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Wilms Tumor
Daniel M. Green, MD Giulio J. D’Angio, MD J. Bruce Beckwith, MD Norman E. Breslow, PhD Paul E. Grundy, MD Michael L. Ritchey, MD Patrick R.M. Thomas, MD

Introduction
Wilms tumor is the most common primary malignant renal tumor of childhood and is the paradigm for multimodal treatment of a pediatric malignant solid
Dr. Green is the Associate Chief of the Department of Pediatrics at Roswell Park Cancer Institute in Buffalo, New York, and a Professor of Pediatrics in the School of Medicine at the State University of New York at Buffalo in Buffalo, New York. Dr. D’Angio is Professor Emeritus in the Department of Radiation Oncology at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania. Dr. Beckwith is a Professor in the Department of Pathology and Human Anatomy at Loma Linda University in Loma Linda, California. Dr. Breslow is a Professor in the Department of Biostatistics at the University of Washington in Seattle, Washington. Dr. Grundy is an Assistant Professor in the Departments of Pediatrics and Oncology at the Cross Cancer Institute and the University of Alberta, Edmonton, in Alberta, Canada. Dr. Ritchey is an Associate Professor in the Division of Pediatric Surgery at the University of Texas in Houston, Texas. Dr. Thomas is a Professor in the Department of Radiation Oncology at the Temple University School of Medicine in Philadelphia, Pennsylvania. Supported in part by USPHS Grant CA-42326. The authors thank the investigators of the Pediatric Oncology Group and the Children’s Cancer Group, the many health care professionals who managed the children entered on the National Wilms Tumor Studies, and Mrs. Diane Piacente for preparation of the manuscript.

tumor. Developments in surgical techniques and postoperative care, recognition of the sensitivity of Wilms tumor to irradiation, and the availability of several active chemotherapeutic agents have led to a dramatic change in the prognosis for most patients with this once uniformly lethal malignancy. We will review the progress made in the diagnosis and management of children with Wilms tumor, emphasizing work completed since the last review of Wilms tumor in this journal.1 The late effects of treatment for childhood cancer have been reviewed in this journal2 and elsewhere3 and will not be discussed in detail.

Epidemiology
The incidence rate of Wilms tumor is 8.1 cases per million in white children less than 15 years of age.4 In 1991 Wilms tumor represented five to six percent of childhood cancers in the United States, where the total incidence was estimated at 460 cases per year.5 The incidence rate is about three times higher for blacks in the United States and Africa than for East Asians, with rates for white populations in Europe and North America intermediate between these extremes.6 Wilms tumor in the United States is slightly less frequent in boys than in girls. The male-to-female ratio for those with a unilateral tumor is 0.92 to 1.00 and for those with bilateral tumors is
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resulting in absence of normal RB gene product within the affected retinal cell.25 The genetics of Wilms tumor. and hypospadias. either a new germinal mutation transmitted from the father22. located at 13q14. and visceromegaly. Subsequently.22 47 . aniridia. however.7 The mean age at diagnosis for those with unilateral tumors is 41. compared with 29. In either case it results in the loss of function of one of the alleles of the retinoblastoma (RB) gene. are more complex.29 Interestingly. genitourinary malformations.20 Genetics Wilms tumor is an important model for the study of fundamental mechanisms of carcinogenesis. and an increased odds ratio for Wilms tumor among the offspring of auto mechanics.27 They also suggest that the disease comprises at least two pathogenetic entities that are identifiable on the basis of distinct precursor lesions. 1 january/February 1996 correlation between paternal occupation and the occurrence of Wilms tumor.5 months for males and 32.C A C a n c e r J C l i n 1 9 9 6 . The genetics of Wilms tumor was thought to follow the pattern of retinoblastoma. and mental retardation (WAGR syndrome) occurs in association with an interstitial deletion of varying length on chromosome 11 (del(llp13)).60 to 1.21 This model has been confirmed in detail in patients with retinoblastoma. hemihypertrophy.5 months for males and 46.8 The constellation of Wilms tumor.17 Previously reported associations between maternal smoking during pregnancy.10.23 or transmitted from a carrier or affected parent. Analysis of the epidemiologic and clinicopathologic features of patients with Wilms tumor has led investigators in the National Wilms Tumor Study Group (NWTSG) to suggest that some bilateral and multicentric tumors may arise from somatic mosaicism rather than germ line mutation.28 The first evidence that a specific chromosomal locus is associated with Wilms tumor was the demonstration that patients with aniridia and Wilms tumor usually have an interstitial deletion at 11p13. in which about ten percent of patients with sporadic unilateral tumors and all patients with bilateral tumors are thought to carry a germ line mutation and the tumor arises only when a second event occurs (the “second hit”). omphalocele. including aniridia.12 The role of parental environmental exposures in the etiology of Wilms tumor is unknown. machinists.7 Children with Wilms tumor may have associated anomalies.9 months for females.30 as with new germinal mutations at 13q14.6 months for females with bilateral tumors. and welders. the function of the remaining normal allele is lost by one of several mechanisms. and hypertension during pregnancy were not confirmed in a large case-control study. 4 6 : 4 6 .19.00. The first event may be constitutional. Fabia and Thuy13 reported no excess of fathers of Wilms tumor patients with hydrocarbon-related occupations.9 Children with pseudohermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have the Denys-Drash syndrome. which is associated with mutations within the same chromosomal segment as the WAGR syndrome. which includes macroglossia. but others have identified an excess of fathers of Wilms tumor patients engaged in occupations with significant lead exposure14. 46 No. tea consumption. No consistent positive findings have emerged from a series of casecontrol studies.26. the deletion occurs preferentially in the paternal allele.6 3 0. cryptorchidism.11 Hemihypertrophy may occur as an isolated abnormality or as a component of the Beckwith-Wiedemann syndrome. an increased proportional mortality rate among kidney tumor patients whose fathers were employed in hydrocarbon-related industries at the time of the patient’s death15.18 Other studies have found no Vol.16.24 or it may be somatic.

