Vascular C3 deposits on renal biopsy in pediatric patients with hematuria.

Isolated deposition of the third component of complement (C3) in the renal arterioles has been noted on biopsy specimens in patients with hematuria. This entity is of little known significance and reports of this finding in pediatric patients with hematuria are rare. We reviewed the clinical histories and biopsies of 17 children with hematuria and vascular C3 deposition on biopsy at Texas Children's Hospital over an 14-year period. The mean age of presentation was 10.8 (range 4.5-16.6) years with a male preponderance (71%). Family history for hematuria was positive in 6 of 17 patients (35%). Light microscopy was normal or showed only minor abnormalities. Immunofluorescence was negative for IgA and IgG in all patients. Seven patients (41.1%) were noted to have diffuse or focally thin basement membranes on electron microscopy in addition to positive C3 immunofluorescence. The mean follow-up time was 23.8 months, during which 2 of 17 patients (12%) developed worsening proteinuria. The etiopathogenesis of this condition remains unclear, but an underlying immunological process cannot be ruled out. It is possible that this condition represents a stage of an acute glomerulonephritis. Clinical follow-up of these patients is warranted, as the long-term prognosis remains unclear.

Renal tubular dysgenesis in twin-twin transfusion syndrome.

In twin-twin transfusion syndrome (TTTS), the disparity in circulation is reflected in discordant fetal growth, urine output, and amniotic fluid accumulation. The effect of uneven shunting of the growth factor and nutrient-rich vasculature on development and differentiation of the kidney has not been well studied. We analyzed renal tubular growth and differentiation in 25 fetal autopsies with TTTS (13 donors and 12 recipients, including 9 sibling pairs) between 18 and 33 weeks gestation. Immunohistochemical markers for fumarylacetoacetate hydrolase (FAH), Leu-M1, and Lotus tetragonolobus (LTA) were used to identify proximal convoluted tubules, and epithelial membrane antigen (EMA) was used to demonstrate distal convoluted and collecting tubules. FAH appeared to be more specific and reliable than either Leu-M1 or LTA in the identification of proximal tubules. Donors tended to demonstrate a paucity of proximal tubules with crowding of glomeruli characteristic of renal tubular dysgenesis (RTD). The degree of dysgenesis was greater in later gestations and associated with more severe growth restriction. Donors in TTTS are at risk for the development of RTD. Several authors suggest ischemia as the underlying cause of "acquired" RTD. However, in this setting there is no evidence of cell death or necrosis, and we suggest that hypoperfusion leading to decreased glomerular filtration is the underlying etiology, with the severity of RTD related to the degree of shunting.

DNA content of ovarian immature teratomas and malignant germ cell tumors.

OBJECTIVE: Ovarian germ cell tumors (GCT) show greater histologic and biologic heterogeneity than their testicular counterparts and remain poorly understood. Ploidy analysis was performed on ovarian GCT registered on Pediatric Oncology Group germ cell tumor protocols 9048 and 9049 to distinguish biologically distinct subsets of immature teratomas and malignant ovarian germ cell tumors. METHODS: Tumors from 22 patients (mean age 12 years) were analyzed and classified according to the submitting diagnosis; when pure samples of different histologic subtypes within a single tumor were possible, these were analyzed separately. Archival tissue was disaggregated and Feulgen stained; DNA index (DI) was determined by static image analysis utilizing internal normal cells as diploid controls. RESULTS: 26 histologic subtypes from 22 patients were analyzed. The tumors of 18 patients were composed of a single histologic subtype according to the submitting institution, including 6 dysgerminomas, 8 immature teratomas (IT), and 4 endodermal sinus tumors (EST). Two tumors contained both IT and EST components that were separately analyzed. Two tumors were classified as mixed germ cell tumors; 1 showed multiple intermingling subtypes unable to be separately analyzed and the second showed three histologic subtypes separately analyzed (IT, EST, embryonal carcinoma). From a total of 15 malignant histologic GCT subtypes in 14 patients, all but 2 demonstrated a DI of 1.4-2.4 (mean 1.85). Two diploid malignant GCT (1 EST, 1 dysgerminoma) were both associated with gonadoblastoma. Overall, 11 IT subtypes were analyzed and 9 were diploid (2 grade 1, 5 grade 2, and 2 grade 3). Two tumors originally submitted and classified as pure IT (grades 2 and 3) were aneuploid with a dominant diploid and a secondary aneuploid peak (both DI 1.7). On central review, both of these tumors demonstrated the presence of subtle patterns of EST that were unrecognized by the submitting institution and were much too small for separate analysis. Analysis of the 3 patients containing sufficient IT and EST to be separately analyzed all showed a diploid IT component and an aneuploid EST component. CONCLUSIONS: Analysis of ploidy data suggests that polyploidization is a consistent finding in malignant ovarian GCT arising in normal patients, similar to the data for adult testicular GCT. Immature teratomas in this pediatric population, however, are most commonly diploid, regardless of grade. The development of EST within an IT is associated with the development of an aneuploid clone. Therefore, the finding of such a clone in an IT may be of diagnostic utility, as EST may be difficult to recognize. Last, the development of a malignant GCT in patients with gonadal dysgenesis may be pathogenetically different from those arising in normal patients, in that polyploidization is not required.

Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group.

Pediatric germ cell tumors (n = 135) with a major component of immature teratoma (IT) registered on Pediatric Oncology Group/Children's Cancer Group treatment protocols from 1990 to 1995 were reviewed. Sixty cases were pure IT with no malignant component and 75 were mixed tumors with a major component of IT. Foci of yolk sac tumor (YST) were present in all 75 mixed tumors; additional malignant components were present in 15. The IT component was as follows: 47% grade 3, 29% grade 2, 24% grade 1. There were no significant correlations between tumor grade and patient age by specific subsets or overall (all p > 0.10). Significant correlations were detected between stage and the presence of foci of YST (p = 0.0145) and grade and the presence of foci of YST (p < 0.001). Serum alpha-fetoprotein concentrations were elevated at diagnosis in 96% of ovarian tumors with foci of YST and were mildly elevated (< 60 ng/dL) in only 16% of tumors without YST. Overall 2- to 6-year survival rate was 96% and was related to the presence of YST. Central pathologic review revealed aspects of morphologic diagnosis that were most frequently misinterpreted by contributing pathologists. These included the classification of differentiating tissues as immature and the failure to recognize two well-differentiated patterns of YST (the hepatoid pattern resembling fetal liver and the well-differentiated glandular pattern resembling fetal lung or intestine). Such foci were often overlooked. The authors conclude that the presence of microscopic foci of YST, rather than the grade of IT, per se, is the only valid predictor of recurrence in pediatric IT at any site.

Increasing incidence of childhood class V lupus nephritis.

OBJECTIVE: Class V lupus nephritis (LN) is reported to occur in 0-23% of patients with LN. To better characterize pediatric LN, we determined at a single center (1) the relative frequency of Class V LN on first and serial biopsies, (2) the frequency of transformation between LN classes on serial biopsies, (3) types of treatment received and outcome to date of different classes of LN. METHODS: All pediatric renal biopsies from 1985 to the present performed for diagnosis and classification of suspected LN were reviewed. Biopsy results were grouped into 2-3 year time intervals to assess trends in the distribution of WHO class diagnoses over time. RESULTS: Sixty patients underwent 97 renal biopsies. Class V LN was present in 28% (17/60) of patients on first biopsy, and in 37% (22/60) on most recent biopsy. Class V LN on first biopsy increased from 17% (8/46) before 1995 to 64% (9/14) after 1995 (p < 0.001). Age at presentation, age at biopsy, time to biopsy, and types of treatment did not differ before and after 1995. Transformation to Class V LN occurred in 19% (5/27) of patients having repeat biopsies. No transformation from Class V LN occurred on repeat biopsy. Renal outcome was available in 48 patients with followup of 4.7 +/- 3.2 years for Class V LN, and 5.2 +/- 2.4 years for non-Class V LN. Five percent (1/20) of Class V LN patients had renal dysfunction or had died compared to 21% (6/28) of non-Class V LN patients (p = NS). CONCLUSION: We found (1) a greater frequency of Class V LN than has been reported, (2) a recent increase in the incidence of Class V LN at our institution, (3) frequent transformation between classes on serial biopsies, and (4) no regression of Class V lesions in patients who had repeat biopsies.

