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Demonstration of renin gene expression in nephroblastoma by in situ hybridization.

Most patients with nephroblastoma have high levels of plasma renin and some are hypertensive. Blood pressure falls after removal of the affected kidney, suggesting that nephroblastoma is associated with renin production either by the tumour or by the kidney. In this study, direct evidence was sought of renin gene expression in nephroblastoma using in situ hybridization. Digoxigenin-labelled riboprobes and an immunoperoxidase technique were used to detect cells containing renin mRNA: this showed renin gene expression in 9 out of 12 cases. There were positive cells within metanephric blastema and in occasional neoplastic glomeruloid structures, confirming that in seven cases nephroblastoma tumour cells expressed the renin gene. However, renin gene expression was also demonstrated in perivascular cells of uncertain lineage in seven cases; in five cases there was evidence of renin gene expression in both tumour cells and perivascular cells. The latter finding raises the possibility that some of the cells expressing the renin gene could be stromal cells. It is concluded that nephroblastomas contain cells that express the renin gene and that some are tumour cells, while other perivascular cells may be stromal cells.

Child↗

Renin gene expression in nephroblastoma.

Most cases of nephroblastoma have high plasma levels of prorenin which is biologically inactive. Plasma prorenin levels fall to normal following nephrectomy. In order to ascertain whether renin synthesis occurs in nephroblastomas we decided to search for renin-specific mRNA using a cDNA probe and Northern blot analyses on total RNA purified from snap-frozen human tumour tissue obtained at nephrectomy. We demonstrated renin-specific mRNA in 5/11 (45 per cent) nephroblastomas. It was 1.6 Kb in length, similar to the mRNA detected in normal kidney tissue and in kidneys with renal artery stenosis. In one of the cases of nephroblastoma, in which we could detect no normal renin mRNA at 1.6 Kb, the cDNA probe hybridized with a higher molecular weight mRNA 3 Kb in length. We conclude that some nephroblastomas synthesize renin.

Gene Expression↗

Adhesive activity of gicerin, a cell-adhesion molecule, in kidneys and nephroblastomas of chickens.

Gicerin, a cell-adhesion molecule belonging to the immunoglobulin superfamily, has both homophilic and heterophilic binding activities to neurite outgrowth factor, an extracellular matrix molecule in the laminin family. Gicerin is thought to play a role in the normal development of chicken kidney, because it is expressed abundantly in the embryonic organ and only slightly in the mature organ. In this study, we have examined the adhesive activity of gicerin in the kidney to characterize its function in organogenesis. We have also examined the function of gicerin in chicken nephroblastomas ("embryonic nephromas"), which show various structures resembling those in embryonic kidneys. Immunohistochemically, the expression patterns of gicerin and neurite outgrowth factor in nephroblastomas are similar to those of embryonic kidneys. Cell-aggregation assays have shown that primary culture cells from both embryonic kidneys and nephroblastomas have strong aggregation activities, and that each aggregation is partially inhibited by gicerin antibody. In contrast, cells from adult kidney exhibit weak aggregation activity that is not inhibited by the antibody. In addition, ligand blot analysis has revealed that gicerins in embryonic kidney and nephroblastoma bind to purified neurite outgrowth factor, whereas extracts from adult kidney show no positive reaction. These findings suggest that the homophilic and heterophilic adhesive activities of gicerin are involved in the formation of both normal kidney and nephroblastoma.

Animals↗

Incidence, histopathologic and electron microscopic features of spontaneous nephroblastomas in rats.

Primary renal neoplasms in the rats are uncommon. Nephroblastoma is the only renal embryonal tumor of the rat; all other tumors are reported in older rats. The occurrence of spontaneous nephroblastoma in rats has been reported. However, metastasis from the nephroblastoma in rat is extremely rare. Data from 2669 Sprague-Dawley control rats and 1060 Fischer-344 rats were reviewed and evaluated to determine the incidence and pathology of nephroblastoma. This tumor was observed in three Sprague-Dawley rats. Metastasis was observed in the lungs and renal lymph nodes in two different rats. No case of nephroblastoma was observed in Fischer-344 rats. Detailed histopathological and electron microscopic features of these neoplasms are described and discussed.

Animals↗

The enhancing role of vitamin A deficiency on chemically induced nephroblastoma in rats.

