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PURPOSE: Children younger than 24 months with small (< 550 g), favorable histology (FH) Wilms tumors (WTs) were shown in a pilot study to have an excellent prognosis when treated with nephrectomy only. PATIENTS AND METHODS: A study of nephrectomy only for the tratment of selected children with FH WT was undertaken. Stringent stopping rules were designed to insure closure of the study if the true 2-year relapse-free survival rate was 90% or lower. RESULTS: Seventy-five previously untreated children younger than 24 months with stage I/FH WTs for which the surgical specimen weighed less than 550 g were treated with nephrectomy only. Three patients developed metachronous, contralateral WT 1.1, 1.4, and 2.3 years after nephrectomy, and eight patients relapsed 0.3 to 1.05 years after diagnosis (median, 0.4 years; mean, 0.51 years). The sites of relapse were lung (n = 5) and operative bed (n = 3). The 2-year disease-free (relapse and metachronous contralateral WT) survival rate was 86.5%. The 2-year survival rate is 100% with a median follow-up of 2.84 years. The 2-year disease-free survival rate (excluding metachronous contralateral WT) was 89.2%, and the 2-year cumulative risk of metachronous contralateral WT was 3.1%. CONCLUSION: Children younger than 24 months treated with nephrectomy only for a stage I/FH WT that weighed less than 550 g had a risk of relapse, including the development of metachronous contralateral WT, of 13.5% 2 years after diagnosis. All patients who experienced relapse on this trial are alive at this time. This approach will be re-evaluated in a clinical trial using a less conservative stopping rule.

We report 31 cases of a novel pediatric renal neoplasm, metanephric stromal tumor (MST). Mean patient age was 2 years, and the most common presentation was that of an abdominal mass. Gross examination typically revealed a fibrous lesion centered in the renal medulla containing smooth-walled cysts (mean tumor size, 5.5 cm). MST is histologically identical to the stromal component of metanephric adenofibroma (MAF, previously termed nephrogenic adenofibroma) and is an unencapsulated spindle cell lesion that entraps native kidney. Characteristic histologic features of MST include alternating cellularity that imparts a nodular low-power appearance, onion-skin cuffing around entrapped renal tubules, heterologous differentiation (glia or cartilage), and vascular alterations (angiodysplasia of entrapped arterioles, juxtaglomerular cell hyperplasia in entrapped glomeruli). Three tumors in which the vascular alterations were particularly florid were associated with extrarenal vasculopathy and attendant morbidity. A majority of cases stained for CD34, although the degree of staining was variable. Most patients were treated with surgical excision alone, and none experienced recurrence or metastasis. Recognition of this entity can spare a child potentially toxic adjuvant chemotherapy that might be used for lesions in its differential diagnosis, specifically clear cell sarcoma of the kidney.

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.

The importance of measuring attitudes of trainee professionals to people with disabilities was addressed. A questionnaire which included the Scale of Attitudes toward Disabled Persons (SADP) and the Intellectual Disability Misconceptions Scale (IDMS) was completed by first and final year tertiary students enrolled in a 3-year course on intellectual disability. The attitude measures did not discriminate between the two groups of students, psychometric properties were poor and the factor structure of the SADP did not replicate previous findings. As expected, there was some convergence between the two attitude measures, and relationships to subject variables were consistent with previous research. Recommendations for subsequent research were discussed.

The existence of extrarenal rhabdoid tumor (ERRT) as a discrete pathologic entity has been controversial despite frequent reports of its occurrence. We performed immunohistochemistry, electron microscopy, or both on 42 cases with this diagnosis sent in consultation to us. Only 12 of the 42 neoplasms had the histological findings of "classic" malignant rhabdoid tumor of the kidney; the remainder displayed a variety of neural, epithelial, myoid, mesenchymal, or ependymal patterns. Electron microscopy also showed that most possessed neural, epithelial, or ependymal features. Immunohistochemistry generally revealed marked polyphenotypia, with immunoreactivity to a wide array of antibodies against neural, epithelial, glial, and myogenic markers. A specific tissue-based diagnostic category could not be assigned in only 11 of the 42 cases, seven of which lacked material for a comprehensive ultrastructural or immunohistochemical study. We conclude that tumors currently diagnosed as ERRT represent a heterogeneous group of neoplasms that may form unique subsets of known entities within the specific site where they arise or that may defy classification into a specific alternative category. Our findings lead us to believe that the term ERRT is not valid as representing a specific diagnostic entity and to prefer the term "poorly differentiated neoplasm with rhabdoid features" for undifferentiated tumors.

Comfort in interacting with people with intellectual disabilities is an important quality for effective professionals. A measure of this variable, the Interaction with Disabled Persons (IDP) Scale (Gething, 1991) was completed by 468 tertiary students, 135 of whom were 1st-, 2nd-, or 3rd-year students of the Bachelor of Applied Science (Intellectual Disability). Items from the scale were presented intact, as well as being dispersed within a broader attitude questionnaire. Retest data were collected (n = 81), and a sub-sample (n = 29) responded to the Marlowe-Crowne Social Desirability Scale (Crowne & Marlowe, 1960). The IDP Scale discriminated between student groups, and this effect was robust when age, gender, and contact with people with intellectual disabilities were treated as covariates. Score distributions were adequate, and there was no evidence of the influence of social desirability. Reliability was optimised by excluding some items and introducing others. The modified measure was relati...

While the feminization of psychology seems remote, socially relevant research is relatively achievable. In the present paper, terminology is initially reviewed, and distinctions are drawn between concepts of sex, gender, and sexuality. Traditional areas of psychological activity in relation to gender differences, gender identity, gender stereotypes, gender and sexuality are noted, and issues of social relevance are highlighted. Possibilities for socially relevant research include investigation of power differences, the subjective experience of oppression, objectification of women's bodies, and the pattern of connections and disconnections between sex, gender, sexuality, and position on feminism.

