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Tumor cells may share some patterns of gene expression with their cell of origin, providing clues into the differentiation state and origin of cancer. Here, we study the differentiation state and cellular origin of 1300 childhood and adult kidney tumors. Using single cell mRNA reference maps of normal tissues, we quantify reference "cellular signals" in each tumor. Quantifying global differentiation, we find that childhood tumors exhibit fetal cellular signals, replacing the presumption of "fetalness" with a quantitative measure of immaturity. By contrast, in adult cancers our assessment refutes the suggestion of dedifferentiation towards a fetal state in most cases. We find an intimate connection between developmental mesenchymal populations and childhood renal tumors. We demonstrate the diagnostic potential of our approach with a case study of a cryptic renal tumor. Our findings provide a cellular definition of human renal tumors through an approach that is broadly applicable to human cancer.

Rationale: Fetal congenital mesoblastic nephroma (CMN) is a rare renal tumor, characterized by polyhydramnios, premature birth, and neonatal hypertension. In the prenatal stage, it is particularly difficult to diagnose CMN either by ultrasonography or magnetic resonance imaging (MRI). Thus, CMN is frequently detected in the third trimester in the clinical scenario., Patient Concerns: A 29-year-old G2P0 pregnant woman took routine prenatal examinations in our hospital. The fetal right kidney abnormality was not observed after 2 systematical ultrasonic examinations (at 24 and 31 weeks of gestation respectively), and only an increase was noticed in the amniotic fluid index (from 19.3 to 20.8 cm)., Diagnosis: CMN was detected by antenatal ultrasonography and MRI as a fetal right renal mass at 35 weeks of gestation in our hospital., Interventions: The pregnant woman was admitted at a gestational age of 38 weeks and 5 days due to alterations in renal function. Further, the pregnant woman was administered with "oxytocin" to promote delivery, and the neonate underwent a right nephrectomy on the 9th day after birth., Outcomes: The pathological examination confirmed a cellular type of right CMN. The neonate recovered well after operation without adjuvant treatment. During 6 months of follow-up, the neonate grew well and showed no signs of recurrence or metastasis., Conclusion: Polyhydramnios detected during prenatal examination required attention due to the risk of malformation of fetal urinary system. Prenatal ultrasonography combined with MRI could not only clearly identify the origin of the tumor, but also distinguish the correlation between the tumor and adjacent structures, thereby leading to early diagnosis and favorable prognosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Imaging plays a key role in the diagnosis and staging of prenatal and neonatal tumors, and is essential in treatment planning. Though obstetrical ultrasound is the first choice prenatally, fetal MRI continues to play an increasing role as experience with this imaging modality increases. In the neonate, in addition to ultrasound and MRI, CT and nuclear medicine studies can also play an important role. We describe the prenatal and neonatal imaging findings of some of the most common congenital abdominal and soft tissue neoplasms including neuroblastoma, renal, liver and soft tissue tumors.

Congenital anomalies of the upper urinary tract are common and frequently diagnosed on prenatal ultrasound. In the absence of infection, these anomalies are often asymptomatic. This article reviews key features and long-term implications to assist in discussions with families. In contrast, a perinatal renal tumor is rare but extremely alarming. This update on the most common tumors and their treatment is useful in reassuring parents that most infants, after primary surgical resection, are cured without adjuvant therapies. To understand renal agenesis and other congenital renal malformations and their associated anomalies, a brief review of normal renal development is presented., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state., (Copyright © 2014 Wiley Periodicals, Inc.)

