Wilms tumor
Authors: D. M. Green, G. J. D'Angio, J. B. Beckwith, N. E. Breslow, P. E. Grundy, M. L. Ritchey, P. R. Thomas
Journal: CA A Cancer Journal for Clinicians (1996)

Wilms tumor is the most common primary malignant renal tumor of childhood and is the paradigm for multimodal treatment of a pediatric malignant solid 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. 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 0.60 to 1.00.7 The mean age at diagnosis for those with unilateral tumors is 41.5 months for males and 46.9 months for females, compared with 29.5 months for males and 32.6 months for females with bilateral tumors.7 Children with Wilms tumor may have associated anomalies, including aniridia, hemihypertrophy, cryptorchidism, and hypospadias.8 The constellation of Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR syndrome) occurs in association with an interstitial deletion of varying length on chromosome 11 (del(11p13)).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.10,11 Hemihypertrophy may occur as an isolated abnormality or as a component of the Beckwith-Wiedemann syndrome, which includes macroglossia, omphalocele, and visceromegaly.12 The role of parental environmental exposures in the etiology of Wilms tumor is unknown. No consistent positive findings have emerged from a series of case-control studies. Fabia and Thuy13 reported no excess of fathers of Wilms tumor patients with hydrocarbon-related occupations, but others have identified an excess of fathers of Wilms tumor patients engaged in occupations with significant lead exposure14; 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; and an increased odds ratio for Wilms tumor among the offspring of auto mechanics, machinists, and welders.16,17 Previously reported associations between maternal smoking during pregnancy, tea consumption, and hypertension during pregnancy were not confirmed in a large case-control study.18 Other studies have found no correlation between paternal occupation and the occurrence of Wilms tumor.19,20 Wilms tumor is an important model for the study of fundamental mechanisms of carcinogenesis. The genetics of Wilms tumor was thought to follow the pattern of retinoblastoma, 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").21 This model has been confirmed in detail in patients with retinoblastoma. The first event may be constitutional, either a new germinal mutation transmitted from the father22,23 or transmitted from a carrier or affected parent,24 or it may be somatic. In either case it results in the loss of function of one of the alleles of the retinoblastoma (RB) gene, located at 13q14. Subsequently, the function of the remaining normal allele is lost by one of several mechanisms, resulting in absence of normal RB gene product within the affected retinal cell.25 The genetics of Wilms tumor, however, are more complex. 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 muta-tion.26,27 They also suggest that the disease comprises at least two pathogenetic entities that are identifiable on the basis of distinct precursor lesions.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 11p13.29 Interestingly, the deletion occurs preferentially in the paternal allele,30 as with new germinal mutations at 13q14.22 Subsequently, several laboratories reported that about one third of Wilms tumors have undergone tumor-specific loss of heterozygosity for polymorphic DNA markers on 11p13.31,32 Isolation of this Wilms tumor gene (WT1)33,34 allowed the sequence of the normal gene to be determined. 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.36 Strikingly, however, constitutional or even tumor-specific mutations of WT1 have been found in far fewer cases than expected.37,38 Furthermore, in some cases with a tumor-specific WT1 mutation of one allele, the remaining allele is normal.37 A second Wilms tumor locus maps to chromosome 11p15.5, based on tumor-specific loss of heterozygosity restricted to this region.32 Beckwith-Weidemann syndrome, which carries a predisposition to embryonal tumors including Wilms tumor, also maps to this location,32 but it is not yet known whether a single gene is involved. It is of interest that the copy of 11p15 lost in Wilms tumor is invariably derived from the mother.31,39,40 This evidence suggests that the 11p15 Wilms tumor locus is subject to genomic imprinting, resulting in a functional difference between the two alleles. The IGF II gene, which codes for an embryonal growth factor, is a candidate for both Wilms tumor and Beckwith-Wiedemann syndrome because it maps to 11p15.5,41 it is imprinted such that it is only expressed from the paternal allele,42 and it is highly expressed in Wilms tumors.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 11p15,42,44 and constitutional loss of the imprint is associated with both generalized somatic overgrowth and Wilms tumor.45 This epigenetic alteration may result in increased IGF II levels, providing a possible autocrine stimulation pathway. Thus loss of heterozygosity for 11p15, which usually results from mitotic recombination rather than deletion, may not represent loss of a tumor suppressor allele, but rather duplication of the only active IGF II allele. It is not yet known whether a separate Wilms tumor suppressor gene might exist adjacent to IGF II. Finally linkage studies of rare, but large, Wilms tumor pedigrees have excluded linkage to 11p13, 11p15,40,46 and 16q.47 In summary the development of Wilms tumor involves at least two genes on chromosome 11p, an as yet unidentified familial locus, and both genetic and epigenetic mechanisms. The gross appearance of the kidney, distorted by the presence of the tumor, seldom gives external evidence pointing to the underlying histopathology. Tumor multifocality or nephrogenic rests, which may manifest as subcapsular pale pink areas or nodules in the non-tumor-bearing kidney substance, are strongly suggestive of Wilms tumor.28 Extensive research has been conducted by the NWTSG to identify gross and histopathologic patterns that correlate with outcome. These are used both for staging purposes (Table 1) and for tumor type categorization. The classic nephroblastoma is made up of three cell types: blastemal, stromal, and epithelial. However, they are not all present in every case (Fig. 1). When anaplastic nuclear changes as described below are not present, the histology is termed "favorable" (FH) by the NWTSG Pathology Center because of the generally good outcome for these patients (Table 2).48,71,72,78 The neoplastic elements often reflect their renal origin, forming primordial tubules and glomeruli with their associated