Cytologic characteristics of Wilms' tumors in fine needle aspirates. A study of ten cases

The cytologic findings observed in fine needle aspiration (FNA) biopsy smears from ten cases of Wilms' tumor are reported. Blastemal cells, small, round cells with slightly oval nucleoli and fine, evenly dispersed chromatin, were recognized in all cases. Stromal (90%) and epithelial components (40%) were also present. Additional recognizable features were anaplasia (in two of three cases having histologic anaplasia), rosettes (four cases), necrosis (six cases) and inflammatory cells (six cases). In six cases, small fragments of tissue were also recovered for histologic examination after paraffin embedding. There were no complications attributable to the procedure. FNA cytology may be used as the sole diagnostic procedure for Wilms' tumors when preoperative chemotherapy protocols are in use.     

Expression of the PAX2 gene in human fetal kidney and Wilms' tumor.

We have examined the pattern of expression of the human PAX2 gene in Wilms' tumors and human fetal kidney by Northern blot and in situ hybridization. Human PAX2 encodes a paired box-containing protein and has a high degree of homology with mouse and Drosophila paired box genes. In situ hybridization analysis reveals that PAX2 is expressed in nephrogenic structures in fetal kidney and also in Wilms' tumors. This pattern of expression suggests that PAX2 may have a role in differentiation of tissues in the kidney. In fetal kidney, PAX2 expression rapidly attenuates following the initial differentiation, but no evidence of attenuation was found in Wilms' tumors. The timing of PAX2 expression is restricted to fetal development, although high levels of expression were also observed in nephrogenic rests of residual normal juvenile kidney tissue adjacent to a Wilms' tumor. Nephrogenic rests are the presumptive precursors of Wilms' tumor but are not necessarily neoplastic. The failure of PAX2 expression to attenuate in Wilms' tumors and nephrogenic rests may be associated with events leading to the onset of Wilms' tumor. By somatic cell hybrid mapping, the PAX2 gene was localized to chromosome 10q22.1-q24.3, although this region has not previously been implicated in Wilms' tumor.     

Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms'' tumor cells.

Children with associated Wilms' tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) frequently have a cytogenetically visible germ line deletion of chromosomal band 11p13. In accordance with the Knudson hypothesis of two-hit carcinogenesis, the absence of this chromosomal band suggests that loss of both alleles of a gene at 11p13 causes Wilms' tumor. Consistent with this model, chromosomes from sporadically occurring Wilms' tumor cells frequently show loss of allelic heterozygosity at polymorphic 11p15 loci, and therefore it has been assumed that allelic loss extends proximally to include 11p13. We report here that in samples from five sporadic Wilms' tumors, allelic loss occurred distal to the WAGR locus on 11p13. In cells from one tumor, mitotic recombination occurred distal to the gamma-globin gene on 11p15.5. Thus, allelic loss in sporadic Wilms' tumor cells may involve a second locus on 11p.     

Retroperitoneal tumors in children; roentgen diagnosis

A study was undertaken to determine whether there are any features of retroperitoneal tumors in children that might be demonstrated on roentgenograms to aid in identifying them preoperatively. Study was limited to Wilms' tumor of the kidney and neuroblastoma. Calcification was found in 57 per cent of the neuroblastomas and in only 12 per cent of Wilms' tumors. Calcifications in neuroblastomas differed from those in Wilms' tumors. Calcification in neuroblastoma was more frequent in older children than in the younger ones. The kidney was frequently displaced by both types of tumor. However, the neuroblastoma always displaced the kidney downward, or downward and slightly outward. In most instances, the Wilms' tumor also displaced the kidney downward and outward, but in some instances upward and medially. This, of course, depended upon the site of origin of the tumor. There was a distortion of the intrarenal structures in 75 per cent of the cases of neuroblastoma and in 71 per cent of the cases of Wilms' tumor.     

Evaluation of polysialic acid in the diagnosis of Wilms' tumor. A comparative study on urinary tract tumors and non-neuroendocrine tumors

The polysialic acid moiety of the neural cell adhesion molecule has been shown to represent an onco-developmental antigen which can be detected in both embryonic human kidney and Wilms' tumor but not in normal adult human kidney. In the present comparative study, Wilms' tumors, clear cell (bone-metastasizing) sarcomas of kidney, cystic nephromas, renal cell carcinomas, transitional cell carcinomas and papillomas of the renal pelvis, ureter and urinary bladder (as well normal transitional epithelium from these regions). Ewing sarcomas, hepatoblastomas, rhabdomyosarcomas, and carcinomas of the stomach, colon, exocrine pancreas, lung, and esophagus, were investigated immunohistochemically for the presence of polysialic acid. In addition, immunoblot analysis was performed in selected tumors. With the exception of Wilms' tumor, none of the tumors investigated was positive for polysialic acid. In Wilms' tumor, blastemal cells and all epithelial components were positive but no immunostaining was observed in the stroma. These observations emphasize the potential value of a monoclonal anti-polysialic acid antibody in identifying blastemal metanephric cells and their epithelial differentiatives in Wilms' tumor.     