Various fetal or placental disorders cause Ballantyne's (mirror) syndrome. For the first time, we report a maternal manifestation of Ballantyne's syndrome occurring concomitantly with the development of fetal congenital mesoblastic nephroma (CMN). In a pregnant woman with a CMN fetus, lung edema, hypertension, hyperthyroidism, and high serum human chorionic gonadotrophin level occurred, all of which characterize maternal manifestation of Ballantyne's syndrome. The fetus and placenta were devoid of 'edema', lacking 'triple edema', and thus this condition was not diagnosed as Ballantyne's syndrome; however, we considered this condition as the maternal manifestation of Ballantyne's syndrome. We performed emergent cesarean section at 28 weeks. Delivery acutely ameliorated maternal symptoms. Tumor was resected and was confirmed as CMN. Maternal manifestations of Ballantyne's syndrome, such as lung edema and hypertension, can occur in a mother with fetal CMN even without fetal and/or placental edema. The clinical course of this patient may suggest an etiology of Ballantyne's syndrome., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Mesoblastic nephroma is by far the most frequent intrarenal fetal tumor. To the best of our knowledge, we report the first case of a newborn with an intrarenal neuroblastoma that was discovered prenatally. An intrarenal echogenic and homogenous mass was observed on routine prenatal ultrasonography, corroborated by magnetic resonance imaging, in a 30-week gestation fetus. A male weighing 3280 g was born with elevated blood pressure and cardiac failure. Postnatal ultrasound confirmed a left intrarenal tumor with microcalcifications and perirenal adenopathy. An open total left nephrectomy by laparotomy was performed. The pathologic study reported that the mass was an intrarenal neuroblastoma with local and regional invasion. Immediate postoperative urine analysis revealed a high level of vanillylmandelic acid, and blood samples showed high levels of normetanephrine. The purpose of this report is to demonstrate that prenatal intrarenal neuroblastoma can clinically and radiologically mimick a mesoblastic nephroma. High blood pressure, calcifications, and lymphadenopathy on ultrasound should raise the index of suspicion for a possible malignant process. Preoperative measurement of urinary vanillylmandelic acid (VMA) and metanephrines should be performed if the diagnosis is in doubt., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Agents that can enhance tumor cell apoptosis and inhibit invasion have potential for the treatment of cancer. Here, we report the identification of escin, a pentacyclic triterpenoid from horse chestnut that exhibits antitumor potential against leukemia and multiple myeloma. Whether examined by esterase staining, phosphatidyl-serine staining, DNA breakage, or caspase-mediated poly(ADP-ribose) polymerase cleavage, escin potentiated tumor necrosis factor (TNF)-induced apoptosis but inhibited tumor cell invasion. This correlated with the down-regulation of bcl-2, cellular inhibitor of apoptosis protein-2, cyclin D1, cyclooxygenase-2, intercellular adhesion molecule-1, matrix metalloproteinase-9, and vascular endothelial growth factor, which are all regulated by the activation of the transcription factor NF-kappaB. When examined by electrophoretic mobility shift assay, the triterpenoid suppressed nuclear factor-kappaB (NF-kappaB) activation induced by TNF and other inflammatory agents, and this correlated with the inhibition of IkappaBalpha phosphorylation and degradation, inhibition of IkappaB kinase complex (IKK) activation, suppression of p65 phosphorylation and nuclear translocation, and abrogation of NF-kappaB-dependent reporter activity. Overall, our results demonstrate that escin inhibits activation of NF-kappaB through inhibition of IKK, leading to down-regulation of NF-kappaB-regulated cell survival and metastatic gene products and thus resulting in sensitization of cells to cytokines and chemotherapeutic agents.

Purpose: We established a vitamin A-deficient (VAD) model of pregnant rats to evaluate the effect of vitamin A deficiency in maternal rats on tumor formation in filial rats., Methods: Ten pregnant Wistar rats were divided into 2 groups: (1) VAD group, 6 rats were given nonvitamin A diet from 2 weeks before mating till delivery and (2) normal diet (ND) group, 4 rats were given normal diet. Twenty random neonatal rats from each group were killed on the next day of delivery. The rest neonates were given normal diet for 1 year until killed. Serum levels of vitamin A, morphology of the kidney, incidence of tumor formation, and retinoid X receptor (RXR) alpha messenger RNA (mRNA) expression in renal tissue were assessed for the filial rats., Results: Fifty-six and 49 neonatal rats were born for VAD group and ND group, respectively. The detection rate of nephrogenic rests (NRs) from neonates in VAD group (50%) was significantly higher than that in ND group (20%; P < .05). The incidence of nephroblastoma was 13.9% in filial rats of VAD group and 0% for ND group. The detection rate of NRs for filial rats of VAD group (30.6%) was significantly higher than that of ND group (6.9%; P < .01). The expression of RXRalpha mRNA in tumor tissue of the filial rats of VAD group (3.17 +/- 0.15) was significantly lower than that in kidney tissue of ND group (3.58 +/- 0.20; P < .01)., Conclusion: Deficiency in vitamin A for pregnant rats resulted in renal dysplasia, increased NRs, and higher incidence of nephroblastoma.