5. Wilms tumor pedigrees have excluded linkage to 11p13. 2). which codes for an embryonal growth factor.28 Extensive research has been conducted by the NWTSG to identify gross and histopathologic patterns that correlate with outcome. constitutional or even tumor-specific mutations of WT1 have been found in far fewer cases than expected. These are used both for staging purposes (Table 1) and for tumor type categorization.71.72.39. which usually results from mitotic recombination rather than deletion.5.46 and 16q. based on tumorspecific loss of heterozygosity restricted to this region.48.32 but it is not yet known whether a single gene is involved. forming primordial tubules and glomeruli with their associated supporting tissues. and epithelial.43 Tumor-specific loss of imprinting at the IGF II locus has been found in many Wilms tumors that have not lost DNA heterozygosity for 11p15.34 allowed the sequence of the normal gene to be determined. seldom gives external evidence pointing to the underlying histopathology. are strongly suggestive of Wilms tumor. Tumor multifocality or nephrogenic rests. Thus loss of 48 heterozygosity for 11p15.41 it is imprinted such that it is only expressed from the paternal allele.40 This evidence suggests that the 11p15 Wilms tumor locus is subject to genomic imprinting.32 Beckwith-Weidemann syndrome. However. Germinal mutations within the WT1 gene have now been identified in patients with Wilms tumor who also have Denys-Drash syndrome35 and in a few patients with bilateral Wilms tumor. It is not yet known whether a separate Wilms tumor suppressor gene might exist adjacent to IGF II.36 Strikingly. they are not all present in every case (Fig. but large.31.38 Furthermore. is a candidate for both Wilms tumor and BeckwithWiedemann syndrome because it maps to 11p15. Pathology The gross appearance of the kidney. an as yet unidentified familial locus. distorted by the presence of the tumor. may not represent loss of a tumor suppressor allele. but rather duplication of the only active IGF II allele. providing a possible autocrine stimulation pathway.42 and it is highly expressed in Wilms tumors. resulting in a functional difference between the two alleles. and both genetic and epigenetic mechanisms.45 This epigenetic alteration may result in increased IGF II levels. 1).40.42.37. The classic nephroblastoma is made up of three cell types: blastemal.78 The neoplastic elements often reflect their renal origin. Finally linkage studies of rare. Anaplasia is recognized by the presence of gigantic polyploid nuclei within the tumor sample (Fig. The IGF II gene.31. The following features should be identified to diagnose anaplasia: (1) nuclei with major diameCa—A cancer Journal for Clinicians . which carries a predisposition to embryonal tumors including Wilms tumor.W i l m s T u m o r Subsequently.47 In summary the development of Wilms tumor involves at least two genes on chromosome 11p. several laboratories reported that about one third of Wilms tumors have undergone tumor-specific loss of heterozygosity for polymorphic DNA markers on 11p13. When anaplastic nuclear changes as described below are not present.32 Isolation of this Wilms tumor gene (WT1)33. stromal. in some cases with a tumor-specific WT1 mutation of one allele. the histology is termed “favorable” (FH) by the NWTSG Pathology Center because of the generally good outcome for these patients (Table 2).37 A second Wilms tumor locus maps to chromosome 11p15. the remaining allele is normal. 11p15. also maps to this location. which may manifest as subcapsular pale pink areas or nodules in the non-tumor-bearing kidney substance.44 and constitutional loss of the imprint is associated with both generalized somatic overgrowth and Wilms tumor. however. It is of interest that the copy of 11p15 lost in Wilms tumor is invariably derived from the mother.

ters at least three times those of adjacent cells and with increased chromatin content and (2) multipolar or otherwise recognizably polyploid mitotic figures.Hematogenous metastases. or beyond. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease before biopsy. when only a small biopsy is available. 46 No. The criteria distinguishing focal from diffuse anaplasia were modified recently. the periaortic chains. Anaplastic nuclear changes present in fewer than 10 percent of microscopic fields were originally designated as focal anaplasia. The new definition of focal anaplasia emphasizes distribution by requiring that cells with anaplastic nuclear changes be confined to sharply restricted foci within the primary tumor and not be present in 49 . There is no residual tumor apparent beyond the margins of resection. lung. bone.Residual nonhematogenous tumor confined to the abdomen: (1) lymph nodes on biopsy are found to be involved in the hilus.. Deposits beyond stage III (e. This criterion permitted the inclusion of tumors where anaplasia was present throughout the tumor. (2) there has been diffuse peritoneal contamination by tumor..g. and/or brain). albeit at low density. There is no residual tumor apparent at or beyond the margins of excision. and cases with anaplasia in extrarenal sites or in metastatic deposits. 1 january/February 1996 amount of anaplasia present. liver.C A C a n c e r J C l i n 1 9 9 6 . the presence of a single. Occasionally.Tumor extends beyond the kidney. The tumor may have been biopsied or there has been local spillage of tumor confined to the flank. but is completely removed. Stage lV .Bilateral renal involvement at diagnosis. and/or (5) the tumor is not completely resectable because of local infiltration into vital structures. There is regional extension of the tumor (i.Tumor limited to kidney and completely excised. (3) implants are found on the peritoneal surface. Stage V . Stage lI . Tumor was not ruptured before or during removal. (4) the tumor extends beyond the surgical margins either microscopically or grossly. such as spillage of tumor beyond the flank before or during surgery or tumor growth that has penetrated through the peritoneal surface.e. Stage llI . The surface of the renal capsule is intact. Anaplastic changes may be either focal or diffuse. 4 6 : 4 6 . multipolar mitotic figure or an unequivocally gigantic tumor cell nucleus will suffice to diagnose anaplasia.6 3 Table 1 National Wilms Tumor Study Clinicopathologic Staging System Stage I . Vessels outside the kidney substance are infiltrated or contain tumor thrombus. penetration through the outer surface of the renal capsule into the perirenal soft tissues).49 The original definition of focal anaplasia was based on the Vol.

whereas the British workers referred to “bone-metastasizing renal tumour of childhood” (BMRTC). a distinctive and highly malignant tumor type. unless (a) it is known that every slide showing anaplasia came from the same region of the tumor or (b) anaplastic foci on the various slides are minute and surrounded on all sides by nonanaplastic tumor. any site outside the kidney parenchyma.48 The tumor. The cell of origin for this distinctive tumor remains unknown. Usually this is noticed Ca—A cancer Journal for Clinicians . However.48 The descriptive term CCSK was used by the NWTSG. characteristically have prominent acidophilic cytoplasm.51. is monomorphous like CCSK. Triphasic Wilms tumor with well-defined tubules surrounded by dense clusters of blastemal cells and zones of pale-staining stromal differentiation (hematoxylin-eosin. extracapsular infiltrates. often resembling that of myoblasts. or (4) present in more than one tumor slide. myxoid. clear cell sarcoma of the kidney (CCSK) is an important entity to consider.58 Rhabdoid tumor of the kidney (RTK). original magnification x100). Diffuse anaplasia is diagnosed when anaplasia is (1) present in any extrarenal site.60 It is not a variant of Wilms tumor and will not be encountered as a focal change in a conventional Wilms tumor. the cytoplasm is negative for ultrastructural or other markers of skeletal muscle (Fig. (2) present in a random biopsy specimen.53 Most CCSK specimens have a distinct and easily recognized histologic appearance. CCSK also is associated with a distinctively high 50 rate of skeletal metastases. Several cases have been reported in which apparently separate primary neuroectodermal tumors of the brain have developed in children with RTK. unlike CCSK. This variant was first recognized in the literature by Kidd50 in 1970 and was independently identified in 1978 by Marsden et al51 in Britain and the pathologists of the NWTSG.54-57 The reader is referred elsewhere for detailed descriptions and illustrations of both the classic and variant patterns. or nodal or distant metastases. and/or polaroid photograph of the gross specimen). (3) unequivocally expressed in one region of the tumor. was identified for the first time in 1978 by NWTSG pathologists.. This topographic definition of focal anaplasia makes it mandatory that pathologists carefully document the exact site from which every section is obtained (e. on a diagram. 3). The cells of RTK.g. specimen photocopy.59. and cystic. 1. Although not currently thought to be a variant of Wilms tumor. 4). such as epithelioid. invite confusion with Wilms tumor or other tumor types (Fig.52. including vessels of the renal sinus. but with extreme nuclear pleomorphism approaching the criteria of anaplasia (extreme nuclear unrest) elsewhere in the lesion. spindling. but a number of variant patterns. CCSK has a much wider distribution of metastases than does FH Wilms tumor.61 Presentation and Evaluation Most children with Wilms tumor are brought to medical attention because of abdominal swelling or the presence of an abdominal mass. previously confused with Wilms tumor. with a strikingly increased number of brain as well as bone metastases. It is associated with a significantly higher rate of relapse and death than FH Wilms tumor.W i l m s T u m o r Fig.