Germ cell tumors.

Germ cell tumors in children are different from those in adults and often differ from each other in the site of the tumor and the age of the child. The appropriate gross examination and processing of these tumors by pathologists are described, and differences according to site and/or age are highlighted. Useful special studies such as immunohistochemistry and cytogenetics are identified, and the appropriate methods for processing material for these studies are discussed. Handling of small biopsy specimens or fine-needle aspirates is also addressed. Staging of germ cell tumors by site according to Pediatric Oncology Group and Children's Cancer Study Group treatment protocols and the most recent adaptation of grading of immature teratomas are outlined.

Pediatric germ cell tumors: protocol update for pathologists.

The therapy for pediatric germ cell tumors has historically been widely variable and institution dependent. The efforts to provide consistent, biology-driven therapy through Intergroup protocols has been a relatively recent phenomenon that has provided the framework for future protocol designs. The first Intergroup protocols confirmed that stage I malignant testicular germ cell tumors and immature teratomas at all sites in children could be treated with surgery alone followed by close observation. Future protocols currently in the planning stages may extend this low-risk category to stage I ovarian germ cell tumors of all histologic types. Low-stage extragonadal germ cell tumors may be placed in a new intermediate risk category. Particular pathologic issues that were raised and reported during the first protocols and that may impact on future protocol design include the presence and size of foci of endodermal sinus tumors within low-stage immature teratomas at all sites. Accurate staging will grow more critical in future protocols. The ability to recruit international cooperative groups will determine the success of chemotherapy tailored to specific subgroups that now must be lumped for statistical purposes. Lastly, companion biologic studies will be critical to defining the different subtypes of germ cell tumors and to determining predictors of biologic behavior.

Age and ethnicity affect the risk and outcome of focal segmental glomerulosclerosis.

In patients with proteinuria, African-American (AA) ethnicity is reported to be a risk factor for focal segmental glomerulosclereosis (FSGS) and its progression to end-stage renal disease (ESRD). We reviewed our single-center experience to determine the probability of FSGS and its progression to ESRD based on ethnicity and age at presentation in children with proteinuria with or without nephrotic syndrome. Proteinuria without systemic disease or acute glomerulonephritis was the presenting feature in 17% (236/1,403) of children in the renal patient database of Texas Children's Hospital, Baylor College of Medicine. Histopathological diagnoses were established in 107 of 236 patients (45%). FSGS was identified in 65 patients, accounting for 28% of all patients with proteinuria and 61% of patients who underwent renal biopsy. FSGS was more prevalent in AA (45%) than in non-AA patients (22%) (P=0.001), and AA patients with FSGS were older at presentation (12.7+/-4.4 years) than non-AA patients (5.6+/-4.6 years) (P<0.001). Among patients who underwent renal biopsy, increasing age at presentation increased the probability of having FSGS in AA but not non-AA patients (P=0.04). Five-year actuarial renal survival of FSGS was worse in AA (8%) than in non-AA patients (31%) (P=0.01). These data suggest an increased risk and worse outcome of FSGS in AA compared with non-AA children.

Splenogonadal fusion with limb deficiency and micrognathia.

Splenogonadal fusion (SGF) is a rare abnormality with two known types. In the continuous type, the spleen is connected to the gonad, and there are often limb defects, micrognathia, or other congenital malformations such as ventricular septal defect, anal atresia, microgastria, spina bifida, craniosynostosis, thoracopagus, diaphragmatic hernia, hypoplastic lung and abnormal lung fissures, polymicrogyria, deficient coccyx, and bifid spine C6-T3. The discontinuous type is usually not associated with congenital defects, and the gonad that fused with an accessory spleen has no connection with the native spleen. The etiology of SGF is not known. Conceivably, a teratogenic insult occurring between 5 weeks' and 8 weeks' gestation could interfere with the normal development of the spleen, gonads, and limb buds. We describe a case of splenogonadal fusion in a stillborn black boy with associated micrognathia and limb deformities. Also, we review the possible teratogenic etiologies and embryonic basis of SGF.

Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice.

Endothelial selectins mediate rolling of leukocytes on endothelium, a crucial step for leukocyte firm adhesion and emigration into sites of tissue injury and infection. To characterize the role of the endothelial selectins during bacterial sepsis in vivo, Streptococcus pneumoniae (1-10 x 10(6) colony-forming units) was inoculated intraperitoneally into wild-type mice and mice with E-, P-, or E-/P-selectin deficiencies. Mice were followed 10 d for morbidity, survival, clearance of bacteremia, and leukocyte migration to the peritoneal cavity and organs 48 h after infection. All selectin-deficient mice showed a more pronounced morbidity, a significantly higher mortality associated with persistent bacteremia, and a higher bacterial load when compared with wild-type mice. These differences were most remarkable in the E-selectin-deficient mice, which showed the highest rate of mortality and bacteremia (P

Deletion of chromosome 22q11 and pseudohypoparathyroidism.

A newborn boy with complex congenital heart disease, unilateral renal agenesis, and hypocalcemia was found to have a submicroscopic deletion of 22q11.2 (DiGeorge anomaly). In evaluating the pathogenesis of the hypocalcemia, repeatedly elevated or normal levels of parathyroid hormone were found, consistent with a diagnosis of pseudohypoparathyroidism. Pseudohypoparathyroidism can be due to mutation of a GTP binding protein (Gs-alpha protein) located on chromosome 20. Since there is another G protein locus (Gz alpha) adjacent to the DiGeorge critical region of chromosome 22, we hypothesized that a more extensive deletion may lead to pseudohypoparathyroidism. Fluorescence in situ hybridization was performed using a probe containing the Gz alpha gene, but no deletion was detected. This patient emphasizes the importance of determining the pathogenesis of the hypocalcemia in cases of DiGeorge anomaly.

Anti-CD11b monoclonal antibody in an infant rat model of Haemophilus influenzae type b sepsis and meningitis.

Five-day-old infant rats were injected intraperitoneally (i.p.) with anti-CD11b monoclonal antibody (1 B6) at a dose of 2 mg/kg or phosphate-buffered saline (PBS) either 1 h before or 3 or 24 h after inoculation with 10(5) cfu Haemophilus influenzae type b (Hib). When administered 1 h before infection, 23% of the 1B6- versus 17% of the PBS-treated rats and 87% of the 1B6- versus 83% of the PBS-treated animals died at 24 and 48 h, respectively. There was a similar mortality for 1B6 or PBS treatment at 3 h after infection. Thirteen of 15 (87%) 1B6 animals versus 16/17 (94%) PBS animals had positive CSF cultures at 48 h. No differences in mortality were observed in separate experiments where animals received 1B6 or PBS 3 or 24 h after infection with Hib and were treated with a single ampicillin dose (100 mg/kg) 24 h after infection. The median CSF white blood cell count/mm3 was 5627 and 4860 for the animals with meningitis receiving 1B6 and PBS, respectively, although the 1B6-treated animals had a lower percentage of polymorphonuclear cells in the CSF (P = 0.05). Histologic examination of the meninges, choroid plexus and cochlea showed a slight decrease in the numbers of inflammatory cells in animals treated with 1B6. 1B6 did not change the incidence of meningitis and only slightly decreased the degree of inflammation within the central nervous system, although animals treated with 1B6 have an altered CSF leucocyte response with the presence of more mononuclear cells as opposed to polymorphonuclear cells in their CSF. 1B6 may play a role in inhibiting neutrophil emigration to sites of inflammation within the central nervous system but is not beneficial in decreasing mortality in an infant rat model of H. influenzae type b sepsis and meningitis.

Renal function following cardiac arrest and resuscitation in the canine.