While the activity of Snail genes is required during embryonic development for the formation of different tissues and organs, they must be repressed in the adult in order to maintain epithelial integrity and homeostasis. Indeed, pathological activation of Snail in epithelial tumors induces malignancy and the recurrence of tumors. Here we show that in dedifferentiated areas of human renal carcinomas, Snail undergoes a process of reactivation. In addition to tumor progression, renal fibrosis is also linked to the activity of Snail genes and indeed, reactivation of Snail in the adult kidney is sufficient to induce fibrosis. Thus, Snail genes illustrate a paradigm whereby reactivation of crucial embryonic genes in adult tissues provokes the onset of devastating diseases.

The von Hippel-Lindau tumor suppressor pVHL plays a critical role in the pathogenesis of familial and sporadic clear cell carcinomas of the kidney and hemangioblastomas of the retina and central nervous system. pVHL targets the oxygen sensitive alpha subunit of hypoxia-inducible factor (HIF) for proteasomal degradation, thus providing a direct link between tumorigenesis and molecular pathways critical for cellular adaptation to hypoxia. Cell type specific gene targeting of VHL in mice has demonstrated that proper pVHL mediated HIF proteolysis is fundamentally important for survival, proliferation and differentiation of many cell types and furthermore, that inactivation of pVHL may, unexpectedly, inhibit tumor growth under certain conditions. Mouse knock out studies have provided novel mechanistic insights into VHL associated tumorigenesis and established a central role for HIF in the development of the VHL phenotype.

Introduction: Wilms' tumor (WT) is the most frequent embryonic renal neoplasia in children., Objective: This study was carried out to investigate risk factors in the development of WT., Material and Methods: A design of cases and controls, proactive, of incident cases, with four controls per case. The study population of cases were children of two oncologic reference Center of the Mexican Institute of Social Security (IMSS) in the Mexican Federal District during 5-year period. For the control group, children were frequency matched by age and sex at with cases from the same clinic. A questionnaire, previously validated, was applied to determine risk factors in both groups., Results: During the period of study, 34 cases and 136 controls were revised. Significant risk factors were: antecedent of a relative with Down syndrome (OR = 7.6, 95%CI 1.4-51.1, p = 0.008), eczema (OR = 3.7, 95%Cl 1.1-12, p = 0.01); having been conceived in autumn (OR = 5.4, 95%CI 1.3-31.6, p = 0.007) or winter (OR = 4.9, 95%Cl 1.1-29.9, p = 0.01), and beet ingestion (OR = S. 7, 95%Cl 1.7-19.4, p = 0.0007)., Conclusions: In this study, influence of prenatal factors are shown and we attempt to explain the etiology of WT, the important of beet ingestion, and conclusions suggest that that more epidemiologic studies are necessary to determine the chain of events that causes Wilms' tumor.

Purpose: The recent basic science literature is replete with new discoveries in the molecular genetics of renal development. However, little of this information has filtered into urological textbooks and journals. An effort is made herein to integrate these new findings and propose a more sophisticated blueprint of renal development than the one traditionally taught in medical school and residency. To accomplish this goal the author offers simple definitions and interpretations of complicated terms and events, and points out how maldevelopment results when mutations take place., Materials and Methods: A review of recent advances in the molecular genetics of renal development and maldevelopment was done., Results: Renal metanephric development results from the expression of many genes in the ureteral bud and metanephric blastema with each sending messages to the other to induce organogenesis., Conclusions: Currently an understanding of normal renal organogenesis stems from a study of disease states resulting from perturbations in molecular genetics. In turn, a better understanding of normal renal organogenesis facilitates an understanding of how dysplasia, hypoplasia, cystic disease and tumors develop when molecular genetics go awry. For each form of renal dysgenesis and for most renal tumors 1 or more gene defects are eventually identified. The young urologist based in these new discoveries would be better prepared to make the breakthroughs in the future that are necessary for advancing the prevention and management of these conditions.

This article discusses the embryology and anatomy of the kidney and ureter. Surgical approaches, such as the lumbar and thoracoabdominal, are provided. Operations for kidney (i.e., radical nephrectomy, nephroureterectomy, and partial nephrectomy) and ureteric tumors also are discussed.

The fetal kidney is formed by the development of nephrons from fetal metanephric blastema surrounding the ureteric bud. The fetal renal tissue matures into normal renal parenchyma during gestation, but, occasionally, fetal tissue persists into infancy as microscopic foci called nephrogenic rests. Nephrogenic rests are found in approximately 1% of infant kidneys at autopsy. Nephrogenic rests are associated with an increased risk of Wilms tumor, and it is theorized that nephrogenic rests undergo neoplastic change into Wilms tumor. Fortunately, this transformation occurs in less than 1% of young children with nephrogenic rests. Nephrogenic rests are associated with many syndromes, including Beckwith-Wiedemann syndrome, hemihypertrophy, and sporadic aniridia. Children with identifiable syndromes, once diagnosed, should be screened for the development of Wilms tumor. Nephrogenic rests are associated with other lesions such as multilocular cystic nephroma and multicystic dysplasia, usually without malignant complications.