Age distributions of parents at birth of patients registered in the National Wilms' Tumour Study were compared to those of the general population. An increasing incidence of sporadic Wilms' tumour with increasing paternal age was found, with a relative risk of 2.1 of tumour in children of fathers over 55 compared to children of fathers younger than 20. A similar effect for maternal age was found, with a relative risk of 1.4 in children of mothers over 40 compared to children of mothers younger than 20. The maternal age effect was much weaker among patients registered later in the study; in the later, more completely ascertained cohort, paternal age appears to be the major contributor to the parental age effect. Little difference in paternal age distribution was found between patients with bilateral and unilateral tumour and between male and female patients. In contrast, patients with reported associated congenital anomalies, patients with evidence of nephrogenic rests, and patients with early or late age-of-onset of tumour had parents who were, on average, substantially older than the remainder. These findings lend support to the idea that many Wilms' tumours result from new germline mutations. Further, the histologic composition of such tumours may be sufficiently distinct as to provide a valuable diagnostic indicator of the etiology of these tumours.

The work of Broverman, Braverman, Clarkson, Rosenkrantz, & Vogel (1970) on gender and judgments of mental health was revisited with 75 student nurses. Health-illness differences were explored in addition to male-female-adult differences. The average age of students was 20.9 years, and 89% were female. The results were different from those of Broverman and colleagues. Images of the healthy male, female, and generic adult were similar. Differences perceived overall between health and illness were more substantial than gender differences. Gender differences which did occur reflected gender stereotypes, but were unflattering to masculinity. The image of the healthy generic adult had more in common with healthy femaleness than with healthy maleness. Possible explanations for the findings are presented.

Purpose This review characterized cases of secondary acute myelogenous leukemia (AML) occurring after treatment of renal neoplasms on protocols of the National Wilms Tumor Study Group (NWTSG) between October 1969 and December 1991. Patients and methods The NWTSG database was reviewed for cases of secondary AML and for WT1 status of the affected patients. Referring institutions were contacted by a confidential letter requesting pathology reports, results of immunophenotyping, cytogenetic, and molecular analyses, and details concerning treatment of AML. Results Of the 5,278 patients treated during the study period, 43 had second malignant neoplasms, and 7 of these 43 had AML. At the time of diagnosis of Wilms tumor, the median age of the seven patients (4 boys) was 3.2 years. Five of the seven renal neoplasms had favorable histologic characteristics. The most common French-American-British morphology was M5. One patient had bilateral tumors, and two were treated for recurrent Wilms tumor. All patients received chemotherapy regimens that included doxorubicin (6) or etoposide (1), and six were treated with infradiaphragmatic irradiation. The median latency period from initial diagnosis of the renal neoplasm to development of secondary AML was 3 years (range, 1.2-4 yrs). One patient had the translocation t(9:11)(p22;q23); WT1 status was not noted for any of the seven patients. Conclusions The development of secondary AML in this subset of patients after treatment of renal neoplasms may reflect the interaction of the effects of treatment and possible genetic predisposition toward cancer.

Nephrogenic adenofibroma is a novel kidney tumor of young people (mean age of presentation, 13 years), who present with polycythemia, hypertension, or hematuria, which resolve following nephrectomy. The typical nephrectomy specimen contains a solitary, nonencapsulated, vaguely circumscribed, irregularly shaped or spherical, firm mass with either tan, gray-white, or pale yellow coloration. Cysts are sometimes present within the tumor. The histologic appearance is distinctive and characterized by a marked proliferation of spindled mesenchymal cells resembling the classical type of congenital mesoblastic nephroma, encasing discrete nodules of embryonal epithelium similar to the hyperplastic nephrogenic rests (nephroblastomatosis) usually associated with Wilms' tumor. The mesenchymal component consists of a fascicular proliferation of tightly interlaced, uniform, benign-appearing spindled cells that immunostatin for vimentin and fibronectin, but not desmin or actin. The epithelial component consists of discrete islands of blastemal cells that are partially or fully differentiated toward tubular, tubulopapillary, or papillary structures. Psammoma bodies are plentiful. Embryonal epithelium immunostains for cytokeratin but not epithelial membrane antigen. The overall histologic appearance of the mesenchymal and epithelial components is benign, and preliminary clinical data suggest that the tumor has a benevolent course. Two cases, however, contained small, well-circumscribed papillary lesions near the renal pelvis that resembled low-grade collecting duct carcinoma. The clinical implications of the latter finding are unclear.

The division of labor in mixed-gender households is discussed on the basis of stereotypical expectations, as well as time-use diary data. The stereotypes as generated by 210 adults, of average age 25 years, were consistent with reality, as depicted by the diary data from an independent study. In both data sets, the image of the double shift emerged. Women were seen as doing most of the unpaid work, and tasks were gender-segregated. Expectations of women, reinforced by values and power differences, appear unchanged by women's increasing participation in paid labor. Social policies which address women's experience of paid labor therefore need to address the division of unpaid labor. Equalising unpaid labor means mobilising men to become involved in essential, but unrewarded, tasks.

A new pseudotumorous lesion found in the adrenal cortex of six infants with Beckwith-Wiedemann syndrome is described. These cystic masses were discovered either prenatally by using sonography or early in the neonatal period as palpable flank masses. Imaging studies, including sonography and CT, could not confidently exclude malignancy. After the masses were removed surgically, histologic examination showed them all to be benign hemorrhagic macrocysts within the capsule or permanent cortex (in contrast to neonatal adrenal hemorrhage, which usually occurs more centrally in the fetal cortex). The cysts were as large as 8 cm in diameter, and in one case a solitary cyst was predominant. Hemihypertrophy was present in all cases. Four of the six lesions were right-sided, and there was a male-female ratio of 5:1. Benign hemorrhagic adrenocortical macrocysts are a cause of abdominal mass in the fetus and neonate with Beckwith-Wiedemann syndrome.

