Douglas A. Weeks

Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognostic significance: a report from the National Wilms Tumor Study Group.

Anaplasia, defined by the presence of extreme nuclear and mitotic atypia, is a potent marker of adverse prognosis in Wilms tumor (WT). Anaplastic WT cells apparently have increased resistance to therapy rather than increased aggressiveness. The distribution of anaplasia should therefore have critical prognostic relevance. The original definitions for focal anaplasia (FA) and diffuse anaplasia (DA) were based on quantitative rather than topographical criteria and lacked prognostic significance. A new definition was developed based on the distribution of anaplastic changes within the tumor: FA applies only to tumors with anaplasia confined to one or a few discrete loci within the primary tumor, with no anaplasia or marked nuclear atypia elsewhere. This revised definition was evaluated in 165 cases with anaplastic WT entered on the third and fourth National Wilms Tumor Study. Only three relapses and one death occurred among 39 cases with FA, regardless of tumor stage, a result comparable to that for nonanaplastic WT. Eight children with metastases at diagnosis and FA in the primary tumor were alive and free of relapse; 22 of 23 children with stage IV DA WT died of tumor. This new definition reinforces the importance of carefully documenting the exact site from which each tumor section is obtained.

Hepatic Angiomyolipoma with Striated Granules and Positivity with Melanoma-Specific Antibody (HMB-45): A Report of Two Cases

Angiomyolipoma occurs rarely in the liver, with only 25 previous cases being reported in the English literature. The article describes two additional cases, one of which was multicentric, with results of ultrastructural and immunocytochemical studies. Many of the tumor cells contained numerous electron-dense granules, some with transverse striations like those found in melanosomes. Both tumors stained positively for S-100 protein and melanoma-specific antibody HMB-45. One case also expressed vimentin and neuron-specific enolase. Both were negative for cytokeratin, carcinoembryonic antigen, alpha-fetoprotein, desmin, muscle-specific actin, factor VIII antigen, and chromogranin. Comparison of our ultrastructural findings with those of classic renal angiomyolipoma raises the possibility that the melanosomelike structures may represent renin granules rather than melanosomes, although the latter are not excluded. Expression of HMB-45 in angiomyolipoma has important biologic and diagnostic implications, whether or not it reflects melanocytic differentiation.

Hypertension After Neonatal Uninephrectomy in Rats Precedes Glomerular Damage

The present study was designed to determine whether adult hypertension caused by a reduced number of nephrons from birth is due to preceding glomerular damage. Newborn male Sprague-Dawley rat pups were uninephrectomized during the first 24 hours after birth (UNX rats). At 20 weeks of age, chronically instrumented UNX animals were hypertensive on a normal-sodium (0.20%) diet compared with sham-operated controls (142±2 versus 124±2 mm Hg in controls). Body weights and the total kidney-to–body weight ratio were not significantly different in adult UNX animals compared with controls. Glomerular filtration rate (GFR) was reduced by 49% in UNX rats (1.85±0.24 versus 3.65±0.22 mL/min). Urine protein excretions were higher in UNX rats (20±2 versus 7±1 mg/d in controls). On a high-sodium (3.15%) diet, arterial pressure increased more in UNX than in controls (28±9 versus 3±1 mm Hg). In contrast, in animals studied at 8 weeks of age, GFR was only reduced by 26% in UNX animals (2.02±0.06 versus 2.73±0.07 mL/min). Their hypertension (125±2 versus 117±2 mm Hg) was also salt sensitive (increase on high-sodium diet of 35±11 versus 8±2 mm Hg in controls) but was not associated with proteinuria or histological signs of glomerular disease. Number of glomeruli per kidney in UNX animals was not different from controls, but individual glomerular volume increased by 41%. Thus, surgical removal of 50% of the nephrons, when done during development, causes reduced renal function and salt-sensitive hypertension in adulthood. Hypertension is present earlier in life than signs of glomerular disease, which suggests that hypertension is a major contributor to rather than primarily resulting from onset of renal disease.

Ultrastructure and Histogenesis of the Renal Tumors of Childhood: An Overview

This review discusses the ultrastructural and immunohistochemical features of the common childhood renal tumors, with an emphasis on their diagnostic usefulness. Speculations regarding their histogenesis also are presented, with the hope that these may serve to diminish some of the confusion surrounding the classification of these morphologically diverse lesions.

Treatment of Wilms tumor relapsing after initial treatment with vincristine and actinomycin D: A report from the National Wilms Tumor Study Group

NWTS‐5 was a multi‐institutional clinical trial for patients less than 16 years of age at diagnosis with specific renal neoplasms who were diagnosed between August 1, 1995 and May 31, 2002. A uniform approach to the treatment of patients with relapse was employed.