The development of a complex tissue from a few simple precursor cells requires the precise activation and repression of tissue-specific genes that determine cell lineages, tissue patterning, and cellular proliferation. In the kidney, a number of recently identified genes are critical for normal development. Among these, the Pax-2 gene encodes a transcription factor that is expressed in the ureter bud, in the induced kidney mesenchyme, and in the progenitor cells of the glomerular and tubular epithelium. Although the differentiation of the renal epithelium requires Pax-2 function, failure to suppress the gene in mature epithelium is detrimental to normal renal function. Recent, data suggest that the Wilms' tumor-suppressor gene WT1 can down-regulate Pax-2 expression, consistent with high levels of Pax-2 in Wilms' tumors. Additional studies suggest that reactivation of this developmental regulator can contribute to a variety of other renal diseases.

The specificity of IGF2 promoter imprinting was examined in embryonal tissues and Wilms tumour. In several fetal tissues of approximately 12 weeks gestation, IGF2 was found to be monoallelically expressed from all IGF2 promoters i.e. P1, P2, P3 and P4. However, in tissues of slightly older gestation age (15-17 weeks) relaxation of imprinting at the P1 promoter was evident, although the P2-P4 promoters remained imprinted. These data indicate that early in embryogenesis a population of cells exists in which all IGF2 promoters are imprinted, but that as development proceeds the imprinting of the P1 promoter is relaxed. The pattern of IGF2 promoter imprinting was also analysed in Wilms tumour. In some tumours, the pattern of promoter imprinting was identical to that found in early fetal kidney, indicating that this tumour originates within early embryonic kidney tissue. In contrast, in tumours in which relaxation of imprinting had occurred, imprinting relaxation affected all IGF2 promoters. This aberrant pattern of promoter imprinting, which was not detected in fetal kidney, provides further evidence that pathological relaxation of IGF2 imprinting is involved in the genesis of Wilms tumour.

The development of a complex, multicellular organ, such as the kidney, from two embryonic progenitor tissues requires the activation and suppression of transcription factors that regulate tissue and cell type-specific gene expression. From areas as diverse as fruit fly development and human cancer genetics, a number of important genes have been identified that help to orchestrate the early events of renal epithelium induction and differentiation. The Wilms' tumor-suppressor gene WT1 is critical for regulating the early response of the kidney mesenchyme to induction and may play multiple roles during the course of renal epithelial cell development and tumor formation. The Pax-2 gene is activated in the mesenchyme after induction and is necessary for condensation and perhaps proliferation of the induced cells. How these two important gene products exert their effects will be discussed in light of recent evidence on DNA binding, transcription repression, and protein interactions.

The formation of all organs during embryogenesis, including the kidney, is dependent on the timed and sequential expression of a number of polypeptide growth factors. Synthesis and actions of one or more members of the insulinlike growth factor (IGF), epidermal growth factor/transforming growth factor-alpha (EGF/TGF-alpha), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and nerve growth factor (NGF) families have been characterized in the developing metanephric kidney. Studies originating from a number of laboratories have defined the localization of growth factor mRNAs, receptors and peptides, have delineated patterns of growth factor synthesis, have established the growth factor-dependency of embryonic kidney development, and have identified abnormalities of growth factor-expression as potentially causative of aberrancies in metanephrogenesis. The results of these investigations are summarized in this review.

Multilocular cyst of the adult kidney is a benign lesion of uncertain pathogenesis. We report a case studied by immunohistochemical techniques. A malformative histogenesis is suggested.

The clinico-pathologic association of nodular renal blastema, multicystic kidney and obstructive uropathy has been recently identified. We report on a female patient diagnosed as having unilater multicystic dysplasia by prenatal ultrasonography. The patient was nephrectomized at the age of 6 1/2 months. Examination of the resected kidney revealed multiple unilocular cysts in the cortex and hypoplasia of the homolateral ureter; histological study confirmed the presence of multiple cysts limited to the renal cortex, and revealed, among them, multiple cortical metanephric blastema cells islands. Our case supports a relationship between nodular renal blastema, cortical cysts and obstructive uropathy; ureter hypoplasia could cause intraluminal back pressure, with consequent abnormal development of the ampullae, normally endowed in nephronic anlagens induction, cystic tubular ectasia and persistence of nodular renal blastema. The peripheral location of renal nodular blastema and cysts supports a late error in nephrogenesis, at the time of formation of the last generation of nephrons.