Organ malfunction often occurs following cardiac arrest and resuscitation. Renal function, inulin clearance (Cln), was examined in 27 dogs before and after (days 2, 4, and 6) cardiac arrest and resuscitation. Group A (n = 7) had no ventricular fibrillation (VF), but cardiopulmonary support was applied for 20 min, and three transthoracic countershocks were delivered. In groups B (n = 7), C (n = 7), and D (n = 6) VF was induced for 2.5, 5.0, and 7.5 min, respectively, followed by cardiopulmonary support for 20, 20, and 15 min, respectively. When necessary, epinephrine and sodium bicarbonate were given during resuscitation. Countershock was applied for defibrillation. Kidneys were examined histologically in groups C and D. Following cardiac arrest, Cln was significantly less in the arrested groups compared to the nonarrested group. Within group C, which received the most epinephrine, Cln correlated negatively with epinephrine administration, and with the energy applied for defibrillation. Histologically, group C showed the highest incidence of cortical tubular cytoplasmic vacuolization, regeneration, inflammation, and tubular casts. Groups C and D showed outer medullary tubular cytoplasmic vacuolization, renal vascular changes, and calcification. In conclusion, cardiac arrest and resuscitation may precipitate acute renal hypofunction as well as reversible and irreversible morphological changes in normal functioning canine kidneys. The confounding effect of pre-existing renal disease remains to be examined experimentally.

Host defenses against disseminated candidiasis are impaired in intercellular adhesion molecule 1-deficient mice.

Genetically engineered mice, which lack normal expression of intercellular adhesion molecule 1 (ICAM-1), were used to study the role of ICAM-1 in the host defense against disseminated candidiasis. The responses of ICAM-1-deficient mice and normal wild type mice were compared following an intravenous challenge with Candida albicans. ICAM-1-deficient mice lost more weight (P < .001) and had a significantly higher mortality (P < .001). Quantitative cultures revealed a greater tissue fungal burden in ICAM-1-deficient mice compared with normal mice, in both the kidney (P < .001) and the brain (P = .007). Extensive inflammation, composed primarily of histiocytes admixed with lymphocytes and occasional neutrophils, was present in the renal tissue of ICAM-1-deficient mice; this contrasted with a more localized and predominantly neutrophilic infiltrate in normal mice. This work suggests that the loss of ICAM-1 significantly impairs host defense against C. albicans, by impairing either neutrophil migration or phagocyte activation or both.

Infant cardiac fibroma with clonal t(1;9)(q32;q22) and review of benign fibrous tissue cytogenetics.

Cardiac fibromas are rare lesions which occur more frequently in infants and children than in the adult population. These tumors are nonmalignant proliferations of connective tissue most often found in the left ventricular myocardium or septal myocardium. No cytogenetic studies of cardiac fibromas have been reported. We report a case of an infant with a subepicardial tumor in whom the cytogenetic analysis showed a clonal reciprocal translocation, 46,XY,t(1;9)(q32;q22),inv(9)(p11q12)c. We review the literature regarding cardiac fibromas and briefly discuss the cytogenetics of benign fibrous neoplasias.

Malignant melanoma of soft parts involving the head and neck region: review of literature and case report.

Malignant melanoma of soft parts (MMSP) was originally described as a distinct entity by Enzinger in 1965 and was termed "clear cell sarcoma of tendons and aponeuroses" because of its association with tenosynovial structures. It has been shown immunophenotypically and ultrastructurally that this tumor is derived from neuroectoderm and shares a number of features with cutaneous melanoma. Over 95% of MMSPs present in the extremities, with the head and neck region (1.9%) being an unusual site. This study presents an additional case of MMSP of the head and neck region involving the posterior cervical region in a 15-year-old Hispanic male and reviews the literature on MMSP. Ultrastructural examination showed rudimentary cell attachments, smooth cell membranes, discontinuous basal lamina, scanty glycogen, and occasional premelanosomes in some tumor cells. Cytogenetic analysis showed a reciprocal translocation between the long arms of chromosomes 12 and 22 [t(12:22)(q13;q12.2)], characteristic for MMSP and not seen in cutaneous melanoma. Survival in MMSP has been correlated with tumor size, tumor necrosis, and ploidy status. Overall reported clinical outcome for this tumor is as follows: died of disease, 45%; alive with disease, 23%; no evidence of disease, 30%; and died of other causes, 2%. MMSP represents a distinct entity with a characteristic ultrastructural appearance and a tumor defining cytogenetic translocation.