patients were alive; the median survival was 19 months for patients dying of disease. Comparison with precursor B-cell acute lymphoblastic leukemia showed several overlapping features, although distinct differences were identified.

Allergic aspergillosis: a newly recognized form of sinusitis in the pediatric population.

In 1983, Katzenstein, et al. first described a form of noninvasive sinusitis in adults, which was histologically identical to allergic bronchopulmonary aspergillosis, with mucin-containing eosinophils, Charcot-Leyden crystals, and fungal elements resembling Aspergillus species. The authors have treated six pediatric patients ages 8 to 16 who had findings typical of allergic Aspergillus sinusitis. All patients presented with nasal polyposis and progressive facial deformity. All patients had computed tomography findings of diffuse expansile sinus disease and four patients had evidence of bony erosion, raising the suspicion of malignancy. At surgery, all were found to have multiple sinuses densely packed with greenish-black inspissated mucin. Therapy consisted of wide surgical drainage with careful follow-up and nasal steroids.

Giant cell transformation cerebrohepatorenal syndrome.

An infant with cerebrohepatorenal syndrome of Zellweger had extensive hepatic giant cell transformation at 6 1/2 weeks of age. At 16 weeks the liver showed early cirrhosis and rare giant cells. Changes previously described have ranged from no abnormality in the neonate to cirrhosis at 20 weeks of age and indicate progression of liver disease in affected patients.

Botryoid Wilms' tumor of the renal pelvis.

We studied a unique example of Wilms' tumor consisting entirely of a polypoid intrapelvic renal mass. Despite a gross appearance akin to sarcoma botryoides, this and related examples of Wilms' tumor with intrapelvic growth should be treated no differently from ordinary Wilms' tumors of similar stage and grade.

Aberrant expression of tumor suppressor proteins in the Ewing family of tumors.

BACKGROUND: Deregulation of tumor suppressor gene function and abrogation of cell cycle control are common features of malignant neoplasms, but corresponding data on Ewing sarcomas and primitive neuroectodermal tumors are relatively scarce. We studied the expression of 4 tumor suppressor proteins in the Ewing family of tumors (EFTs). DESIGN: We examined a series of 20 pediatric EFTs for abnormal expression of p16(INK4a), p14(ARF), p21(WAF1), and pRB by immunohistochemical analysis of pretreatment, nondecalcified archival specimens. Clinical follow up was available in all cases (median, 21 months; range, 5-103 months). Five patients presented with metastatic disease, 8 had no evidence of disease at last follow up, and 12 had an adverse outcome (death or progressive tumor posttherapy). RESULTS: Twelve cases (60%) demonstrated abnormal expression of at least one tumor suppressor protein. There were 11 cases (55%) with loss of p21(WAF1) expression, 4 (20%) with down-regulation of p16(INK4a), 2 (10%) with absence of pRB, and one case (5%) with loss of p14(ARF) expression. Loss of p16(INK4a) expression correlated with metastatic disease at presentation (P =.026), and showed a trend toward shortened survival (P =.20). The p21(WAF1), p14(ARF), and pRB status was not significantly correlated with either metastatic disease at presentation or outcome. CONCLUSION: Abrogation of the G1 checkpoint was common in this series of EFTs, and down-regulation of p21(WAF1) and p16(INK4a) were the most frequent findings. Loss of p16(INK4a) expression may identify a subset of cases with a more aggressive phenotype.

Vaterite otoconia in two cases of otoconial membrane dysplasia.

Scanning electron microscopy, electron microprobe analysis, and x-ray powder diffraction were used to study temporal bone specimens obtained at autopsy from an infant with Potter syndrome and from a second trimester fetus, which was the product of an elective abortion. The mothers of both the infant and fetus were juvenile-onset rheumatoid arthritis patients who took prostaglandin inhibitors during pregnancy. The infant's external ears were low set and the left ear canal was stenotic. The vestibular maculae on the left were covered by aberrant otoconia composed of vaterite. In the right inner ear, otoconia were entirely absent, although the gelatinous otoconial membranes were intact. Only the left saccule and right utricle from the fetus were studied; both contained vaterite crystals similar to those in the infant. In addition, apatite was present in the fetal utricle, apparently lying on the macula beneath the vaterite otoconia.