Present knowledge of the pathogenesis of Wilms' tumor can be used to plan further epidemiologic investigations in a logical manner. Table 3 summarizes the epidemiologic evidence presently available that implicates various exposures. The proportion of cases of Wilms' tumor that arise from germline mutations is unknown. Future case-control studies could contribute to providing such information by systematically collecting and preserving constitutional genetic material from cases and their parents and neoplastic genetic material from their tumors. The studies that have demonstrated germline mutations so far have involved small numbers of subjects, being the equivalent of "case reports" (36, 37, 45-47, 50, 53). The techniques of molecular biology will be necessary to distinguish germline mutations or equivalent events that have been transmitted by parents from those that have arisen de novo. (Since it has already been shown that phenotypically unaffected parents can transmit relevant mutations to offspring who become affected (45, 46), the presence or absence of phenotypic abnormalities in the parents cannot be used to infer whether germinal mutations have arisen de novo.) Such studies will be laborious and expensive. The best strategy to minimize cost and labor would be restriction on age; the cases diagnosed relatively early in life (before the age of 2-3 years) are more likely to have arisen from germline mutations than those diagnosed later (34). The existence of de novo germline mutations relevant to the development of Wilms' tumor should prompt epidemiologists to search for causal exposures before conception. Preliminary evidence suggests that males have a higher germinal mutation rate (48). On the basis of the epidemiologic evidence to date, Olshan et al. have suggested the following: "paternal preconceptional exposures may play a more important role in the etiology of Wilm's tumor than maternal factors"(8,p.943). Pathologic and molecular biologic studies have shown that Wilm's tumor arises from nephrogenic rests that represent renal stem cells, the development of which has been arrested before normal differentiation occurs (2,44). Exposures that occur during intrauterine life are likely to be relevant to this process; these can be studied with epidemiologic methods, and clues have emerged (7,86,89). It is important to realize, however, that the fetus may be exposed in utero to substances to which the mother was exposed prior to conception, if these substances are excreted slowly or not at all, such as the persistent organochlorine pesticides (96,98). Study of the determinants of the growth behavior of nephrogenic rests (persistence, regression, generalized growth, or malignant transformation (2)) may be possible only in an animal model of Wilm's tumor, if one can be found in which nephroblastoma arises from nephrogenic rests. Ethylnitrosurea, an alkylating agent, causes renal tumors identical to Wilm's tumor in the opossum when given early in postnatal life (103) and in the rabbit when given transplacentally (104). Nephroblastoma in animals is one of the very few types of tumors that is inducible by chemicals via the transplacental route. This mode of induction should be regarded as as an etiologic possibility in humans as well as animals (105). As Hard, however, has pointed out, "nodular renal blastema [now known as nephrogenic rests] or nephroblastomatosis...have [sic] never been described in conjunction with nephroblastoma of animals" (105,p.184). the renal stem cells that give rise to Wilm's tumor normally disappear 4-6weeks prior to birth (19). If they persist after birth, as nephrogenic rests or otherwise, postnatal exposures could contribute to the development of Wilm's tumor. Cases diagnosed later, especially those presenting with lower stage disease, are more likely to have arisen from mutations occurring after birth. Potential carcinogens in children's diet and the home environment are worthy of close study.

Wilms' tumour, a paediatric malignancy of the kidney, is a striking example of the relationship between aberrant development and cancer. Several different genetic loci have been implicated in the aetiology of the tumour; genomic imprinting also plays a role. One Wilms' tumour predisposition gene (WT1), encoding a zinc finger protein, is expressed in a limited set of tissues, including developing nephrons and gonads. The biology and genetics of Wilms' tumour underline the developmental relationship between kidneys and gonads.