Relationships between approaches to learning, as measured by the Study Process Questionnaire (SPQ), prior knowledge of subject area, and performance on a multiple-choice test following a 15 × 2 hour unit in basic psychology were investigated. Subjects were 105 first year tertiary students, of mean age 19.9 years, and predominantly female (82.9%). Approaches to learning were unrelated to assessment performance, and prior knowledge did not relate to a deep approach although it did predict performance. The findings were interpreted in terms of additional elements in the teaching-learning process, and the role of the SPQ was seen as a stimulus to thinking about that process.

Adults with Wilms' tumor (WT) have had a poor prognosis. More recently, therapies used in children, who have a better outlook, are also being employed for adults. This study was undertaken to see whether adults with WT have benefited. The results of treatment of 27 adults with WT were reported to the National Wilms' Tumor Study (NWTS) from 1979 to 1987. The ages of the 27 adults ranged from 16 to 74 years (median, 24 years). Four had anaplastic WT, and 23 had favorable histology (FH) WT. All but one patient underwent nephrectomy, 21 were given postoperative radiation therapy, and 25 received chemotherapy. The agents used most often included actinomycin D (AMD), vincristine (VCR), and doxorubicin (Adriamycin; ADR). There were six Stage I, five Stage II, four Stage III, 11 Stage IV, and one Stage V patients. The 3-year survival rate is 67%. These results are better than the 24% reported by the NWTS in the past for adults with WT. Analyses of the therapies given to the 27 adults lead to the following recommendations: for Stage I/FH patients, 6 months of postoperative chemotherapy using AMD + VCR without postoperative radiation therapy; and for Stage II, III, and IV/FH, VCR + AMD + ADR for 15 months + 2000 cGy to the tumor bed, 1200 to 1500 cGy to the lungs, 2000 cGy to the liver, and 3000 cGy to other sites as appropriate in patients with metastases at diagnosis.

The lethal white foal syndrome (LWFS) is a congenital abnormality of overo spotted horses which is a model for human aganglionic megacolon or Hirschsprung disease. Foals with LWFS have an all white, or nearly all white, coat. They also present clinically with an intestinal obstruction that proves fatal within the first few days of life. The LWFS involves both melanocytes and intestinal ganglion cells, and appears to result from a genetic defect involving neural crest cells. This report describes pathologic studies of two recent cases of LWFS. Two different hypothetical models of inheritance of LWFS are presented and discussed.

The unbalanced translocation, der(17)t(X;17)(p11.2;q25), is characteristic of alveolar soft part sarcoma (ASPS). We have recently shown that this translocation fuses the TFE3 transcription factor gene at Xp11.2 to ASPL, a novel gene at 17q25. We describe herein eight morphologically distinctive renal tumors occurring in young people that bear the identical ASPL-TFE3 fusion transcript as ASPS, with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors. A relationship between these renal tumors and ASPS was initially suggested by the cytogenetic finding of a balanced t(X;17)(p11.2;q25) in two of the cases, and the ASPL-TFE3 fusion transcripts were then confirmed by reverse transcriptase-polymerase chain reaction. The morphology of these eight ASPL-TFE3 fusion-positive renal tumors, although overlapping in some aspects that of classic ASPS, more closely resembles renal cell carcinoma (RCC), which was the a priori diagnosis in all cases. These tumors demonstrate nested and pseudopapillary patterns of growth, psammomatous calcifications, and epithelioid cells with abundant clear cytoplasm and well-defined cell borders. By immunohistochemistry, four tumors were negative for all epithelial markers tested, whereas four were focally positive for cytokeratin and two were reactive for epithelial membrane antigen (EMA) (one diffusely, one focally). Electron microscopy of six tumors demonstrated a combination of ASPS-like features (dense granules in four cases, rhomboid crystals in two cases) and epithelial features (cell junctions in six cases, microvilli and true glandular lumens in three cases). Overall, although seven of eight tumors demonstrated at least focal epithelial features by electron microscopy or immunohistochemistry, the degree and extent of epithelial differentiation was notably less than expected for typical RCC. We confirmed the balanced nature of the t(X;17) translocation by fluorescence in situ hybridization in all seven renal tumors thus analyzed, which contrasts sharply with the unbalanced nature of the translocation in ASPS. In summary, a subset of tumors previously considered to be RCC in young people are in fact genetically related to ASPS, although their distinctive morphological and genetic features justify their classification as a distinctive neoplastic entity. Finally, the finding of distinctive tumors being associated with balanced and unbalanced forms of the same translocation is to our knowledge, unprecedented.

In the Third National Wilms' Tumor Study, (NWTS-3), 190 patients with Favorable Histology (FH) Wilms' tumor (WT) were identified as having tumor adherent to, directly invading, or metastatic to the liver at diagnosis. Analyses of the 3-year relapse-free survival and survival of these patients show that adhesion to the liver surface, direct invasion of the liver, and liver metastases have no additional detrimental effect on prognosis stage-for-stage. The authors conclude that hepatic involvement, when present at the time of diagnosis, should not be regarded as different from other patterns of the disease. Treatment policies should follow those appropriate for stage.

Loss of heterozygosity (LOH) for markers on chromosome arm 16q in Wilms tumor has been linked to an increased risk of treatment failure. We therefore postulated that fluorescence in situ hybridization (FISH) with probes from this region might enhance current strategies for identifying high-risk patients at diagnosis. In a blinded comparative pilot study of 19 Wilms tumor samples from 18 patients with favorable histology, FISH and DNA polymorphism analysis yielded concordant results in 14 cases, either retention (n = 6) or loss (n = 8) of chromosome arm 16q markers. Discordant findings in 4 of the 5 remaining cases resulted from detection of LOH, but no loss by FISH. Two of these cases, directly comparable at marker D16S422, appeared to have tumor-specific uniparental disomy, in that 2 copies of D16S422 and the 16 centromere were evident, despite LOH. In 2 other cases, the discrepancies could be explained by LOH confined to loci distal to the D16S422 locus. In the fifth case, FISH detected 2 distinct populations of tumor cells, one characterized by normal diploidy and the other by monosomy 16, whereas DNA polymorphism analysis failed to indicate LOH altogether. Thus, FISH confirmed the presence of allelic loss (hence, the possible location of biologically important tumor suppressor genes) on the distal long arm of chromosome 16 in cases of favorable-histology Wilms tumor, with the advantages of technical simplicity, successful analysis of samples that were otherwise uninformative by analysis of DNA polymorphisms, and the addition of internal controls for chromosomal aneusomy. We suggest that combined analysis of the chromosome 16q region in Wilms tumor by FISH and DNA polymorphism analysis would improve evaluations to identify high-risk patients who might benefit from alternative therapy.