PURPOSE: Vitamin A plays an important role in the prevention of neoplasia. The occurrence of nephroblastoma, a common renal malignancy of childhood, is said to be closely correlated with retardation of differentiation of metanephric blastema. The aim of this study was to clarify the effect of vitamin A deficiency (VAD) in experimental nephroblastoma. METHODS: Sixty weaning outbred female Wistar rats weighing 40 to 50 g were injected with 0.35% dimethylhydrazine dihydrochloride (DMH) subcutaneously and divided into 2 groups. Animals were fed with diets containing vitamin A, normal diet (ND group; n = 30), and vitamin A-deficient diet (VAD group; n = 30). Serum concentrations of vitamin A on day 120 after DMH injection were assayed. The incidence of nephroblastomas in 2 groups was recorded. The renal tissues were prepared for morphological studies and WT1 messenger RNA (mRNA) detection on day 365 after DMH injection. RESULTS: The average serum concentrations of vitamin A in the ND group (2.60 +/- 0.53 mumol/L) were significantly higher than that in the VAD group (0.51 +/- 0.26 mumol/L, P < .05) 120 days after DMH injection. On day 365, the incidence of renal tumors in the VAD group (36.7%) was significantly higher than that of the ND group (13.3%, P < .05). Certain histological and ultrastructural features and WT1 mRNA expression patterns observed in these tumors showed that they had a resemblance to human nephroblastomas. Nephrogenic rests (NRs) could be seen in the adjacent normal renal parenchyma. The incidence of NRs in the VAD group (16.7%) was significantly higher than that in the ND group (3.3%, P < .05). The mutant WT1 mRNA expression levels in the VAD group (0.75 +/- 0.11) were significantly higher than those in the ND group (0.24 +/- 0.06, P < .05). CONCLUSIONS: Vitamin A deficiency can increase development of nephroblastomas in rats, probably via a mechanism of elevated NR remnants and WT1 expression.

Animals↗

Treatment of cystic nephroma and cystic partially differentiated nephroblastoma--a report from the SIOP/GPOH study group.

PURPOSE: Cystic partially differentiated nephroblastoma is a rare variant of Wilms tumor, and might be confused with cystic nephroma. Definitive diagnosis can only be made by histological examination. Therefore, initiation of therapy, either primary nephrectomy or preoperative chemotherapy, might create a dilemma when radiological diagnosis is doubtful. MATERIALS AND METHODS: To define treatment strategies for these entities, we reviewed the records of 1,245 patients enrolled in SIOP (International Society of Pediatric Oncology) trials 93-01 and 2001 GPOH (German Society of Pediatric Oncology and Hematology) between July 1993 and August 2004. Data were collected retrospectively. Therapy, outcome and preoperative management were evaluated. To confirm diagnosis of cystic nephroma/partially differentiated nephroblastoma, all patients underwent review by the Reference Pathology Center of SIOP/GPOH. RESULTS: A total of 14 patients with diagnoses of cystic nephroma (7) and cystic partially differentiated nephroblastoma (7) were identified. Median patient age at diagnosis was 1 year (0.46 to 3). Two patients received preoperative chemotherapy. Primary nephrectomy was performed in 12 patients. Two patients underwent partial nephrectomy. In 1 child postoperative chemotherapy was administered. None of the patients had progression of disease or recurrence. Overall survival was 100%. Median followup was 2.41 years (0.3 to 9). CONCLUSIONS: In cystic renal tumors radiological findings should always be reviewed by the reference radiologist of the treatment protocol study group. Irrespective of the chosen therapy, outcome of cystic nephroma and cystic partially differentiated nephroblastoma is favorable. Even in large international trials the number of patients with cystic nephroma or cystic partially differentiated nephroblastoma is too small for statistical analysis.

Child, Preschool↗

Adult nephroblastoma--five cases treated by surgery, radiotherapy and chemotherapy.

Nephroblastoma in adults is rare; consequently very little experience of treatment for adult cases has been reported. We report five cases of adult nephroblastoma managed by nephrectomy, radiotherapy and combination chemotherapy. The treatment schedules were derived from childhood nephroblastoma regimens. However, four of the five patients were dead within 12 months of nephrectomy and all five had progression of disease whilst on combination chemotherapy. A good prognosis should not be anticipated for adult nephroblastoma. The chemotherapy schedules which are so successful in childhood nephroblastoma may require modification to improve prognosis in adults.

Adult↗

Cystic partially differentiated nephroblastoma and polycystic Wilms tumor: a spectrum of related clinical and pathologic entities.