The method of separation of germ layers of rodent embryos by treating the embryonic shields with proteolytic enzymes and by microsurgery with the subsequent transplantation to ectopic sites has helped to gain a more detailed insight into what is going on during gastrulation in mammals. The space under the kidney capsule of adult animals seems to be the most appropriate ectopic site for transplantation of early postimplantation rat embryos or separated germ layers. After transplantation the grafts develop into teratomas whose complex histological structure reflects the initial developmental capacities of the graft. At the pre-primitive streak and the early primitive streak stages the primitive ectoderm differentiates into tissue derivatives of all three definitive germ layers, often in complex organotypic combinations. This is indirect evidence that all cells of the embryonic body originate from the primitive embryonic ectoderm. Halves of the primitive ectoderm obtained by a longitudinal or transverse cut through the egg cylinder give the same result. At the head fold stage the capacity for differentiation of the ectoderm is restricted to ectodermal and mesodermal derivatives. One day before gastrulation the isolated primitive ectoderm is not able to differentiate as renal isograft. The mesoderm isolated at the head fold stage and at later stages when its segmentation occurs, differentiates almost exclusively into the brown adipose tissue. The embryonic endoderm differentiates only in combination with the mesoderm. After transplantation the embryonic ectoderm loses its epithelial organization and breaks up into a mass of mesenchyme-like cells in which epithelial structures subsequently appear and differentiate in a way reminiscent of the reaggregation of cells in mixed cell suspension in vitro.

Nephroblastomatosis (NB), a persistence of abnormal embryonal renal tissue beyond 36 weeks' gestation, is often associated with Wilms' tumor. The exact relationship of NB to the development of Wilms' tumor is unclear. Four cases are presented that elucidate the entire morphological spectrum of this disease. Analyses of these cases suggest these conclusions: (1) the NB complex is a spectrum of lesions from benign multifocal nodular renal blastema, resembling residual nephrogenic zones of immature fetal kidney, to Wilms' tumor; (2) infantile NB is a premalignant variant of Wilms' tumor with a favorable outcome usually, when treated early; (3) neonatal nephromegaly requires a complete evaluation and follow-up imaging; persistence mandates biopsy; (4) "second-look" laparotomy is unnecessary with state-of-the-art imaging; and (5) standardization of terminology is essential.

A description of the experimental approaches devised to control the growth of tumors induced by transplacental exposure to carcinogens is given. Due to the massive cell proliferation and differentiation taking place during embryogenesis, fetal tissues are believed to be privileged targets of neoplastic changes. As a consequence, trace amounts of environmental carcinogens capable of accumulating into the conceptuses may determine the appearance of tumors in the offspring, a possibility documented in several animal species including humans. Endogenous and exogenous factors counteracting this process have potential application as regulators of developmental carcinogenesis. Their identification is regarded as a means to chemoprevent pediatric tumors and can be instrumental in the analysis of the aetiopathogenesis of neoplastic phenotypes.

Histochemical characteristics on lectin binding of 16 cases of nephroblastoma and of 57 cases of renal cell carcinoma were studied on those of six embryonal and fetal kidneys in 4 to 24 gestational weeks and in six normal adult kidneys using four biotinylated lectins (PNA, LTA, SBA and UEA-1), which show segment specific binding for normal nephron. In normal nephrogenesis, Gal beta 1-3 GalNAc (PNA receptor) appeared at first in developing tubuli of the metanephros at 10 gestational weeks, and remained positive in proximal tubuli of 13 gestational weeks, where the Lewis X antigen (LTA receptor) emerged. In adult kidneys, Gal beta 1-3 GalNAc distributed along distal tubuli and collecting ducts and not in proximal tubuli. Type 2 H antigen (UEA-1 receptor) was confined to collecting ducts. In nephroblastomas, positive reaction to these lectins were almost exclusively confined to tubular structures. Gal beta 1-3 GalNAc was constantly positive there. Intensely positive stain of Lewis X antigen was observed in three cases of histologically well differentiated type. Lewis X antigen positive tubuli co-expressed Gal beta 1-3 GalNAc. There were six type 2 H antigen positive cases showing differentiation toward ureteric bud or collecting ducts. In view of the cell surface glycosylation, regular differentiation of fetal renal tubuli was also retained in nephroblastomas according to their degree of histological differentiation. In renal cell carcinoma, Gal beta 1-3 GalNAc was positive in 49% (28/57) and Lewis X antigen was positive in 54% (31/57). Type 2 H antigen was completely negative. In contrast to the nephroblastoma, there was no correlation between histological features and lectin binding patterns in renal cell carcinoma.