The laboratory evaluation should inVol.0%) 26 NWTS-3 1. document the patency of the inferior vena cava.62 During the physical examination.8%) 138* *Combined total for CCSK and RTK. These findings help differentiate Wilms tumor from splenomegaly and neuroblastoma.397 2. a differential white blood cell count. gross hematuria. It is also important to note specifically any signs of syndromes associated with Wilms tumor. 4 6 : 4 6 . or genitourinary abnormalities. partial or complete hemihypertrophy. liver function tests. which may be elevated in patients with RTK and mesoblastic nephroma. and demonstrate the presence or absence of pulmonary metastases.8%) 24 11 31* 8 421 478 56 1. However a rigorous comparison of the value of computed tomography to that of abdominal ultrasonography in patient management is lacking.3%) 61 32 Total 2.047 (89. This will demonstrate whether the mass is cystic or solid and will help define the organ from which the tumor originated (Fig.2%) 111 (4. A varicocele secondary to obstruction of the spermatic vein may be associated with the presence of a tumor thrombus in the renal vein or inferior vena cava. Current data suggest that conventional radiographic techniques. 1 january/February 1996 clude a complete blood count. 5). Computed tomography of the abdomen will establish the origin of most abdominal masses (Fig.71. it is important to note the location and size of the abdominal mass and its movement with respiration. The radiographic evaluation should establish the presence of an intrarenal mass and a normally functioning contralateral kidney. and urinalysis.248 (89.72.6 3 Table 2 Pathologic Distribution of Pediatric Renal Tumors NWTS-1 Favorable Histology Wilms Tumor Anaplastic Wilms Tumor Clear Cell Sarcoma of the Kidney (CCSK) Rhabdoid Tumor of the Kidney (RTK) Total 378 (89. including the presence of aniridia. NWTS = National Wilms Tumor Study Data from National Wilms Tumor Studies. and fever are other frequent findings at diagnosis.C A C a n c e r J C l i n 1 9 9 6 . renal function tests.78 by a parent while bathing or dressing the child. Persistence of the varicocele when the child is supine is highly suggestive of venous obstruction. Abdominal pain. a platelet count. 6). the latter often arising in the celiac axis or extending across the midline because of lymph node involvement. 46 No.62 The initial study should be an abdominal ultrasound examination.296 NWTS-2 421 (88. including ultra51 . serum calcium. such as hypospadias and cryptorchidism.

if any.66. original magnification x200). kidney. the proximal extent of the thrombus must be established prior to operation. on rare occasions.65 Lesions are rarely identified using computed tomography in patients with a negative plain chest radiograph.64 Plain chest radiographs. suggesting that the added information is of limited. Clear cell sarcoma of the kidney. classical pattern.63. provide sufficient information on which to make a decision for laparotomy in most children. Upon entering the abdomen. darkly stained multipolar mitotic figure near the center and a markedly enlarged interphase nucleus to its left. The tumor. These may not be identified on preoperative imaging studies. Nuclei throughout this field exhibit increased variation in size and shape (hematoxylin-eosin. but it can. preferably including both oblique views. should be obtained to determine if pulmonary metastases are present. When tumor is identified within the inferior vena cava.W i l m s T u m o r Fig. The patency of the inferior vena cava can be established with the use of ultrasonography. especially if they are small and/or flat. and a generous segment of ureter should be dissected free and removed en bloc. The adrenal gland should be included in the resection if the tumor is adherent to the gland or if the tumor originates in the upper pole of the kidney. value.68 52 A radionuclide bone scan and skeletal survey should be obtained postoperatively on all children with CCSK. Cords and nests of pale-stained tumor cells are separated by a delicate but distinct network of fine vascular septa. Anaplastic Wilms tumor with a large. Fig. The goal of abdominal exploration is radical or modified radical nephrectomy. Ca—A cancer Journal for Clinicians . the opposite kidney should be inspected on all its surfaces for evidence of a synchronous bilateral tumor or evidence of nephrogenic rests. 2. be responsible for sudden death following manipulation and embolization of the tumor at laparotomy.67 In addition the prognosis for children with densities identified only by computed tomography who are treated according to the stage of their renal tumor is excellent. A magnetic resonance image of the brain should be obtained on all children with RTK or CCSK. the liver should be inspected. Nuclei are vesicular. Surgery The treatment of children with Wilms tumor begins with abdominal exploration. with poorly stained chromatin and inconspicuous nucleoli (hematoxylin-eosin. 3. After the primary tumor has been removed. sonography. using the transabdominal approach. renal hilar structures. The role of computed tomography of the lungs in the evaluation of children with Wilms tumor is controversial. Cardiac extension of such a tumor thrombus may produce few or no signs. original magnification x600).

Staging The staging system used to describe children with Wilms tumor considers several physical features of the tumor that increase the risk of local or distant recurrence and therefore dictate therapeutic modifications. Fig.70 Tumor shrinkage usually follows. have hyaline globular cytoplasmic inclusions. In addition.73 Chemotherapy The use of dactinomycin for the adjuvant treatment of children with Wilms tumor was pioneered by Farber and his 53 . but that whole abdomen irradiation is advisable when contamination of the entire peritoneal cavity has occurred.72 Analyses also indicate that flank irradiation is sufficient for children with tumor spill confined to the flank. single nucleolus. complex. including one near the center. then a random biopsy should be obtained. Rhabdoid tumor. Prone sagittal scan of right renal fossa demonstrates a large.69 A biopsy should be obtained from the kidney in this situation only if a tumor nodule cannot be identified at some other site. Wilms tumor sonogram. Most nuclei have a large. If enlarged nodes are present. usually composed of vimentin (hematoxylin-eosin. such as the peritoneal surface or the liver. imparting an “owl’s eye” appearance to the nucleus. If all of the para-aortic lymph nodes appear to be normal. mainly solid intrarenal mass. The staging system employed by the NWTSG is detailed in Table 1. Fig. making the standard transabdominal approach feasible. Radiation Therapy Postnephrectomy operative-bed radiation therapy was advocated for every child with Wilms tumor at the time the first National Wilms Tumor Study (NWTS-1) was initiated in 1969. 4 6 : 4 6 . Occasionally at laparotomy the tumor is found to be so large or vital structures are so compromised that tumor excision is not possible without increased surgical morbidity. 1 january/February 1996 and dactinomycin.69 Preoperative chemotherapy should be administered to patients who have intracaval and atrial extension of the tumor. The para-aortic lymph nodes should be inspected.C A C a n c e r J C l i n 1 9 9 6 . these should be biopsied. NWTS-1 and subsequent studies have demonstrated that flank irradiation is not necessary for any child with a stage I or II/FH Wilms tumor.71. attempts at primary surgical excision of the tumor and caval extension are associated with increased surgical morbidity.6 3 Biopsies should be obtained from areas that are grossly suspicious for tumor. if treatment includes combination chemotherapy with vincristine Vol. 46 No. Ultrastructurally the latter inclusions consist of whorled masses of intermediate filaments. original magnification x600). Several cells. 4. 5.