A common region of loss of heterozygosity in Wilms' tumor and embryonal rhabdomyosarcoma distal to the D11S988 locus on chromosome 11p15.5

The development of Wilms' tumor has been associated with two genetic loci on chromosome 11: WTI in 11p13 and WT2 in 11p15.5. Here, we have used loss of heterozygosity (LOH) in Wilms' tumors to narrow the WT2 locus distal to the D11S988 locus. A similar region was apparent for the clinically associated tumor, embryonal rhabdomyosarcoma. We have also demonstrated that a constitutional chromosome translocation breakpoint associated with Beckwith-Wiedemann syndrome and an acquired somatic chromosome translocation breakpoint in a rhabdoid tumor each occur in the same chromosomal interval as the smallest region of LOH in Wilms' tumors and embryonal rhabdomyosarcoma. Finally, we report the first Wilms' tumor without a cytogenetic deletion that shows targeted LOH for 11p15 and 11p13 while maintaining germline status for 11p14.     

An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor

We have recently described the isolation of a candidate for the Wilms' tumor susceptibility gene mapping to band p13 of human chromosome 11. This gene, primarily expressed in fetal kidney, appears to encode a DNA binding protein. We now describe a sporadic, unilateral Wilms' tumor in which one allele of this gene contains a 25 bp deletion spanning an exon-intron junction and leading to aberrant mRNA splicing and loss of one of the four zinc finger consensus domains in the protein. The mutation is absent in the affected individual's germline, consistent with the somatic inactivation of a tumor suppressor gene. In addition to this intragenic deletion affecting one allele, loss of heterozygosity at loci along the entire chromosome 11 points to an earlier chromosomal nondisjunction and reduplication. We conclude that inactivation of this gene, which we call WT1, is part of a series of events leading to the development of Wilms' tumor.     

Metanephric adenoma.

In a recent survey of more than one hundred childhood renal tumors in our Laboratory files, we identified a unique case characterized by an unusual degree of differentiation and cell maturity. Histologically this case was notable for an orderly array of small and uniformly-packed tubules with a rosette-like configuration. The nuclei were oval, smooth and of a bland appearance. Mitoses were absent. Many glomerular figures were intermingled. This renal tumor picture is somewhat different from that known as tubular Wilms' tumor because of the well-differentiated adenomatous pattern and the absence of any blastema. The term metanephric adenoma is suggested for this tumor, which may represent the benign counterpart of Wilms' tumor.     

Effect of chemo- and radiotherapy on the growth of human strains of respiratory and excretory organ tumors transplanted in athymic mice

The effect of single and five-fold administration of 12 chemotherapeutic drugs on human strains of larynx, lung and kidney cancers and Wilms' tumor transplanted in nude mice was studied. Wilms' tumor was found to be more responsive to dactinomycin and cyclophosphamide. Larynx, lung and kidney cancers were resistant to all the chemotherapeutic drugs studied. The effect of irradiation of larynx cancer which resulted in short-term tumor growth retardation was also studied.     

Metanephric adenoma vs. Wilms' tumor: a report of 2 cases with diagnosis by fine needle aspiration and cytologic comparisons

BACKGROUND: Metanephric adenoma (MA) is a rare benign renal neoplasm that can occur at any age, whereas, Wilms' tumor (WT) is the most common malignant renal neoplasm in children and is occasionally seen in adults. CASES: In case 1, a 26-year-old male had a left renal mass. Fine needle aspiration (FNA) showed 3-dimensional sheets of cells with nuclear overlapping, molding, irregular nuclear membrane and distinct nucleoli. Frequent mitotic figures could be seen. The cytologic differential diagnosis included Wilms' tumor, neuroectodermal tumor and metanephric adenoma. Nephrectomy revealed Wilms' tumor. In case 2, a 24-year-old female presented with erythrocytosis and a right renal mass. FNA showed small, uniform cells with smooth nuclear membrane, fine chromatin and inconspicuous nucleoli. A diagnosis of metanephric adenoma was made and confirmed on nephrectomy. CONCLUSION: Differentiating MA from WT based on cytologic features on FNA biopsy prior to surgical resection can he difficult.     

Adult Wilms' tumor. Intraoperative cytology and ancillary studies performed in a case as an adjunct to the histologic diagnosis.

A case of blastema-predominant Wilms' tumor in a 64-year-old woman is reported. Intraoperative cytology of a renal mass was used to rule out malignant lymphoma and neuroendocrine carcinoma. Light and electron microscopy, immunocytochemical staining and flow cytometry (FCM) were also performed. Immunoperoxidase studies of smears showed positive staining for vimentin and negative staining for cytokeratins and epithelial membrane antigen. FCM DNA analysis of paraffin-embedded tissue showed no aneuploid peak. Frozen section interpretation of such tumors as seen in this case may be difficult, requiring distinction among several small-blue-cell neoplasms, including Wilms' tumor, neuroendocrine carcinoma and malignant lymphoma; intraoperative cytology can provide a valuable adjunct to frozen section diagnosis.     