Erroneous quotations in the literature and Cohnheim's statement, in his Lectures on General Pathology, that the Wolffian body or mesonephros is the first anlage of the urogenital system prompted this description of the growth of our knowledge of the early development of the kidney. Some of the pertinent older literature is reviewed, and the concept of the holonephros, as opposed to the trinephric view of kidney development, is discussed. Emphasis is placed on the decreasing functional significance of the pronephros with evolutionary development, to the extent that the role of the pronephros in the human is questioned. Cohnheim's seemingly erroneous reference to the development of the kidney is shown to be merely a reflection of the views current at his time.

Wilms' tumour or nephroblastoma is one of the commonest solid paediatric malignant diseases, accounting for 8% of childhood cancers. The tumour arises through aberrant differentiation of metanephric mesenchyme and thus represents a paradigm for the relationship of cancer and development. There is considerable heterogeneity in the pathology of Wilms' tumour and several genes have been implicated in its aetiology. One of these genes, located at chromosome 11p13, is categorised as a 'tumour suppressor' gene since loss of function can lead to malignancy. It has not been possible as yet to correlate the involvement of a particular locus with a subset of tumour pathology. The recently cloned Wilms' tumour gene encodes a putative transcription factor which is likely to activate or repress the expression of other genes in kidney development. We have shown by in situ hybridization that expression of this gene is restricted to specific cell types within the developing kidney. It is also expressed in a limited range of embryonic tissues, including the gonad, spleen and mesothelium. With the benefit of this new information, we speculate on the part played by this gene in normal kidney development, in tumorigenesis and in other aspects of Wilms' tumour; these include associated congenital abnormalities, genetic predisposition to second tumours and inheritance of Wilms' tumour.

Wilms tumour (WT) is a developmental anomaly of the kidney which results from loss of function of at least one so called tumour suppressor gene on chromosome 11. The position of the gene at chromosome 11p13 is known through the association of WT with aniridia (lack of an iris), mental retardation and genitourinary abnormalities in the WAGR syndrome. Here we discuss the high resolution mapping studies to locate the position of the gene and conclude that the gonadal abnormalities in WAGR patients may be due to a defect in the WT gene itself. In support of this role in genitourinary development we show that a candidate WT gene is expressed in specific regions of the developing kidney and in fetal and embryonic gonads.

N-Nitrosomethylurea (NMU) (20 mg/kg) was i.p. administered to rats on the 21st day of pregnancy. A decrease of glucose utilisation in the oral glucose tolerance test was found in 3 month old female progeny of NMU-treated rats. The serum insulin level did not differ from control, but serum cholesterol level was higher in offspring of NMU-treated rats. The ability of diethylstilboestrol to inhibit compensatory ovarian hypertrophy was decreased in female hemicastrated 3 month old rats whose mothers were treated with NMU. Postnatal administration of the antidiabetic drug buformin decreased the malignant neurogenic tumor incidence 3.5 times (to rats transplacentally treated with NMU).

The association of nodular renal blastema, renal dysplasia and duplicated collecting systems may represent more than a histopathological observation. Based on the "double hit" theory of oncogenesis, the appearance of this histologic pattern in kidneys with other developmental alterations may account for an increased risk of neoplasia.

With the aim of expanding knowledge on the pathogenesis of nephroblastomata, an embryological organ culture system (Grobstein, 1956) was tested for its applicability to in vitro carcinogenesis experiments by using murine sarcoma virus (MSV-M) and 3-methylcholanthrene (MCA). Treatment of CBA/H-T6 mouse metanephrogenic mesenchyma with MSV-M at the pretubular stage neither disturbed the glomerulogenesis nor induced rapid malignant transformation. Treatment of the same tissues with MCA considerably inhibited the glomerulogenesis but failed to also reduce rapid malignant transformation. However, one MSV-M, one MCA and two untreated cultures showed malignant transformation after prolonged survival in vitro and produced different histological types of tumours upon transplantation into newborn CBA/H-T6 mice.

133 patients in whom a Wilms' tumour had been diagnosed between 1971 and 1986 were evaluated retrospectively for presence of congenital anomalies of the genitourinary tract. These were detected in 51 patients, 38.3%. A comparison was made between the incidence of each detected malformation in the patient group and in the general population. Some anomalies seemed to have a high association with the nephroblastoma; sharing the same basic embryological disorder is suggested as a possible explanation for this association.