76 Vincristine was evaluated as singleagent adjuvant chemotherapy by investigators at the MD Anderson Hospital and the Pediatric Division of the Southwest Oncology Group. The relapse-free survival rate for children treated with vincristine was 78 percent compared with 54 percent for children treated with dactinomycin.77.7 percent for those who received three agents.4 percent compared with 91. The addition of doxorubicin did not improve the relapse-free survival rate of those patients with an unfavorable histology tumor or group IV disease. vincristine. The relapse-free survival rate after randomization for those children who received six months of chemotherapy was 97.78 a difference that was statistically significant.4 percent at four years compared with 56.71. FH patients treated with two agents was 65. None of these patients received postoperative abdominal irradiation.1 percent for those who were treated for 15 months. Patients with nonmetastatic. FH patients treated with two agents was 78.71.78 a difference that was not statistically significant. All children received local irradiation. Overall there was a statistically significant improvement in relapse-free survival among those patients randomized to receive the three-drug regimen. Computed tomography scan of the abdomen showing a right renal tumor and a normal appearing left kidney.5 percent.W i l m s T u m o r Fig. children were randomized to therapy with multiple courses of 54 dactinomycin or vincristine after receiving a postoperative course of dactinomycin. children with group I tumors were randomized to six or fifteen months of adjuvant chemotherapy with vincristine and dactinomycin.5 percent for those treated with three agents. the combination of vincristine and dactinomycin was compared with the same two agents plus doxorubicin in children with stage II to IV. These investigators reported that such therapy improved the survival rate of patients compared with that observed when nephrectomy was followed only by abdominal irradiation. or the combination. the NWTSG. The relapse-free survival rate for children treated with the combination of vincristine and dactinomycin was 77. 6.0 percent at four years for children treated with dactinomycin. The benefit reported in NWTS-2 from the addition of doxorubicin may be due to the greater intensity of the threeCa—A cancer Journal for Clinicians . The relapsefree survival rate following randomization for group III. colleagues.79 In NWTS-2.78 The relapse-free survival rate following randomization among group II. locally advanced tumors in the NWTS-1 trial were randomized to receive dactinomycin. children randomized to therapy with vincristine actually received combination chemotherapy. or RTK.4 percent compared with 87.74 Others have demonstrated that multiple courses of dactinomycin decrease the frequency of recurrence compared with a single course. FH or anaplastic Wilms tumor. In NWTS-2. significantly better than for either single agent. The relapse-free survival rate for children treated with vincristine was 54. Thus. in addition to postoperative abdominal irradiation. and the Medical Research Council. CCSK.75.4 percent compared with 88.78 In the trial by the Medical Research Council.

VCR = vincristine.000 rad Stage III (any age) Surgery 1. any stage All stage IV. 46 No. CPM = cyclophosphamide.000 rad Stage II (any age) Surgery No radiation therapy Intensive DACT + VCR for 15 months 2. 4 6 : 4 6 .000 rad Intensive DACT + VCR for 15 months 2.000 rad DACT + VCR + DOX for 15 months 2.6 3 Favorable Histology (FH) DACT + VCR for 10 weeks Stage I (any age) Surgery No radiation therapy DACT + VCR for 6 months No radiation therapy DACT + VCR + DOX for 15 months 2. Vol.000 rad Unfavorable Histology (UH) and All Stage IV Radiation therapy All UH. 1 january/February 1996 55 .000 rad 1.C A C a n c e r J C l i n 1 9 9 6 . DACT = dactinomycin. FH + UH Surgery Radiation therapy DACT + VCR +DOX for 15 months DACT + VCR + DOX + CPM for 15 months Fig. DOX = doxorubicin. 7. Treatment randomization for patients entered on National Wilms Tumor Study-3.

0 87.9 drug regimen. The four-year.0 Stage I Il Ill IV Four-Year Overall Survival (Percent) 95. This hypothesis was tested in NWTS-3 (Fig.W i l m s T u m o r Table 3 Results of Treatment of Children with Favorable Histology Wilms Tumor on National Wilms Tumor Study–3 Four-Year Relapse-Free Survival (Percent) 89. relapse-free survival rate for all NWTS-3 patients with RTK randomized according to Figure 7 was about 25 percent. and (3) 1. and the overall four-year survival rate was the same.0 79. In the NWTS-1. 56 All NWTS-3 patients with CCSK received abdominal radiation therapy and were randomized to the same three. (2) postoperative abdominal irradiation does not improve the relapse-free survival rate of children with stage II Wilms tumor. only nine of 30 children (30 percent) with bilateral disease had bilateral.72 This result for patients with diffuse anaplasia (stages II to IV) has been confirmed with additional patient accrual on NWTS-4.000 and 2.6 91.4 82. rather than the addition of a third agent. and doxorubicin.72 Bilateral Wilms Tumor Wilms tumor occurs simultaneously in both kidneys in about seven percent of cases. and the four-year overall survival rate was 74. The four-year.6 percent. palpable Ca—A cancer Journal for Clinicians .versus four-drug comparative regimens. anaplastic Wilms tumor. relapse-free survival rate for CCSK patients treated with three drugs was 70.72 Early NWTS-3 analyses suggested that patients with stage II to IV. The results of this trial demonstrated that (1) intensive treatment with vincristine and dactinomycin was equivalent to therapy with these two drugs plus doxorubicin.9 80. 7).8 percent. vincristine. Most children with bilateral Wilms tumor are not diagnosed on the basis of the physical examination.000 cGy are equally effective in controlling microscopic residual disease in children with stage III tumors who were treated with the three-drug regimen (Table 3). who all received radiation therapy.80 There is no beneficial effect of adding cyclophosphamide in patients with tumors having only focal anaplasia. benefited from the addition of cyclophosphamide to the combination of dactinomycin. There was no statistically significant improvement in those given the fourth drug (cyclophosphamide).1 90.52 Patients with RTK have responded poorly to all the treatments used in the NWTS.