Cystic partially differentiated nephroblastoma is a rare neoplasm occurring in young children and demonstrating features of classic nephroblastoma (Wilms tumor) and multilocular cysts. Cystic partially differentiated nephroblastoma actually represents a spectrum of cystic renal tumors in which varying amounts of blastema, stroma and epithelial structures are present. Some of these lesions should, perhaps, be classified more accurately as polycystic nephroblastoma. The clinical and pathologic findings, and management of 2 infants with cystic partially differentiated nephroblastoma are presented. The controversy over the histogenesis of these lesions and whether they should be considered benign or potentially malignant is discussed.

Diagnosis, Differential↗

[Aniridia and Wilms tumor: 2 cases of fetal rhabdomyomatous nephroblastoma].

BACKGROUND: Wilms tumor is associated in 7 to 10% of patients with congenital abnormalities. Among those, aniridia is the most constant feature of the WAGR syndrome that includes, in one third of cases. Wilms tumor. We report two cases of aniridia associated with fetal rhabdomyomatous nephroblastoma. CASE REPORTS: Case 1. A one-year old girl with congenital aniridia was admitted for macroscopic hematuria. Abnormal ultrasonography and tomodensitometry revealed a large, bilateral, kidney tumor. The patient was given actinomycin and vincristine, without efficacy. Bilateral tumorectomy was performed 6 months later and the histological study showed a fetal rhabdomyomatous nephroblastoma. This patient is in remission at the age of 5. Case 2. A boy, also with congenital aniridia, presented with macroscopic hematuria at the age of 2 years revealing a nephroblastoma located on his right kidney. Preoperative chemotherapy remained uneffective and the nephrectomy performed 1 month later permitted the diagnosis of fetal rhabdomyomatous nephroblastoma. The patient is well 4 years later. CONCLUSION: Both cases of fetal rhabdomyomatous nephroblastoma, a histological variant of Wilms tumor, seem to be the first reported in the WAGR syndrome.

Aniridia↗

[Histopathology of nephroblastomas (author's transl)].

Nephrectomy specimens from 42 patients with nephroblastoma were investigated. With the exception of one specimen (the patient had been treated preoperatively), all of the tumors were suitable for grading procedures. When the tumors were classified by the grading procedure of Lawler et al. (1975), the moderately tubulus-rich type++ was the most common (22 out of 41 patients). When the classification of Beckwith and Palmer (1978) was applied, the mixed type of nephroblastoma dominated correspondingly (19 out of 41 patients). Patients with an increased risk can be identified particularly well with the classification of Beckwith and Palmer. The following histologic features are indications of an unfavourable prognosis: focal or diffuse "anaplasia" of the tumor tissue, or a sarcomatous component in a stroma-rich nephroblastoma. The children with sarcomatous nephroblastoma (5 patients) were remarkably young (the oldest was 16 months of age), whereas the children with anaplastic nephroblastoma (3 patients) were much older (62, 67, and 72 months). In five children equivalents of the nephroblastomatosis complex (nodular renal blastema in all 5 patients, sclerosing metanephric hamartoma in 2 patients, and Wilms' tumorlet in one patient) were found in the non-infiltrated tissue of the same kidney.

Age Factors↗

Nephroblastoma in the rat: histology of a spontaneous tumor, identity with respect to renal mesenchymal neoplasms, and a review of previously recorded cases.

The histology of a spontaneously occurring neoplasm of the rat kidney conforming to a classification of nephroblastoma is described and compared with that of N-nitrosodimethylamine-induced renal mesenchymal tumors. This rat nephroblastoma was an encapsulated epitheloid neoplasm with a uniform histologic pattern. Clumps of densely crowded, hyperchromatic cells frequently associated with central, well-differentiated ducts were supported by a less cellular, interconnecting stroma of loose areolar or mature fibrous connective tissue. Neoplastic cells were organized into primitive, ill-defined tubular formations. The neoplastic cell component strongly resembled metanephrogenic blastema. In contrast, the renal mesenchymal tumor was nonencapsulated and consisted of a heterogeneous mixture of connective tissue elements including fibroblast-like spindle cells, smooth muscle, and embryonic mesenchyme that engulfed and sequestered preexisting renal tubules and glomeruli. The separate morphologic identities and apparently unrelated existence of rat nephroblastoma and renal mesenchymal tumor were stressed. The rat nephroblastoma morphologically resembled the malignant epithelial component of human Wilms' tumor, whereas rat renal mesenchymal tumor appeared to have counter-parts in the mesenchymal component of Wilms' tumor and in congenital mesoblastic nephroma (leiomyomatous hamartoma) of infancy. The histologic descriptions of previously recorded occurrences of spontaneous and experimentally induced rat neoplasma classified as nephroblastoma or its synonyms were reevaluated in comparison to the present case. In all but four instances, in which sufficient histologic detail was provided in previous reports, a consistent histologic pattern emerged for this neoplasm in the rat.