Four children who developed oncocytoid renal cell carcinoma (RCC) after neuroblastoma are reported. One patient had multiple, bilateral RCCs. The mean age at time of diagnosis of RCC was 8.8 years (range, 5-13 years). The mean interval between neuroblastoma and RCC was 7.15 years (range, 3.1-11.5 years). The histologic findings of these RCCs did not fit within the spectrum of known renal epithelial neoplasms. Most of the neoplastic cells in all cases had eosinophilic, oncocytoid cytoplasm and were arranged in solid and papillary growth patterns. A subset of cells with reticular cytoplasm was also present. Immunohistochemical studies demonstrated keratins 8 and 18 in all neoplasms and keratin 20 in two cases. DNA ploidy analysis revealed that two of three neoplasms assessed were aneuploid. Cytogenetic studies revealed 45, XX, add or dup (7)(q32q36) in one neoplasm, and 83-89, XXXX, -1 ,-3, del (3)(q11.1q2?1), der(4)t(4;?22) (q32;q11.2), -14, -22 in a second tumor. Microsatellite polymerase chain reaction analysis detected no abnormalities in one neoplasm and allelic imbalance of chromosomes 2p31-32.2, 8p22, 9p22-24, 13q22, 20q13, and 22q11 in a second tumor. In case 4, two different RCCs excised 6 months apart were analyzed. The initial neoplasm showed allelic imbalance of chromosomes 2q31-32.2, 5q22, 5q31, 10p13-14, 13q22, 14q31, and 20q13. The subsequent neoplasm showed allelic imbalance of chromosomes 3p21.3, 14q31, and 20q13. The common presence of 14q31 and 20q13 abnormalities suggests that these two neoplasms were genetically related. In aggregate, these findings are distinctive, are not found in known types of RCC, and support the morphologic impression that oncocytoid RCC after neuroblastoma is a distinct clinicopathologic entity.

Approximately 1% of children with unilateral Wilms tumor develop contralateral disease. The authors assessed the demographic and histologic features associated with metachronous bilateral Wilms tumor (BWT).Characteristics of all children registered on the first four National Wilms Tumor Studies (NWTS) were recorded. The primary endpoint for evaluation was the first appearance of Wilms tumor in the remaining kidney. The cumulative risk of contralateral disease as a function of time since initial presentation was calculated as 1 minus the Kaplan-Meier estimate of remaining free of contralateral disease. A matched case control study was conducted to determine whether the presence and type of nephrogenic rests (NRs) were associated with metachronous BWT.Fifty-eight of 4669 registered children developed metachronous BWT; 38 of 2445 females (expected, 30.2) versus 20 of 2224 males (expected, 27.8) (P = 0.04) developed BWT. The cumulative incidence of contralateral disease 6 years after initial diagnosis decreased from greater than 3% in the first NWTS to approximately 1.5% in the three subsequent studies (P = 0.08). Patients with NRs had a significantly increased risk of metachronous BWT. This was particularly true for young children (20 of 206 age12 months compared with 0 of 304 age12 months). Data from the matched case control study confirmed the increased relative risk associated with young age and the presence of NRs.Children younger than 12 months diagnosed with Wilms tumor who also have NRs, in particular perilobar NRs, have a markedly increased risk of developing contralateral disease and require frequent and regular surveillance for several years. Surveillance is also recommended for those with NRs who are diagnosed after the age of 12 months.

PURPOSE National Wilms' Tumor Study (NWTS)-4 was designed to evaluate the efficacy, toxicity, and cost of the administration of different regimens for the treatment of Wilms' tumor (WT). PATIENTS AND METHODS Between August 6, 1986 and September 1, 1994, 905 previously untreated children aged younger than 16 years with stage II favorable histology (FH) WT (low-risk [LR]), stages III to IV FH WT, or stages I to IV clear-cell sarcoma of the kidney (high-risk[HR]) were randomized after the completion of 6 months of chemotherapy to discontinue (short) or continue for 9 additional months (long) treatment with chemotherapy regimens that included vincristine and either divided-dose (standard [STD]) courses (5 days) or single-dose (pulse-intensive [PI]) treatment with dactinomycin. HR patients also received either divided-dose (STD) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS The 4-year relapse-free survival (RFS) rates after the second randomization for LR patients were 83.7% for the 190 patients treated with short and 88.2% for the 187 patients treated with long chemotherapy (P = .11). The 4-year RFS rates after the second randomization for HR FH patients were 89.7% for the 256 patients treated with short and 88.8% for the 246 patients treated with long chemotherapy (P = .87). The charge for treatment with the short PI treatment regimens for all children with stages I through IV FH WT was approximately one half of that with the long STD treatment regimens. CONCLUSION The short administration schedule for the treatment of children with WT is no less effective than the long administration schedule and can be administered at a substantially lower total treatment cost.