4 6 : 4 6 . such as the bones and heart. CARDIAC COMPLICATIONS Congestive heart failure is a known complication of therapy with an anthracycline.89 with impairment of diastolic function clearly related to dose. Bone. The treatment of children with bilateral Wilms tumor must be individualized. and NWTS-3. and other sites are only occasionally involved. initial relapse has been diagnosed as long as eleven years after diagnosis.94 In a preliminary analysis of the frequency of and risk factors for congestive heart failure in patients entered on NWTS-1.81 These data emphasize the importance of contralateral renal exploration at the time of laparotomy. Initial treatment is with the combination of vincristine and dactinomycin. brain. opposite kidney. NWTS-2. original tumor bed.7 percent among doxorubicin-treated patients. Bilateral disease was identified in only 17 of 30 children (56.93 and may be precipitated by a physiologic stress such as pregnancy. A reevaluation is performed to determine if there has been sufficient response of the tumors to allow tumor resection. relapse to the lungs only. relapse in the abdomen of a patient who Vol. with a reported incidence of congestive heart failure of about five percent in patients who received a cumulative dose of 400 to 500 mg/m2. Additional statistically significant 57 Treatment of Recurrent Disease Wilms tumor has a tendency to recur in several sites.C A C a n c e r J C l i n 1 9 9 6 . and only about 10 percent of those found at laparotomy to have bilateral disease were previously identified using computed tomography. may be necessary for the management of children whose tumors respond poorly to the combination of vincristine and dactinomycin. such as doxorubicin.6 percent) by intravenous urography. 1 january/February 1996 . In addition both chemotherapeutic agents and radiation therapy can induce second malignant neoplasms. leading in some cases to sudden death.87 The frequency is directly proportional to the cumulative dose of doxorubicin received. with or without radiation therapy. and other intra-abdominal sites.86 Those factors that favorably affect the success of further therapy include initial treatment with only vincristine and dactinomycin. liver.82-84 The approach presently recommended is initial bilateral renal biopsy with staging of each kidney.6 3 abdominal masses. The most frequent site of recurrent disease is the lung. received no prior abdominal irradiation. Additional chemotherapeutic agents. 46 No. with preservation of a substantial amount of normal renal tissue.90 Although the initial reports of congestive heart failure were limited to the first year after completion of therapy.88 Subclinical effects are observed in up to 57 percent of patients. and relapse more than twelve months after diagnosis.85 Although most first relapses are diagnosed within the first two years after nephrectomy. The cumulative frequency of congestive heart failure was 1. eight cases of congestive heart failure not related to renal failure or pulmonary hypertension were identified in patients who remained continuously free of disease following their initial course of therapy for Wilms tumor. including lung. The goal of therapy is to eradicate all tumor and to preserve as much normal renal tissue as possible. are now appearing for patients treated four to 20 years earlier92. All eight patients received doxorubicin as part of their chemotherapy regimen.91 reports of cardiac failure and dysrythmias. Sequelae of Treatment The treatment that children receive for Wilms tumor may cause damage to other structures or organs. with the hope of decreasing the frequency of chronic renal failure among these children.

g. stage III With NR. US = ultrasonography.W i l m s T u m o r Table 4 Selection of Imaging Studies for Follow-up of Children with Renal Neoplasms of Proven Histology and Free of Metastases at Diagnosis Imaging Study Schedule Following Primary Therapy Tumor Type Wilms Tumor FH.85 58 Ca—A cancer Journal for Clinicians . every 6 months x 6 Irradiated patients. spine +/. any stage Bony structure* (e. CT = computed tomography NR = nephrogenic rests in one or both kidneys Adapted with permission from D’Angio et al. then every 3 months x 5. MRI = magnetic resonance imaging. FH = favorable histology. † To detect second neoplasms. then every 6 months x 10 As for FH Rhabdoid Tumor of the Kidney (RTK) Brain MRI &/or opacified CT Chest films As for CCSK As for FH *To include any irradiated osseous structures. any stage Stage II and III anaplastic Abdominal US Abdominal US Abdominal US Chest films Abdominal US Clear Cell Sarcoma of the Kidney (CCSK) Brain MRI &/or opacified CT. yearly x 5 As for FH Every 3 months x 8. Skeletal survey & bone scan Chest films When CCSK is established. benign (osteochondromas) or malignant. every 6 months x 3.. yearly x 2 Yearly to full growth.pelvis) Without NR. then every 5 years indefinitely† Yearly x 3 As for chest films Every 3 months x 8. any stage and anaplastic stage I Chest films 6 weeks and 3 months postoperatively. every 6 months x 6. stages I & I I Without NR.

96. even those patients whose therapy included only dactinomycin and vincristine. One would expect the least deformity in nonirradiated patients. should they occur. careful palpation of the abdomen.98-101 Heaston et al100 reported the frequency of spinal abnormalities in patients treated with megavoltage irradiation following nephrectomy. Longer follow-up is necessary to confirm the observation by Heaston et al100 that the severity of deformities is less than observed following orthovoltage irradiation.103-105 Most of these. which recorded 66 instances of musculoskeletal difficulties (not otherwise defined) among 88 irradiated stage I children followed for five or more years versus seven in 93 nonirradiated children. such as bone. but no patient had a curve that exceeded 25 degrees. Suspicious findings on physical examination may be clarified using abdominal ultrasonography or computed tomography (Table 4).100 Other investigators identified scoliosis in seven of 12 patients (58 percent)99 and 35 of 57 patients (61 percent)102 treated with megavoltage irradiation following nephrectomy. without radiation therapy.102 Vol. The first site of disease recurrence in these patients is most frequently the lung. had an increased risk of cancer compared with the US population. Follow-up Children who have been treated for Wilms tumor should be examined regularly by a physician who is familiar with the natural history of this tumor and the complications of therapy. and not vitiate what has been gained from so many years of successful clinical research. These patients should have frequent. Significantly. Initial treatment that included doxorubicin increased this risk. These data suggest that the frequency of spinal deformity may not decrease with the use of megavoltage radiation sources. including five who did not have scoliosis.108 have occurred in irradiated areas. Children who have gross residual abdominal disease (stage III and stage IV) have a greater risk of local tumor recurrence.104 It is obvious that Wilms’ tumor survivors must be followed carefully for life so that late adverse effects of therapy can be detected early. Careful palpation of the abdomen is essential to detect local tumor recurrence or tumor growth in the liver or contralateral kidney.107 and thyroid cancers.85 59 .C A C a n c e r J C l i n 1 9 9 6 . The indicated radiographic examinations depend upon the original stage of the tumor.97 Further follow-up of the NWTSG cohort is needed to define more accurately the magnitude of the risk for late congestive heart failure. 4 6 : 4 6 .6 3 risk factors included prior whole lung irradiation and concurrent therapy with cyclophosphamide. Scoliosis was diagnosed in six of 16 patients (38 percent) who had entered the adolescent growth spurt. Local tumor recurrence and recurrence at other intra-abdominal sites is very uncommon among children with stage I or II Wilms tumor.95 Others have reported congestive heart failure in Wilms tumor patients who received doxorubicin and left ventricular irradiation from the abdominal radiation therapy treatment portal. The most significant risk factor for the occurrence of a second malignant neoplasm in the NWTSG cohort was treatment with radiation therapy. 1 january/February 1996 SECOND MALIGNANT NEOPLASMS Second malignant neoplasms can develop in Wilms tumor survivors. 46 No.106 breast. That expectation has been documented by the NWTSG.95 ABNORMAL TRUNK DEVELOPMENT The late effects of trunk irradiation— scoliosis and soft tissue underdevelopment—are still being seen since the advent of megavoltage irradiation. Eight patients (50 percent) had kyphosis.