9,10-Dimethyl-1,2-benzanthracene↗

Expression of calbindin-D28K in sporadic nephroblastomas of the chicken.

Calbindin-D28K (Ca-D28K) is a calcium-binding protein. In the kidney, Ca-D28K is present in the distal nephron, but not in the proximal nephron. This site-specific distribution in the kidney indicates that Ca-D28K is a potential marker for the differentiation of the distal nephron. In this study, we have examined the expression of Ca-D28K in 25 sporadic cases of chicken nephroblastomas. All cases of nephroblastomas were composed of atypical tubular structures, blastemal cells, and fibrous stroma in varying degrees of differentiation. Immunohistochemically in all nephroblastoma specimens, Ca-D28K was expressed in the epithelial cells of the subsets of tubular structures, but not in the blastema or the stroma. These results suggested that the tubuli in the nephroblastomas are able to differentiate into the phenotype of distal nephrons. Furthermore, Ca-D28K might develop as a novel diagnostic marker for nephroblastomas because this molecule is reported to be completely negative in other renal tumors, including renal cell carcinoma, chromophobe carcinomas, and oncocytoma.

Animals↗

Differential expression of the multidrug resistance-related protein MRP1 in the histological compartments of nephroblastomas.

Nephroblastomas (Wilms' tumors) are curable with survival rates above 80%. Some tumors, however, fail to respond to therapy and those patients have a poor prognosis. In a search for prognostic markers, we investigated the expression of the multidrug resistance-related protein 1 (MRP1) in 32 nephroblastomas by means of immunohistochemistry. The immunohistochemical results were validated with a real-time RT-PCR technique. MRP1 expression was heterogeneous and predominantly found in the blastemal and epithelial compartments compared to the stromal elements of nephroblastomas. We found significant relationships of MRP1 expression to survival of patients and to expression of p53, HSP70, and LRP/MVP. The relationship between MRP1 and p53 expression is a clue that the transcriptional control of MRP1 by p53 reported for other tumor types may also take place in nephroblastomas. The correlation of MRP1 to other drug resistance genes, e.g. HSP70 and LRP/MVP in nephroblastomas indicates that the co-expression of different drug resistance genes may be under a common regulation of still unknown transcription factors.

ATP-Binding Cassette Transporters↗

[Expression of p53 in nephroblastoma and neuroblastoma].

We studed on the expression of p53 in 48 nephroblastomas and 32 neuroblastomas wit, immunohistochemical method of avidinbiotinperoxidase complex. 11 of the nephroblastomas were positive and all neuroblastomas were negative. Statistical analysis revealed that abnormal expression of p53 was significantly correlated with NWTS--II classification, NWTS--III clinical pathology stages and metastasis of nephroblastoma. The results indicate that abnormal expression of p53 is not only involved in the development, but also in the differentiation and metastasis of nephroblastoma. Therefore, detection of p53 expression may have significant clinical importance in the evaluation of prognosis of nephroblastoma. However, the absence of expression of p53 in neuroblastomas suggests that the inactivation of this gene does not play a significant role in the tumor's occurring and progression.

Child↗

[The diagnostic and prognostic characteristics of nephroblastoma recurrences in children].

A total of 450 children with nephroblastoma were treated in the children's oncological department of the All-Union Cancer Research Centre, the USSR Academy of Medical Sciences, between 1976 and 1986. Tumour relapses were diagnosed during various terms of postsurgery in 131 (29.1 per cent) of them: true relapses in 58 (44.1); retroperitoneal lymph nodal metastases in 56 (42.7 per cent) and the both patterns in 17 (13.2 per cent) patients. The majority of the children were older than 3 years. The initial and the most common manifestations of nephroblastoma relapses were the following symptoms: weakness and diminished appetite (93.1 per cent) pale skin (78.6 per cent), abdominal pains (77 per cent), enlarged abdomen (73 per cent), a palpable tumour (82.4 per cent), neurological symptomatology: defecation and urination disorders (12.9 per cent), pareses and paralyses of lower extremities (6.8 per cent). Timely usage of diagnostic complex measures (palpation under the control of myorelaxants, ultrasonic and computed tomography, angiography) enables one to diagnose nephroblastoma relapses. Such histological patterns of nephroblastoma as nondifferentiated blastema, sarcomatoid and rhabdoid tumours were considered as prognostically unfavourable ones. More relapses were diagnosed in children over 4 years. Some cases of nephroblastoma relapses are also caused by the operative technique (lumbar incision in nephrectomy) and extension of the tumour (into the adjacent organs and tissues--Stage II disease). Pre- of intraoperative ruptures of tumour capsules is a principal factor contributing to relapses. Radiation and chemotherapy are found to be mandatory for the prevention of the ruptures.