Congenital mesoblastic nephroma (CMN) is an infantile spindle cell tumor of the kidney that is subdivided into "classical" and "cellular" forms based on the degree of cellularity and mitotic activity. The histogenesis of CMN remains obscure, but relationships to other pediatric renal neoplasms have been proposed. However, cellular CMN is virtually identical histologically to congenital fibrosarcoma (CFS), a malignant tumor of fibroblasts in children of the same age group. Moreover, cytogenetic studies have reported common trisomies in CFS and cellular CMN, particularly of chromosome 11. We show here that t(12;15)(p13;q25)-associated ETV6-NTRK3 gene fusions described in CFS are also present in cellular CMN. ETV6-NTRK3 chimeric transcripts were detected in 8 of 9 cellular CMNs and 2 of 2 mixed CMNs. In contrast, all of the four classical CMNs tested were negative, as were cases of Wilms' tumor and clear cell sarcoma of the kidney. Moreover, we found trisomy 11 only in cellular or mixed CMNs with the ETV6-NTRK3 gene fusion. Our studies indicate that classical and cellular CMN have different genetic features and support the concept that cellular CMN is histogenetically related to CFS. They also provide insight into potential mechanisms involved in the transformation of the classical into the cellular form of CMN.

Nephrogenic rests (NR) are abnormally persistent clusters of embryonal cells, representing microscopic malformations (dysplasias) of the developing kidney. Though NR are best known as precursors of Wilms tumor (WT), many alternative fates are observed, and most rests are destined for eventual atresia. Biological and clinical distinctions between the two major NR categories, perilobar and intralobar rests (PLNR and ILNR) are emphasized. PLNR occur in fetal overgrowth and with certain overgrowth syndromes. ILNR are frequently associated with deletions or mutations of WT1. Data are presented concerning the prevalence of NR in general pediatric autopsy populations, and in selected syndromes. The age at diagnosis of WT was determined for the largest series of patients with WT-associated syndromes reported to date. These data provide a basis for determining how long patients with these conditions are at risk for WT development.

Vignettes of several stages in the evolution of present concepts of overgrowth and related syndromes are presented. The scientific study of this topic did not begin until the 18th century because of its delayed emergence from superstition and fallacy. Examples of early superstitions concerning gigantism are presented, with some historical comments on infant giants. The pioneering contributions of Isodore Geoffroy Saint-Hilaire to the scientific analysis of overgrowth are emphasized. Details concerning the early history of the growth syndrome associated with the names of Wiedemann and Beckwith is presented, with emphasis on cases reported prior to ours.

Morphologic analysis of malignant renal tumors of childhood and adolescence has resulted in the identification of a variety of tumor types with characteristic histology and clinical behavior. The authors report a case of renal sarcoma in a 19-year-old male that differs in morphology from the various established categories of primitive renal tumors.Sections taken from the nephrectomy specimen were stained by routine methods and by immunohistochemistry for stromal and epithelial markers, and for proliferation markers. In addition, ultrastructural studies were undertaken.The tumor, which the authors termed cystic embryonal sarcoma, was comprised of poorly differentiated malignant mesenchyme in a myxoid stroma. Numerous epithelial-lined cysts were present. The distribution of the cysts and proliferation kinetics of cyst-lining epithelial cells suggested that they were derived from entrapped renal tubules. The tumor showed early recurrence postoperatively and after aggressive chemotherapy. The pathologic features and clinical behavior of the tumor resemble those of 2 previously reported cases and an additional 25 cases from the files of the National Wilms' Tumor Study Pathology Center.The clinical and histologic features of cystic embryonal sarcoma differ from those of other renal tumors of childhood and adolescence, and the tumor appears to be a novel form of renal malignancy.

Purpose: Malignant ectomesenchymomas are tumors that exhibit both mesenchymal and neuroectodermal elements (1). We report a case thought to represent a malignant ectomesenchymoma arising in the kidney with cytogenetic abnormalities that may provide insight into the biologic basis for this unusual tumor. Methods: We discuss the clinical features, histopathologic findings, cytogenetics, treatment, and outcome of a child with a malignant ectomesenchymoma arising in the kidney. Results: An asymptomatic 16-month-old boy had a large abdominal mass. The resected tumor contained sheets of spindled cells that expressed mesenchymal markers and cartilaginous differentiation, interspersed with clusters of ganglion cells that expressed neural markers. No blastemal or epithelial elements were demonstrated. Cytogenetic analysis of the tumor revealed a hyperdiploid count with multiple numerical and structural abnormalities, including a translocation between chromosomes 12 and 15. In addition to the surgical resection, the patient was successfully treated with adjuvant chemotherapy and local radiation therapy. Conclusion: This is the first report of which we are aware of an ectomesenchymoma arising within the kidney. A subset of malignant ectomesenchymomas may be related to the Ewing's family of tumors (EFTs) (2), but this case did not exhibit cytogenetic features consistent with EFT. Thus, the malignant ectomesenchymoma phenotype probably represents a heterogeneous group of tumors with different genotypes and origins. Cytogenetic analysis may be instrumental in determining the appropriate therapeutic approach when faced with such a neoplasm. The outcomes of 12 other children with ectomesenchymoma are reviewed.

Medullary dysplasia may be present in the kidneys of children with the Beckwith-Wiedemann Syndrome (BWS). This is usually visible only at the microscopic level, but superimposed pyelonephritis in a child with the BWS led to gross changes that produced a filling defect on CT scanning of the remaining kidney. The finding could have been misinterpreted as a metachronous wilms tumor.

Among 6,209 patients with Wilms' tumor entered on the National Wilms' Tumor Study (NWTS), 93 patients (1.5%) from 63 families had a positive family history. In 30 of these 63 families a (half) sibling or parent of the NWTS patient was confirmed to have had Wilms' tumor. Fifteen (16.1%) of the familial, but only 7.1% of sporadic cases, had bilateral disease. Mean ages at diagnosis were 15.8 vs. 35.2 months (P = 0.012) for bilateral vs. unilateral familial cases and 32.0 vs. 44.7 months for sporadic cases. Intralobar nephrogenic rests were found twice as frequently in association with the tumors of familial as with those of sporadic cases. Cases of bilateral and metastatic disease tended to cluster within specific families, suggesting heterogeneity in the genetic etiology. The number and age distribution of familial cases transmitted through the father were about the same as those of cases transmitted through the mother. This finding is inconsistent with models of genomic imprinting that involve familial transmission of a tumor-suppressor gene and it casts further doubt on the hypothesis that all bilateral cases are hereditary.