Long-term outcomes for infants with very low risk wilms tumor treated with surgery alone in national wilms tumor study-5

Objective:To determine the event-free survival (EFS) and overall survival (OS) of children with very low risk Wilms tumor (VLRWT) treated with surgery only. Background:Previous studies suggested that postoperative chemotherapy had not improved the prognosis of children with VLRWT. A total of 77 children <24 months of age with small (<550 g) Stage I favorable histology Wilms tumors were treated with surgery only. This study was closed based on stopping rules to ensure that the 2-year EFS was ≥90%. Methods:A total of 77 children were assessed for EFS and OS. Of these patients, 21 enrolled at the time of closure were recalled, treated with dactinomycin and vincristine (regimen EE4A), and censored for analysis thereafter. About 111 children subsequently treated with EE4A were available for comparison. Results:Median follow-up of surviving patients was 8.2 years for surgery only (range, 1.9–11.8 years) and 5.2 years for the EE4A group (range, 1.6–8.9 years). The estimated 5-year EFS for surgery only was 84% (95% confidence interval [CI]: 73%, 91%); for the EE4A patients it was 97% (95% CI: 92%, 99%, P = 0.002). One death was observed in each treatment group. The estimated 5-year OS was 98% (95% CI: 87%, 99%) for surgery only and 99% (95% CI: 94%, 99%) for EE4A (P = 0.70). Conclusion:The surgery-only EFS was lower than anticipated but, coupled with a much higher than anticipated salvage rate of the chemotherapy naive patients whose disease recurred, led to an observed long-term OS equivalent to that seen with 2-drug chemotherapy. This approach to the treatment of patients with VLRWT eliminates the toxic side-effects of chemotherapy for a large majority of patients. A follow-up study is underway to confirm these findings.

Primary Leiomyosarcoma of Brain in an Adolescent with Common Variable Immunodeficiency Syndrome

A 14-year-old girl with common variable immunodeficiency syndrome was found to have a low-grade malignant neoplasm arising in the left temporal lobe of the brain. Ultrastructural and immunohistochemical studies established a diagnosis of leiomyosarcoma, despite the rarity of this tumor in children. In situ hybridization with the EBER probe revealed essentially all of the neoplastic cells to be infected with Epstein-Barr virus (EBV). Children with the acquired immunodeficiency syndrome (AIDS) are known to exhibit an increased incidence of smooth muscle tumors associated with EBV. Similar tumors have been reported in EBV-infected patients undergoing therapeutic immunosuppression. This appears to be the first reported case of childhood leiomyosarcoma where the cause of the underlying immunodeficiency was a genetic rather than acquired disorder. The authors conclude that electron microscopy, immunohistochemistry, and other ancillary techniques are essential in the evaluation of unusual tumors in immunocompromised children, whether the cause is hereditary or acquired.

Meningioma with Chordoid Features

Meningioma is a relatively common intracranial tumor, occurring most frequently in adults, and is capable of a wide variety of growth patterns. We describe a meningioma in a child that had a peculiar chordomalike appearance. The pathologic findings and distinction from chordoma are discussed.

Ependymoma with signet-ring cells.

Two patients presented with unusual primary brain tumors having abundant signet-ring cells, for which electron microscopic study was necessary to establish the diagnosis of ependymoma. The light and electron microscopic features of these tumors are discussed, with brief comments on the differential diagnosis.

Naturally occurring intrauterine growth retardation and adult blood pressure in rats.

In humans, infants who are born small have been reported to have higher blood pressure in adulthood than do larger infants. This suggests that factors in the intrauterine environment that affect fetal growth can program the individual for hypertension later in life. The present study determined whether there is a similar, naturally occurring relationship between birth weight and adult blood pressure in rats. Female Sprague-Dawley rats bred in our colony were fed a normal diet during pregnancy. On the day of delivery, any pups that weighed <90% of the mean pup weight for the litter were identified as runts. For each runt, a sex-matched littermate of normal weight was also identified and assigned to this study. These pairs were chronically instrumented at ∼20 wk of age. Mean arterial pressure was significantly higher in runt male and female offspring compared with their normal birth weight littermates (males: 149 ± 7, runts versus 129 ± 4 mm Hg, controls; females: 128 ± 1, runts versus 119 ± 2 mm Hg, controls). Although the runts had smaller body weights at study than did their littermate controls, the kidney-to-body weight ratio and renal function normalized to kidney or body weight were not different. These studies indicate that adult blood pressure is related to birth weight in rats, as it is in humans. The relative hypertension in runt animals is not due to gross differences in renal function but may be related to more subtle renal structural and/or functional differences.