Induction of antiproliferative connective tissue growth factor expression in Wilms' tumor cells by sphingosine-1-phosphate receptor 2

Connective tissue growth factor (CTGF), a member of the CCN family of secreted matricellular proteins, regulates fibrosis, angiogenesis, cell proliferation, apoptosis, tumor growth, and metastasis. However, the role of CTGF and its regulation mechanism in Wilms' tumor remains largely unknown. We found that the bioactive lipid sphingosine-1-phosphate (S1P) induced CTGF expression in a concentration- and time-dependent manner in a Wilms' tumor cell line (WiT49), whereas FTY720-phosphate, an S1P analogue that binds all S1P receptors except S1P2, did not. Further, the specific S1P2 antagonist JTE-013 completely inhibited S1P-induced CTGF expression, whereas the S1P1 antagonist VPC44116 did not, indicating that this effect was mediated by S1P2. This was confirmed by adenoviral transduction of S1P2 in WiT49 cells, which showed that overexpression of S1P2 increased the expression of CTGF. Induction of CTGF by S1P was sensitive to ROCK inhibitor Y-27632 and c-Jun NH2-terminal kinase inhibitor SP600125, suggesting the requirement of RhoA/ROCK and c-Jun NH2-terminal kinase pathways for S1P-induced CTGF expression. Interestingly, the expression levels of CTGF were decreased in 8 of 10 Wilms' tumor tissues compared with matched normal tissues by quantitative real-time PCR and Western blot analysis. In vitro, human recombinant CTGF significantly inhibited the proliferation of WiT49 cells. In addition, overexpression of CTGF resulted in significant inhibition of WiT49 cell growth. Taken together, these data suggest that CTGF protein induced by S1P2 might act as a growth inhibitor in Wilms' tumor.     

Molecular analysis of aniridia patients for deletions involving the Wilms' tumor gene

A human aniridia candidate (AN) gene on chromosome 11p13 has been cloned and characterized. The AN gene is the second cloned gene of the contiguous genes syndrome WAGR (Wilms' tumor, aniridia, genitourinary malformations, mental retardation) on chromosome 11p13, WT1 being the first gene cloned. Knowledge about the position of the AN and WT1 genes on the map of 11p13 makes the risk assessment for Wilms' tumor development in AN patients possible. In this study, we analyzed familial and sporadic aniridia patients for deletions in 11p13 by cytogenetic analyses, in situ hybridization, and pulsed field gel electrophoresis (PFGE). Cytogenetically visible deletions were found in 3/11 sporadic AN cases and in one AN/WT patient, and submicroscopic deletions were identified in two sporadic AN/WT patients and in 1/9 AN families. The exact extent of the deletions was determined with PFGE and, as a result, we could delineate the risk for Wilms' tumor development. Future analyses of specific deletion endpoints in individual AN cases with the 11p13 deletion should result in a more precise risk assessment for these patients.     

Wilms' tumor. Role of fine needle aspiration and DNA ploidy by image analysis in prognostication

OBJECTIVE: To evaluate the utility of cytomorphologic features and DNA ploidy estimation in fine needle aspirates (FNAs), from Wilms' tumors for prognostication. STUDY DESIGN: Twenty-three cases of Wilms' tumor having FNA and follow-up data were selected. Cytomorphology was analyzed by two observers. DNA ploidy was determined in 19 cases by image cytometry by destaining Papanicolaou-stained slides and restaining with Feulgen stain. Various parameters and patient outcomes were compared, and statistical evaluation was done. RESULTS: Poor outcome (12/23 cases) was associated with age < 2 years (P = .01), severe pleomorphism of blastemal cells (4/23 cases, P < .05), very large nucleoli (5/23 cases, P = .075), atypical mitosis (6/23 cases, P = .032) and aneuploidy/tetraploidy of tumor cells (6/29 cases, P = .005). Term unfavorable cytology is proposed when a combination of severe pleomorphism, very large nucleoli and atypical mitosis is seen in FNA smears. Four Wilms' tumor FNAs were characterized as showing unfavorable cytology, and all had a poor outcome (P = .0351). Three of the six cases with aneuploid/tetraploid features also showed unfavorable cytology. CONCLUSION: Unfavorable cytology and aneuploidy/tetraploidy in FNA smears of Wilms' tumor are associated with a poor prognosis.     

Ectopic production of ACTH by Wilms' tumor

The authors present the 2nd documented case of Wilms' tumor associated with the "ectopic ACTH syndrome'. This is a 7 1/2-year-old girl who, on examination at the time of admission, had the classical cushingoid appearance. A large hard mass was palpable in the right side of the abdomen. Hormonal assays were consistent with Cushing's syndrome; the serum ACTH levels were extremely high. After surgical removal of the mass, we suspected a stage I Wilms' tumor; this was confirmed by histopathological studies. After surgery, the girl quickly lost her cushingoid appearance and weight excess. Postoperative serum ACTH levels were normal. Ectopic hormone syndromes associated with tumors in childhood are discussed as well as the possible mechanism involved in the ectopic production of ACTH.