The clinical behavior and outcome for any neoplasm are determined originally by its aggressiveness. As adjuvant therapy becomes increasingly effective for that neoplasm, responsiveness to therapy assumes a larger role in determining outcome. Wilms' tumor (WT) provides instructive examples of the dissociation of aggressiveness from responsiveness. The presence of gigantic nuclei with multipolar mitotic figures (anaplasia) appears to be a marker of resistance to therapy, but not of increased aggressiveness. For this reason, anaplasia in a stage 1 WT and anaplasia confined to discrete foci within the primary tumor have no adverse prognostic significance following surgical resection. The prognostic significance of anaplasia is apparently limited to those patients in whom anaplastic cells remain following attempted surgical resection. WT with predominantly epithelial differentiation usually have a low degree of aggressiveness. In this study, 81.3% of WT with this pattern were stage 1. This feature accounts for the high cure rate associated with this pattern prior to the advent of effective adjuvant therapy. However, epithelial predominant WT that present with advanced stage disease may be quite resistant to therapy, with relapse and death rates higher than for more aggressive WT patterns. In contrast, the diffuse blastemal pattern is associated with marked aggressiveness, but with high survival rates suggesting it is usually responsive to current therapy. These features illustrate the independence of aggressiveness and responsiveness in determining outcome for some patients with cancer. Grading systems must be reevaluated with each significant change in therapy. In order to formulate rational therapy, it is important to determine whether prognostic markers are associated with aggressiveness or responsiveness.

To correlate pathologic, computed tomographic (CT), and ultrasound (US) characteristics of nephrogenic adenofibromas and embryonal adenomas (uncommon pediatric renal tumors) in children.Medical records and imaging and pathologic findings were reviewed in three children (aged 6 1/2, 7, and 11 years) with adenomatous renal tumors and polycythemia. Specimens were reviewed at the National Wilms Tumor Study Pathology Center (Loma Linda, Calif).All tumors were smaller than 3 cm in greatest dimension. They were hyperechoic on US scans and had high attenuation on unenhanced CT scans. Two patients underwent nephrectomy for initial diagnosis of Wilms tumor. The third underwent local excision. At pathologic examination, embryonal-appearing adenomatous epithelial cells were found to form tubules and papillae with abundant psammomatous calcifications. Two masses were classified as embryonal adenomas and one as nephrogenic adenofibroma.Increased attenuation on CT scans and increased echogenicity on US scans of renal adenomatous tumors are distinctive findings that may reflect the presence of tubulopapillary structures and psammomatous calcifications.

Rhabdoid tumors of the kidney are highly malignant neoplasms that occur primarily within the first 3 years of life. Although they are regarded as distinct from Wilms' tumors, their pathogenesis remains unclear. Whereas most cytogenetic studies of these tumors have revealed normal karyotypes, a few reports have indicated abnormalities at chromosome regions 22q and 11p15.5. We analyzed 30 primary renal rhabdoid tumors for loss of heterozygosity (LOH) at both regions and found that 24 of 30 tumors (80%) had LOH at chromosome arm 22q and that 5 of 30 (17%) had LOH at chromosome band 11p15.5. All of the five tumors with LOH at chromosome arm 11p also had LOH at chromosome arm 22q. The data suggest that there is a gene in chromosome 22, probably a tumor suppressor, inactivation of which may be involved in the genesis of renal rhabdoid tumors. A second gene in chromosome segment 11p15.5, in the region of the putative WT2 gene, may also be involved, in at least a subset of rhabdoid tumors. In addition, five tumors were characterized by microsatellite instability at three or more of 21 loci examined, suggesting a possible role for a replicative error in tumorigenesis or progression in some cases of renal rhabdoid tumors. Genes Chromosom Cancer 15:10-17 (1996).

Wilms tumor is the most common primary malignant renal tumor of childhood, representing about six percent of all childhood cancers in the United States. Developments in surgery, radiation therapy, and chemotherapy have led to a dramatic change in the prognosis for most patients, and Wilms tumor has become a paradigm for multimodal treatment of a pediatric malignant solid tumor. The authors review the progress made in the diagnosis and management of children with Wilms tumor.

The different subtypes of childhood renal tumors are well defined both clinically and pathologically. Classification and estimation of prognosis are feasible even after chemotherapy. A small group of tumors remains in which an estimate of prognosis is difficult. This is especially true for Wilms tumors with persistent blastema after chemotherapy. It is to be hoped that studies of the molecular genetics of these tumors will yield new data that will help refine therapeutic strategies.

Neonatal renal tumors are very rare. We have identified 15 cases of Wilms' tumors diagnosed in the first 30 days of life. The most common presentation was an abdominal mass on routine newborn examination, and three tumors were noted on an antenatal ultrasound. All of the infants underwent primary excision of the tumor. Five infants were not given postoperative chemotherapy after surgical excision. One of these children had a relapse and later died of progressive disease. The remaining children are alive at a median follow-up of 31 months. Eight of the tumors had evidence of nephrogenic rests. More frequent follow-up physical and imaging examinations are indicated in children not given adjuvant chemotherapy or whose tumors show nephrogenic rests.