22. brain. Baltimore.2:131-137. Ejima Y. 10. 21. Pelletier J: Denys-Drash syndrome: Relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1.68:820-823. Med Pediatr Oncol 1993. DeLaat CA. CA Cancer J Clin 1992. The National Foundation—March of Dimes. Dryja TP. Wiggs J. Dryja TP. Yandell D. Kramer S. et al: Prediction of the risk of hereditary retinoblastoma. Meigs JW.79:118-123. 14.62:1026-1030. Breslow NE. Tanooka H: Types.21:172-181. et al: Cancer in children of parents exposed to hydrocarbon-related industries and occupations. Vol 5. The tumor bed of patients who present with hematogenous metastases and patients without metastases CA should be evaluated (Table 4). 7. 6.35: 245-250. J Pediatr 1993. Knudson AG: Mutation and cancer: Statistical study of retinoblastoma. Cancer Res 1989. Cancer Genet Cytogenet 1980. Cannon S. Meadows AT: Parental occupation and Wilms’ tumor: Results of a case-control study. Kun LE: Common solid tumors of childhood. Nass CC. 2. Proc Natl Acad Sci USA 1971. J Pediatr 1985. Petersen R. Hall JG. 17. Manning MD: Association of Wilms’s tumor with aniridia. Green DM: Long Term Complications of Therapy for Cancer in Childhood and Adolescence.318:151-157. Falletta JM. Evidence on physical examination of enlargement and/or nodularity of the liver should be confirmed with computed tomography. New York. Am J Epidemiol 1980. and/or liver) require regular evaluation of these sites.49:725-729. Crist WM.123:673-678. 19.72:938-944. N Engl J Med 1964. Beckwith JB: Macroglossia. Beckwith JB. McKusick VA.53:1637-1643. N Engl J Med 1988. pp 188-196. 5.28:98-100. rates. Sasaki MS. Miller RW. 42:263-282. 11. J Natl Cancer Inst 1994. 13. Br J Cancer 1990. origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. 15. 23. Nature 1983. glomerulopathy.111:329-336. Phillips RA. Coppes MJ. 24. Green DM: Epidemiology of Wilms tumor. Breslow N. Olshan AF. 18. Fabia J. 3. Belasco J.339:556-558. 12. Olshan A. J Epidemiol Community Health 1981. White GC. Caldwell GG. Nordenskjold M. 16. 1989. Olshan A.86:49-51. in Bergsma D. Hittner HM. Eddy AA. et al: Childhood cancer and occupational radiation exposure in parents. hemihypertrophy and other congenital malformations. Bones known to be involved with tumor and areas of bone pain in patients predisposed to bone metastases (CCSK) should be evaluated with plain radiographs. Draper GJ: Occupations of fathers of children dying from neoplasms. 1969.50:3212-3217. D’Angio GJ: Wilms’ tumor. Lampkin BC: Long-term survivors of childhood cancer: Evaluation and identification of sequelae of treatment. 9. Thuy TD: Occupation of father at time of birth of children dying of malignant diseases. Hum Genet 1988. CA Cancer J Clin 1981. Olshan AF. J Epidemiol Community Health 1979. Stiller CA. Daling JR. Riccardi VM. Beckwith JB.85 References 1. et al: The aniridia-Wilms tumor association: The critical role of chromosome band 11p13. Johns Hopkins University Press. prognosis and follow-up of children with Wilms’ tumor. Breslow N. 25. Zack M. et al: Wilms’ tumor and paternal occupation. omphalocele. Scott CI (eds): Birth Defects: Original Article Series. Sanders BM. Mukai S. Francke U. Cancer 1993. 33:253-256. A radionuclide bone scan should be obtained when the plain radiographs are negative and the symptoms are highly suggestive of a bone metastasis. Huff V. diagnosis. et al: Risk factors for Wilms tumor: Report from the National Wilms Tumor Study. Flannery JT: Occupations of fathers of patients with Wilms’s tumour. and hyperplastic visceromegaly. Parkin DM: International variations in the incidence of childhood renal tumours. Br J Prev Soc Med 1974. Fraumeni JF Jr.324:461-471. et al: Parental origin of mutations of the retinoblastoma gene. gigantism. Mauer SM: Pseudohermaphroditism. et al: Ethnic variation in the incidence. Nature 1989. Curnen MG. using DNA polymorphisms within the retinoblastoma gene. 4. The liver should be palpated at each follow-up visit. Breslow NE. Kaneko A.31:258-270. bone. adrenal cytomegaly. N Engl J Med 1991.305: 60 Ca—A cancer Journal for Clinicians . Bunin GR. Loyd D. 20. Cancer Res 1990. Hicks N. 8.106:584-587. Zack M. The brain is most easily evaluated using magnetic resonance imaging. et al: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma.W i l m s T u m o r Patients who present with hematogenous metastases (lung. Cavenee WK. Cancer 1984. Kantor AF.270:922-927. and Wilms’ tumor (Drash syndrome): Frequency in end-stage renal failure.