Mesoblastic nephroma (individualized by Bolande in 1967) is a congenital renal tumor sometimes locally and regionally aggressive but never giving metastases, in contrast with nephroblastoma. It almost always occurs in the newborn. Therefore, every renal tumor discovered before twelve months must evoke mesoblastic nephroma. No preoperative adjuvant treatment must be used in infants under six months old. Considering five personal observations and review of literature, the authors expose the main etiologic and clinical characteristics of the disease, the gross and microscopic features which allow its diagnosis and the histogenetic theories of this curious lesion, probably border-line between neoplasias and dysplasias of renal parenchyma.

Gestational risk factors for Wilms' tumor were investigated in a pair-matched case-control study. Cases who were under 15 years of age at diagnosis during 1970-1983 were identified through the registries of the three main hospitals treating childhood cancer in the greater Philadelphia area. Controls were selected by random digit dialing and were matched to cases on race, birth date, and telephone area code and exchange. Because of a low participation rate among nonwhites, results are reported only for the 88 white matched pairs whose parents were interviewed by telephone. Of the hypothesized risk factors, maternal use of hair-coloring products in the year prior to the index child's birth (odds ratio, 3.6; P = 0.003) and hypertension or fluid retention during pregnancy (odds ratio, 5.0, P = 0.01) were significantly associated with increased risk of Wilms' tumor. Use of hair-coloring products was strongly associated with cases in which Wilms' tumor was diagnosed before 2 years of age (odds ratio, 15; P = 0.001). For two other gestational factors, tea drinking and vaginal infection, the odds ratios were significantly elevated for all cases and the effects were concentrated among the nongenetic cases. Bilateral cases had a significantly higher mean birth weight than did their controls. Older maternal age was significantly associated with the genetic form of Wilms' tumor. Adjustment for possible confounders and consideration of the time interval between the index pregnancy and the interview did not substantially alter the findings.

A karyotypically normal male embryonal carcinoma (EC) cell line, P19, produced large numbers of chimaeras in midgestation after groups of cells were injected into mouse blastocysts. A wide variety of apparently normal tissues were colonized by the EC cells but most chimaeras were also morphologically abnormal. Few live chimaeras were produced and all contained tumours of EC cell origin as well as EC contributions to normal tissues. This apparently incomplete regulation of the EC cells by the embryonic environment was not due to EC cell variation, since a clonal subline. P19S18, produced similar patterns of colonization. It was also not caused by the inability of the blastocyst to regulate large numbers of injected EC cells, since a single P19S18 cell could contribute to both normal and tumour tissue in the same mouse. Neither a high rate of colonization of the embryo nor a normal karyotype is, therefore, sufficient to ensure reversion of EC cells to normal embryonic behaviour.

We report on a developmental malformation of the lung and kidney which has not been previously described and which we have chosen to call "cystic hamartomata of the lung and kidney" to emphasize the non-malignant nature of these lesions. We also confirm a previous case report by Weinberg and Zumwalt [1977] as a different distinct disorder that results in a multifocal cystic hamartomata of the lung with associated marked parenchymal overgrowth of the kidney (the Weinberg-Zumwalt syndrome). These cases represent a spectrum of abnormal morphogenesis affecting both kidney and lung. Patients 1 and 2 presented during infancy with abdominal masses and hypertension due to bilateral multilocular cysts of the kidney with associated hamartomatous pulmonary cysts; patient 2 also had one area of cellular mesoblastic nephroma. Patient 3 demonstrated markedly hyperplastic renomegaly with medullary dysplasia in association with bilateral cystic hamartomata of the lungs. During the fifth week of gestation, the ureteric bud invades the unsegmented mesoderm that becomes the metanephric system, and the lung bud invades the splanchic mesoderm, which provides the stimulus for its growth. We suggest that the predominant pattern of a congenital kidney or lung hamartoma might reflect the timing of a prenatal neoplastic event affecting these developmental processes.

A case of Wilms' tumor occurring in a horseshoe kidney is reported in which bona fide nervous tissue containing ganglion cells was observed. This finding cannot be reconciled with the currently held "metanephrogenic blastema" theory of the histogenesis of this tumor. Masson's concept of "neuroepithelial origin" of the Wilms' tumor should be re-evaluated.

A case is reported of a child with male pseudohermaphroditism in whom Wilms tumor developed at age twenty-two months. The tumor was treated accordingly, but the child subsequently died of nephrotic syndrome with renal failure at age thirty-two months. After reviewing the similar concurrence of these disorders described as a syndrome, it was suggested that they may have basic embryologic abnormalities in common and that all of them originate during embryogenesis. The importance of bearing this syndrome in mind in the management of a child with abnormal gonadal differentiation is stressed.