The p53 gene product is required for activation of an apoptotic pathway triggered by oncogenes and cytotoxic agents. Wilms' tumor, a pediatric renal malignancy, provides a paradigm for evaluating genetic events involved in tumor progression. This malignancy is generally not associated with p53 mutations, and even in advanced disease states is quite responsive to current treatment regimens. The anaplastic histological variant of Wilms' tumor, however, is frequently associated with p53 gene mutations and shows poor prognosis. We analyzed seven Wilms' tumors for which we had paired samples from nonanaplastic and anaplastic regions. p53 mutations were detected in six of these tumors, five of which demonstrated mutations restricted to anaplastic regions. Nonanaplastic cells of the sixth sample were heterozygous for a p53 mutation, whereas the anaplastic area of this tumor showed reduction to homozygosity. These results indicate that progression to anaplasia is associated with clonal expansion of cells which have acquired a p53 mutation. We demonstrated that tumor cells with p53 mutations show attenuated apoptosis, suggesting that such lesions may provide a selective advantage in vivo by decreasing cell death.

The existence of extrarenal rhabdoid tumor (ERRT) as a discrete pathologic entity has been controversial despite frequent reports of its occurrence. We performed immunohistochemistry, electron microscopy, or both on 42 cases with this diagnosis sent in consultation to us. Only 12 of the 42 neoplasms had the histological findings of "classic" malignant rhabdoid tumor of the kidney; the remainder displayed a variety of neural, epithelial, myoid, mesenchymal, or ependymal patterns. Electron microscopy also showed that most possessed neural, epithelial, or ependymal features. Immunohistochemistry generally revealed marked polyphenotypia, with immunoreactivity to a wide array of antibodies against neural, epithelial, glial, and myogenic markers. A specific tissue-based diagnostic category could not be assigned in only 11 of the 42 cases, seven of which lacked material for a comprehensive ultrastructural or immunohistochemical study. We conclude that tumors currently diagnosed as ERRT represent a heterogeneous group of neoplasms that may form unique subsets of known entities within the specific site where they arise or that may defy classification into a specific alternative category. Our findings lead us to believe that the term ERRT is not valid as representing a specific diagnostic entity and to prefer the term "poorly differentiated neoplasm with rhabdoid features" for undifferentiated tumors.

PURPOSE To evaluate the effect of the combination of vincristine, dactinomycin, and doxorubicin with (regimen J) or without (regimen DD-RT) cyclophosphamide on the relapse-free survival of children with stages II to IV Wilms' tumor and focal or diffuse anaplasia. PATIENTS AND METHODS We reviewed the clinical courses of all randomized patients from National Wilms' Tumor Study (NWTS)-3 and NWTS-4 with stages II to IV anaplastic Wilms' tumor, and determined the 4-year relapse-free survival rate separately for those with focal or diffuse anaplasia. Anaplasia was evaluated using newly developed topographic definitions for focal and diffuse anaplasia. RESULTS The 4-year relapse-free survival rate for five children with focal anaplasia who received regimen DD-RT was 80.0%, compared with 100.0% for eight children who received regimen J (P = .68). The 4-year relapse-free survival rate for 29 children with diffuse anaplasia treated with regimen DD-RT was 27.2%, compared with 54.8% for 30 children treated with regimen J (P = .02). CONCLUSION We conclude that children with focal anaplasia have an excellent prognosis when treated with vincristine, doxorubicin, and dactinomycin. The addition of cyclophosphamide to the three-drug treatment regimen improved the 4-year relapse-free survival rate of children with stage II to IV diffuse anaplasia. This result suggests that further intensification of the treatment regimen for children with diffuse anaplasia may result in an additional improvement in prognosis.

PURPOSE To evaluate the effect of the sequential addition of doxorubicin (DOX) and cyclophosphamide (CTX) to the combination of vincristine (VCR) and dactinomycin (AMD) on the relapse-free survival of children with clear-cell sarcoma of the kidney (CCSK). PATIENTS AND METHODS We determined the 6-year relapse-free survival rate for patients with CCSK treated on National Wilms' Tumor Study (NWTS)-1, NWTS-2, or NWTS-3 with the combination of VCR and AMD, with or without DOX, and for patients treated on NWTS-3 with the combination of VCR, AMD, and DOX with (regimen J) or without (regimen DD-RT) CTX. RESULTS The 6-year relapse-free survival rate for the eight children with CCSK treated with VCR, AMD, and radiation therapy was 25.0%, compared with 63.5% for the 58 children treated with VCR, AMD, DOX, and radiation therapy (P = .09). The 6-year relapse-free survival rate for children with CCSK treated on regimen DD-RT was 64.6%, compared with 58.2% for those treated on regimen J (P = .79). CONCLUSION We conclude that the addition of DOX to the combination of VCR plus AMD appeared to improve the 6-year relapse-free survival rate of children with CCSK. The addition of CTX in the dose and schedule used in NWTS-3 did not improve the 6-year relapse-free survival rate of children with CCSK. Because 30% of relapses occurred more than 2 years after diagnosis, prolonged follow-up evaluation of patients with CCSK is necessary.

The purpose of this study was to determine the relationship between histologic microsubstaging variables, patient age, and tumor specimen weight in patients with Stage I/favorable histology Wilms' tumors.The authors reviewed all randomized patients from the Fourth National Wilms' Tumor Study, who had Stage I/favorable histology Wilms' tumors evaluated for one or more of the microsubstaging variables: (1) the presence of an inflammatory pseudocapsule, (2) renal sinus invasion, (3) tumor in the intrarenal vessels, and (4) tumor capsule invasion. The authors determined the correlation between microsubstaging variables and age at diagnosis or tumor specimen weight.Patients who were younger than 2 years of age at diagnosis were significantly more likely to have all negative microsubstaging variables. Patients who had tumors weighing less than 550 g were more likely to have all negative microsubstaging variables. However, neither renal sinus invasion nor tumor in the intrarenal vessels was more frequent in tumors weighing more than 550 g.An age at diagnosis of younger than 2 years and a tumor specimen weight of less than 550 g are highly correlated with the absence of adverse microsubstaging variables. The clinical variables of age at diagnosis and tumor specimen weight, compared with the assessment of microsubstaging variables, have the practical advantage of being more objectively determined and not requiring a central pathologic review for confirmation.