Adolescent↗

Avian nephroblastomas induced by a retrovirus (MAV-2) lacking oncogene. II. Search for common sites of proviral integration in tumour DNA.

To demonstrate the existence of a common site of integration in independent tumour clones, restriction mapping of the vicinity of integrated MAV-2 proviruses in nephroblastoma DNA was performed, using Southern hybridization with an MAV-2 specific probe U3(pAT). The results have shown that (1) nephroblastomas are of semiclonal origin. (2) Nephroblastoma cells contain an average of 5 clonally located integrated proviruses per diploid genome; they do not contain any detectable amount of non-integrated proviruses. (3) In the DNA from independent nephroblastoma clones, there appear at an increased frequency Tth111I fragments of 14.6 and 17.8 kb that hybridize with the U3(pAT) probe. Considering a random selection of integration sites, such coincidence is of little probability. Thus we suppose that these fragments represent a common site(s) of integration with an MAV-2 proviral insert. Two hypotheses concerning possible mechanisms of nephroblastoma induction are discussed: proto-oncogene insertional activation and anti-oncogene insertional inactivation.

Animals↗

[The place of conservative surgery in the treatment of nephroblastomas (author's transl)].

The authors report their experience with partial nephrectomy for nephroblastoma in children. In a series of 83 cases, 10 had this operation in order to avoid chronic renal insufficiency: six for nephroblastomas which were bilateral from the onset; two for nephroblastoma in a single remaining kidney; one for nephroblastomatosis, and one operated with an erroneous diagnosis. In bilateral nephroblastomas they advise two stage operations with extemporaneous histologic control. The easiest side to operate is operated the first, and a urographic examination is done prior to the second operation. The location of the tumor, more than its size, is a determining factor for this conservative intervention. One must be prepared to do minute dissection of the pedicle. However, if there remains too little renal parenchyma, it is not worthwhile to preserve the pedicle. Contraindications for conservative surgery are: thrombosis of the renal vein, central location of the tumor, fragility of the tumor risking rupture during surgical manipulation, and spread of the tumor beyond the capsule. In 13 partial nephrectomies there was a single failure due to thrombosis of a renal vein. Ten children are alive with a follow up of nine months to eight years. None have a progressive tumor. It is certain that with chemiotherapy tumorectomies are reasonable in certain cases of nephroblastoma.

Child↗

Enucleative surgery for stage I nephroblastoma with a normal contralateral kidney.

PURPOSE: Tumor enucleation is not recommended for children with nephroblastoma and a normal contralateral kidney. However, in adults with unilateral low stage renal cell carcinoma tumor enucleation may offer an alternative to radical nephrectomy, since functioning renal tissue is preserved without a greater risk of residual microscopic disease. Enucleative surgery may be more reasonable in children with nephroblastoma, because the risk of relapse can be reduced with chemotherapy. Therefore, we prospectively evaluated the feasibility of enucleative surgery in children with stage I unilateral nephroblastoma. MATERIALS AND METHODS: Between 1992 and 1995, 13 children with nephroblastoma and a normal contralateral kidney were consecutively admitted to our surgical unit. Possible candidates for tumor enucleation were evaluated according to certain criteria, including stage I disease at diagnosis, well-defined margins on post-contrast computerized tomography and at least 50% of the functioning kidney could be preserved. Preoperative and postoperative chemotherapy was given in all cases. RESULTS: Of 4 children with preservation of more than 50% of the functioning kidney 3 were considered eligible for enucleation. The tumors, which were confined to the mid kidney in 2 children and upper renal pole in 1, were successfully enucleated without hypothermia or vascular occlusion. All 3 children are disease-free at 49, 48 and 26 months of followup, respectively. Renal function has been almost completely restored postoperatively. CONCLUSIONS: These preliminary data suggest that enucleative surgery may be a reasonable option in select children with stage I nephroblastoma and a normal contralateral kidney.

Child↗