Miwa H.44:711-719. Heyting C. Nature 1993.5:408-412. Beckwith JB.336:377-378. Rainier S. Haber DA. 51. et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cavenee W. Huff V. Becroft DM. Radiology 1983. Glaser T. Pediatrics 1978. Ogawa O. Hum Pathol 1983. 55. Grundy P. et al: Constitutional relaxation of insulin-like growth factor II gene imprinting associated with Wilms’ tumour and gigantism. Cancer 1985. 37.C A C a n c e r J C l i n 1 9 9 6 . Marsden HB. Mod Pathol 1993. Nature 1990. 48:1653-1657. Haber DA. 10:1-36. et al: Bone metastasizing renal tumor (clear cell sarcoma) of childhood with epithelioid elements. et al: Familial Wiedemann-Beckwith syndrome and a second Wilms tumor locus both map to 11p15. Nat Genet 1993. Francke U: Chromosomal imbalance in the Aniridia-Wilms’ tumor association: 11p interstitial deletion.9:211-218. 91:3554-3558. Lamego CM. Beckwith JB. Nature 1988. Riccardi VM. 44.41: 1937-1948. Schroeder WT. Meadows A. et al: Nonrandom loss of maternal chromosome 11 alleles in Wilms tumors. 4 6 : 4 6 . Virchows Arch [Pathol Anat] 1980. Ciol M.362:749751. et al: Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Eccles MR. Pelletier J. Eccles MR. Sharples K: Age distribution of Wilms’ tumor: Report from the National Wilms’ Tumor Study.61:1257-1269. Harms D. 47. Kashtan CE. Cancer Res 1988. et al: Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumor.310:784-786. Koufos A. Nature 1985. 56. Mannens M. et al: Lack of linkage of familial Wilms’ tumour to chromosomal band 11p13. Case T: Clear cell sarcoma of kidney. Cancer Res 1992.52:61176120. Am J Pathol 1970. Varanasi R. 31. Chao LY. Morgan K. Kiviat NB. Cancer 1984. Bardeesy N. 68:429-436.14:481-492. 48. Dobry CJ. Slater RM. Breslow NE. 46 No. Lawler W. Ghahremani M.317:258-260. Kumar PM: Bone metastasizing renal tumor of childhood: Morphological and clinical features and differences from Wilms’ tumor. Beckwith JB.81:41-48. 58. Vol. 1 january/February 1996 61 . Cancer 1978. 35. Grundy P. Proc Natl Acad Sci USA 1994. Beckwith JB: Wilms’ tumor and other renal tumors of childhood: A selective review from the National Wilms’ Tumor Study Pathology Center.61:604-610. 26. Nature 1984. 56:609-613. et al: Familial predisposition to Wilms’ tumour does not map to the short arm of chromosome 11. 46. Am J Hum Genet 1987. 28. Cell 1990. 32.6:3p. 27.5. Faria P. 38. Bonadio JF: Nephrogenic rests. 43.48:997-1003. Call KM.67:437-447. 30. Beckwith JB. 41. et al: Homozygous deletion in Wilms tumours of a zincfinger gene identified by chromosome jumping. Nature 1988. et al: Localization of insulin-like growth factor genes to human chromosomes 11 and 12. 52. J Natl Cancer Inst 1982. Dao DD. 50. Pediatr Pathol 1989. Reeve AE. Koufos A. Poustka A. Gessler M. Cell 1991. 336:374-376. Kidd JM: Exclusion of certain renal neoplasms from the category of Wilms’ tumor (Abstract). Pediatr Pathol 1990. Larson E. Cell 1990. 36. 34. 49. Am J Hum Genet 1991. Breslow NE. Ito CY.12:2132-2137. Lawler W: Bone metastasizing renal tumour of childhood: Histopathological and clinical review of 38 cases.387:341-351.60:509-520.59:16a. Marsden HB. Huff V. Compton DA. 42. Tricoli JV. et al: An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms’ tumor. Am J Hum Genet 1989. Beckwith JB: Clear cell sarcoma of the kidney with emphasis on ultrastructural studies. Am J Hum Genet 1990.6 3 779-784. Rall LB. Glaser T. et al: Treatment of children with clear-cell sarcoma of the kidney: A report from the National Wilms Tumor Study Group. nephroblastomatosis. Haas JE. Bonadio JF. Sujansky E. Green DM. Scott J.47:155-160. 33. et al: Relaxation of imprinted genes in human cancer. Ogawa O. 45. Schmidt D. Zerbini MC: Bone-metastasizing primary renal tumors in children. Riccardi VM.362:747-749. Hum Genet 1988.147:449-454.54:2978-2987. Morgan K. Huff V. et al: Evidence for WT1 as a Wilms tumor (WT) gene: Intragenic germinal deletion in bilateral WT.40:413420. Bruening W.343:774-778. Wilkins RJ. Nature 1993. and the pathogenesis of Wilms’ tumor. Huff V. 54. et al: Nonlinkage of 16q markers to familial predisposition to Wilms’ tumor. Reeve AE. 29. Johnson LA. Morison IM. Breslow NE. et al: Molecular nature of genetic changes resulting in loss of heterozygosity of chromosome 11 in Wilms’ tumors. Beckwith JB. Chao LY. Leppert M. Cancer 1978. et al: Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Smith AC. Beckwith JB: A new definition of focal anaplasia (FA) in Wilms tumor (WT) identifies cases with good outcome: A report from the National Wilms Tumor Study (Abstract). 40. 39. Buckler AJ. 53. Palmer NF: Histopathology and prognosis of Wilms tumors: Results from the First National Wilms’ Tumor Study. Szeto J. Beckwith JB: Epidemiological features of Wilms’ tumor: Results of the National Wilms’ Tumor Study.42:1922-1928. et al: Expression of insulin-like growth factor-II transcripts in Wilms’ tumour. Evers KG. 57. J Clin Oncol 1994. et al: Parental origin of de novo constitutional deletions of chromosomal band 11p13.

Ritchey ML. Blute ML.21:205-212. Cancer 1989. Weinberg AG. 64. Cancer 1980. D’Angio GJ. 65.54:2137-2146.12:631-638. 70. J Urol 1987.91:710-717. J Urol 1994. Breslow N.141:375-378. 63. 76. Ihrke H. Provisor A. Palmer NF. et al: Bilateral Wilms tumor. Green DM: Diagnosis and Management of Malignant Solid Tumors in Infants and Children. et al: Longterm evaluation of single versus multiple courses of actinomycin D therapy of Wilms’ tumor. Beckwith JB.37:2768-2772. Borow KM. D’Angio GJ. Lipshultz SE.47:2810-2816.151:329A. Evans AE. Riggs JM.53:112-119. Fernbach DJ. Weetman R: Efficacy of whole lung tomography in diagnosing metastases from solid tumors in children. Magill HL.60:309-315. et al: Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1974. Smith WL. Goldman A. 85. N Engl J Med 1991. 66. Morf G. et al: Risk factors for doxorubicin-induced congestive heart failure. 71. 74. J Clin Oncol 1988. 90. D’Angio GJ. Tan CT. Mierau GW. Med Pediatr Oncol 1982. Cancer 1976.42:30A. Weeks DA. Basa P. Palmer NF.53:903-905. et al: The treatment of children with stages II to IV anaplastic Wilms tumor: A report from the National Wilms’ Tumor Study Group. Beckwith JB. Breslow N. Wilimas JA. Kelalis PP. Bishop HC. Shurin SB. 80. Beckwith JB: Ultrastructure of malignant rhabdoid tumor of the kidney: A distinctive renal tumor of children. pp. Beron G. Layard MW. Rubinstein LJ. 72. D’Angio GJ. D’Angio GJ: Survival in bilateral Wilms’ tumor: Review of 30 National Wilms’ Tumor Study cases.290:84-86. 79.10:557-561.324:808-815. Evans A. Am J Surg Pathol 1989. Haase GM. 91. Cohen M. et al: Congestive heart failure due to adriamycin cardiotoxicity: Its natural history in children. Kelalis PP. et al: Significance of pulmonary computed tomography at diagnosis in Wilms’ tumor. Radiology 1981. Gilladoga AC. Breslow NE. JAMA 1966. 83. Med Pediatr Oncol 1993. et al: The treatment of Wilms’ tumor: Results of the National Wilms’ Tumor Study. Manuel C.37:1070-1078. J Clin Oncol 1994. et al: The treatment of Wilms’ tumor: Results of the Second National Wilms’ Tumor Study.138:968-973. Grant W 3rd: Postoperative radiation therapy for residual Wilms’ tumor: Review of Group III patients in the National Wilm’s Tumor Study. 101:559-562. Ann Intern Med 1979. 62 Ca—A cancer Journal for Clinicians .279:290294. Cancer 1981. Conrad WG: Fatal intraoperative pulmonary embolization of Wilms tumor. Clausen N: Late recurrence of Wilms tumor. Blute ML. 68. Tefft M. Surg Gynecol Obstet 1992. Breslow N. Green DM. Tefft M. Wolff JA. Boston. et al: Long term doxorubicin cardiotoxicity in childhood: Non-invasive evaluation of the contractile state and diastolic filling. D’Angio GJ. Bonnin JM. Breslow NE. et al: Wilms’ tumor: An update. Beckwith JB. 61. Br J Anaesth 1981. Green DM. D’Angio GJ. Evans AE. Gauderer MWL. Clin Res 1994. 86.47: 2302-2311.71:41044110. Kelalis PP. Von Hoff DD. Medical Research Council’s Working Party on Embryonal Tumours in Childhood: Management of nephroblastoma in childhood: Clinical study of two forms for maintenance therapy. J Pediatr Surg 1977. 73. Ritchey ML. Sharples K. et al: Surgical complications after nephrectomy for Wilms’ tumor. Breslow N. Breslow N. Green DM. Haas JE. 84. Douglass EC.38:633-646. et al: Treatment of Wilms’ tumor: Results of the Third National Wilms’ Tumor Study.45:17911798. 88. Colan SD. 81. Cancer 1993. Arch Dis Child 1978. Hartmann J. et al: Computed tomography versus chest radiography in the detection of pulmonary metastases in Wilms tumor (Abstract). et al: Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms tumor. 89. Beckwith JB. et al: Preoperative therapy for intracaval and atrial extension of Wilms tumor. Br Heart J 1988. 87. Dahms BB. 129186. Beckwith JB: The association of embryonal tumors originating in the kidney and in the brain. 1985. Newton WA Jr. Goorin AM. Rosenberg H.13:439458.9:1776-1781. et al: The treatment of Wilms’ tumor patients with pulmonary metastases detected only with computed tomography: A report from the National Wilms’ Tumor Study. Ritchey ML.W i l m s T u m o r 59. Norkool P. Wooton SL.64:349360. Hausdorf G. Farber S: Chemotherapy in the treatment of leukemia and Wilms’ tumor. Cancer 1976. Martinus Nijhoff Publishing. Cancer 1976. Breslow N. Gelber RD. Arslan G: Pulmonary embolism during surgery for a Wilms’ tumor (nephroblastoma). 75. 6:1144-1146. Akyon MG. Montgomery BT.175:507514.12:646-657. 78. Hum Pathol 1981.12:2126-2131. 67. Cancer 1984. D’Angio GJ: Single versus multiple dose dactinomycin therapy of Wilms’s tumor. J Clin Oncol 1991.198:826- 836. 82. 69. Kelalis PP. 60. N Engl J Med 1968. et al: Position paper: Imaging methods for primary renal tumors of childhood: Costs versus benefits. Luckey DW: Rhabdoid tumor of kidney: A report of 111 cases from the National Wilms’ Tumor Study Pathology Center. Wolff JA. 62. 77. et al: Extended followup of bilateral Wilms tumor: Results of the National Wilms Tumor Study. J Urol 1991. J Pediatr 1982. Cancer 1981.146:514-518. et al: The cardiotoxicity of adriamcyin and daunomycin in children. Krivit W. D’Angio G.