An analysis of over 1800 patients with Wilms' tumor revealed significantly higher birth weights than newborns in the general United States population. The highest birth weights were found not only in patients diagnosed with the Beckwith-Wiedemann syndrome (mean, 3.78 kg), as had been expected, but also in those with hemihypertrophy (3.80 kg) or perilobar nephrogenic rests (3.56 kg) in addition to their Wilms' tumor. The birth weights of Wilms' tumor patients with intralobar nephrogenic rests (3.43 on average kg) and of those without associated anomalies (3.45 kg) were slightly but still significantly higher on average than national birthweights (overall mean, 3.35 kg) adjusted for gender, race, and year of birth in each subgroup. Birth weights of children with aniridia and Wilms' tumor (2.99 kg) were lower than the national mean. Among more than 3000 patients with Wilms' tumor, heights and weights at diagnosis were significantly higher for the subgroups of patients with Beckwith-Wiedemann syndrome or hemihypertrophy, and height was lower for those with aniridia or characteristic genitourinary anomalies, when compared to other patients with Wilms' tumor. These data suggest prenatal effects of growth factors on the development of Wilms' tumors, or vice versa, and provide further epidemiological support for heterogeneity in the pathogenesis of Wilms' tumors associated with perilobar nephrogenic rests versus intralobar nephrogenic rests.

A preterm boy was born at 34 weeks. Prenatal ultrasonography showed oligohydramnios, fetal ascites, large kidneys, and small thorax. He died 21 h after birth of respiratory insufficiency. Autopsy revealed Potter's-like facies, hypoplastic lungs, ascites, and bilateral nephromegaly (renal weight almost 10 times normal). The kidneys were finely nodular externally, solid, and cerebriform on cut section. Histologically, they showed a diffusely distorted architecture of jumbled lobules, hyperplasia of cortical-type tissue with inconspicuous proximal tubules, relative hypoplasia of medullary tissue, tubulointerstitial dysplasia, and perilobar nephrogenic rests. The renal features represent a variety of the universal or panlobar (also called pancortical or infantile) type of nephroblastomatosis. To our knowledge, this is only the third such case reported. In the brain, each lateral ventricle contained a yellow gelatinous mass. Histologically, the masses consisted of a pseudomyxoid matrix with delicate fibers and focal adipocyte clusters, all confined within choroid plexus. We consider these lesions fibrolipomatous hamartomas.

Congenital mesoblastic nephroma (CMN) is generally considered to be a benign neoplasm requiring only total excision. Rare local recurrences have usually been related to incomplete removal, and distant metastases to the lung have been reported three times.The authors reported the first case of CMN metastatic to the brain, illustrating a comparison of the histopathology of the primary and secondary lesions.The gross appearance of the renal tumor was that of a benign CMN. On histopathologic examination, there was a single nodule of more cellular tissue with focal necrosis. This area was diagnosed as within the designation "cellular" mesoblastic nephroma. The appearance of the brain metastasis corresponded to that of the cellular nodule.This report expands the spectrum of metastatic potential of CMN. Though a rare event, this case underscores the need for close follow-up of infants with CMN.

Histologic specimens of the distal femoral growth plates of 10 patients treated surgically for osteosarcoma were examined retrospectively. Eight of the patients received preoperative chemotherapy. None of the specimens showed complete growth arrest. The gross thickness of the plates was preserved. Columnar arrangement of the cells was minimally disrupted. The number of proliferative cells in each column was decreased, and the number of hypertrophic cells, was increased slightly. The metaphysis showed longitudinal trabeculations with a high chondroid content. Growth arrest lines were evidenced by transverse trabeculations with a high osteoid content. Our findings provide histologic support for previous clinical studies. Absence of complete growth arrest and evidence of a resumption of growth are relevant in planning limb salvage procedures in patients receiving pre- and postoperative chemotherapy for skeletal malignancy.

To evaluate the usefulness of regular radiographic screening to detect an asymptomatic intraabdominal tumor in patients with an increased risk of developing Wilms tumor, we reviewed the files of patients with hemihypertrophy, aniridia, or Beckwith-Wiedemann syndrome who were registered on the National Wilms Tumor Studies. Screening was employed infrequently in the management of children with hemihypertrophy, with only 25% (6/24) of those whose hemihypertrophy was identified more than 30 days prior to the diagnosis of Wilms tumor undergoing such examinations. Most patients with aniridia were evaluated regularly for the occcurrence of Wilms tumor. There were more stage 1 tumors identified in patients whose tumor was detected only through radiographic evaluation. The role of routine radiographic screening needs to be carefully evaluated in a homogeneous group of patients such as those with aniridia using a prospective study design to determine if such screening improves the survival rate of children with this rapidly growing, but readily treatable form of childhood cancer. © 1993 Wiley-Liss, Inc.

PURPOSE Retrospective analyses were performed to determine the effect of tumor weight and therapy modifications on outcome in patients less than 2 years of age with stage I favorable-histology Wilms' tumors. PATIENTS AND METHODS The 4-year relapse-free and overall survival percentages for patients randomized to different treatment regimens in National Wilms' Tumor Studies (NWTS)-1, -2, and -3 were calculated and compared. RESULTS The 4-year relapse-free survival percentages of patients whose specimen weight was less than 550 g were found to be 89.1% on NWTS-1, 96.0% on NWTS-2, and 93.2% on NWTS-3. There was no evidence that the relapse-free survival of these patients had improved over time (P value for trend = .99). The 4-year relapse-free survival percentage for similar age and stage patients whose specimen weight was 550 g or greater was significantly poorer than that of patients with smaller tumors (P = .02). CONCLUSION Changes in the NWTS treatment regimens over a period of more than 20 years have not improved on the excellent prognosis of patients who are less than 2 years of age at diagnosis and who have a stage I, favorable-histology Wilms' tumor with specimen weight less than 550 g. These data could be used as the basis for a future trial in which a subgroup of such patients is treated with nephrectomy only.