Libshitz HI. Takashima JR. et al: Musculoskeletal deformities following treatment of Wilms’ tumor. et al: Doxorubicin cardiomyopathy in children with left-sided Wilms tumor. Morris-Jones PH. Davis LE. J Clin Oncol 1995. Olshan A. 93. Norkool P. Chauvenet AR. Tucker MA. Norkool PA. sponsored by Amgen. Cancer 1973.32:634-639. Bhanot P. Green DM. 97. Candidates must have been a fellow for at least two years but no more than five years prior to the beginning of the award year (July 1996). Breslow NE. et al: Late effects of treatment for Wilms’ tumor: A report from the National Wilms’ Tumor Study Group. Cancer Res 1991. The deadline is February 15. Philipart A. and its 1996 Research Fellowship in Basic Research is to foster meritorious clinical/ translational or basic research in the US or Canada by a young scientist currently at the postdoctoral or clinical research fellow level. Perez-Atayde AR. N Engl J Med 1987. Oliver JH.10:483-488. American Association for Cancer Research. Evans I. telephone 215-440-9300. et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. Boice JD Jr.. Whitton JA. Public Ledger Building. Kaplan HS: Growth retardation in children after megavoltage irradiation of the spine. et al: Initial congestive heart failure. 106. Pinkel D. 99.67:331-336. Probert JC. D’Angio GJ.95:561-563. et al: Second malignant neoplasms following treatment for Wilms tumor: A report from the National Wilms’ Tumor Study Group. 1 january/February 1996 63 .C A C a n c e r J C l i n 1 9 9 6 . et al: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. Yan JC. Inc. 46 No. et al: Effect of abdominal irradiation on growth in boys treated for a Wilms’ tumor.35:161A. JAMA 1991. Candidates must be nominated by a member of the AACR and submit a detailed application. et al: Second neoplasms after Wilms’ tumor in childhood. Tucker MA. 100. Boice JD Jr. Pediatr Res 1994. J Natl Cancer Inst 1993. Jones PH. Chan RC: Skeletal effects of megavoltage irradiation in survivors of Wilms’ tumor. (Abstract).133: 389-395. Hancock SL. Obstet Gynecol 1988. graduate or medical students. Can Med Assoc J 1978. Goorin AM. Academic faculty holding the rank of assistant professor or higher. Li FP. J Pediatr 1979. J Pediatr 1990. 4 6 : 4 6 . Breslow NE. 94. 103. J Natl Cancer Inst 1988. Steinherz LJ. Suite 816. Gledhill RB. Tucker MA. Med Pediatr Oncol 1990.80:592-595. and employees of private industry are not eligible. fax 215-440-9313. Cancer 1991. 104. American Association for Cancer Research 1996 Research Fellowships The purpose of the AACR’s 1996 Research Fellowship in Clinical Translational Research. Med Pediatr Oncol 1982. Shalet SM. contact Jenny Anne Horst-Martz. 105. Kun L. Cushing B.119:459-464.51: 2885-2888. et al: Second malignant neoplasms in survivors of Wilms’ tumor: A report from the National Wilms’ Tumor Study.71:506-508.13:1851-1859.266:1672-1677.6 3 92. Both fellowships provide a one-year grant of $30.85:25-31. 108. Philadelphia. Sallan S. Hoppe RT: Breast cancer after treatment of Hodgkin’s disease. Brown CE: Peripartum heart failure in a patient treated previously with doxorubicin.116:144-147. AJR Am J Roentgenol 1979. Parker BR. 95. Camitta B.18:441-446. government employees. Steinherz PG. 102.317:588-593. 98. 150 South Independence Mall West.71:1205-1209. 96. Heaston DK. For application information. Tan CT. Breslow NE. J Natl Cancer Inst 1983. Wallace WH. 107. et al: Hepatic irradiation and adriamycin cardiotoxicity. six to ten years after doxorubicin chemotherapy for childhood cancer. Vol. Moksness J. D’Angio GJ: Congestive heart failure following initial therapy for Wilms tumor: A report from the National Wilms Tumor Study. 101. PA 191063483. et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer.000. Evans AE. Gluck G.