supporting tissues. Anaplasia is recognized by the presence of gigantic polyploid nuclei within the tumor sample (Fig. 2). The following features should be identified to diagnose anaplasia: (1) nuclei with major diameters at least three times those of adjacent cells and with increased chromatin content and (2) multipolar or otherwise recognizably polyploid mitotic figures. Occasionally, when only a small biopsy is available, the presence of a single, multi-polar mitotic figure or an unequivocally gigantic tumor cell nucleus will suffice to diagnose anaplasia. Anaplastic changes may be either focal or diffuse. The criteria distinguishing focal from diffuse anaplasia were modified recently.49 The original definition of focal anaplasia was based on the amount of anaplasia present. Anaplastic nuclear changes present in fewer than 10 percent of microscopic fields were originally designated as focal anaplasia. This criterion permitted the inclusion of tumors where anaplasia was present throughout the tumor, albeit at low density, and cases with anaplasia in extrarenal sites or in metastatic deposits. 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 any site outside the kidney parenchyma. Triphasic Wilms tumor with well-defined tubules surrounded by dense clusters of blastemal cells and zones of pale-staining stromal differentiation (hematoxylin-eosin, original magnification × 100). Diffuse anaplasia is diagnosed when anaplasia is (1) present in any extrarenal site, including vessels of the renal sinus, extracapsular infiltrates, or nodal or distant metastases; (2) present in a random biopsy specimen; (3) unequivocally expressed in one region of the tumor, but with extreme nuclear pleomorphism approaching the criteria of anaplasia (extreme nuclear unrest) elsewhere in the lesion; or (4) present in more than one tumor slide, 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. This topographic definition of focal anaplasia makes it mandatory that pathologists carefully document the exact site from which every section is obtained (e.g., on a diagram, specimen photocopy, and/or polaroid photograph of the gross specimen). Although not currently thought to be a variant of Wilms tumor, clear cell sarcoma of the kidney (CCSK) is an important entity to consider. It is associated with a significantly higher rate of relapse and death than FH Wilms tumor. CCSK also is associated with a distinctively high rate of skeletal metastases. 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.48 The descriptive term CCSK was used by the NWTSG, whereas the British workers referred to "bone-metastasizing renal tumour of childhood" (BMRTC). CCSK has a much wider distribution of metastases than does FH Wilms tumor, with a strikingly increased number of brain as well as bone metastases.52,53 Most CCSK specimens have a distinct and easily recognized histologic appearance, but a number of variant patterns, such as epithelioid, spindling, myxoid, and cystic, invite confusion with Wilms tumor or other tumor types (Fig. 3).54–57 The reader is referred elsewhere for detailed descriptions and illustrations of both the classic and variant patterns.51,58 Rhabdoid tumor of the kidney (RTK), a distinctive and highly malignant tumor type, was identified for the first time in 1978 by NWTSG pathologists.48 The tumor, previously confused with Wilms tumor, is monomorphous like CCSK. The cells of RTK, unlike CCSK, characteristically have prominent acidophilic cytoplasm, often resembling that of myoblasts. However, the cytoplasm is negative for ultrastructural or other markers of skeletal muscle (Fig. 4). The cell of origin for this distinctive tumor remains unknown.59,60 It is not a variant of Wilms tumor and will not be encountered as a focal change in a conventional Wilms tumor. Several cases have been reported in which apparently separate primary neuroectodermal tumors of the brain have developed in children with RTK.61 Most children with Wilms tumor are brought to medical attention because of abdominal swelling or the presence of an abdominal mass. Usually this is noticed by a parent while bathing or dressing the child. Abdominal pain, gross hematuria, and fever are other frequent findings at diagnosis.62 During the physical examination, it is important to note the location and size of the abdominal mass and its movement with respiration. These findings help differentiate Wilms tumor from splenomegaly and neuroblastoma, the latter often arising in the celiac axis or extending across the midline because of lymph node involvement. 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. Persistence of the varicocele when the child is supine is highly suggestive of venous obstruction. It is also important to note specifically any signs of syndromes associated with Wilms tumor, including the presence of aniridia; partial or complete hemihypertrophy; or genitourinary abnormalities, such as hypospadias and cryptorchidism. The laboratory evaluation should include a complete blood count; a differential white blood cell count; a platelet count; liver function tests; renal function tests; serum calcium, which may be elevated in patients with RTK and mesoblastic nephroma; and urinalysis. The radiographic evaluation should establish the presence of an intrarenal mass and a normally functioning contralateral kidney, document the patency of the inferior vena cava, and demonstrate the presence or absence of pulmonary metastases.62 The initial study should be an abdominal ultrasound examination. This will demonstrate whether the mass is cystic or solid and will help define the organ from which the tumor originated (Fig. 5). Computed tomography of the abdomen will establish the origin of most abdominal masses (Fig. 6). However a rigorous comparison of the value of computed tomography to that of abdominal ultrasonography in patient management is lacking. Current data suggest that conventional radiographic techniques, including ultrasonography, provide sufficient information on which to make a decision for laparotomy in most children. Anaplastic Wilms tumor with a large, darkly stained multipolar mitotic figure near the center and a markedly enlarged interphase nucleus to its left. Nuclei throughout this field exhibit increased variation in size and shape (hematoxylin-eosin, original magnification × 600). The patency of the inferior vena cava can be established with the use of ultrasonography. When tumor is identified within the inferior vena cava, the proximal extent of the thrombus must be established prior to operation. Cardiac extension of such a tumor thrombus may produce few or no signs, but it can, on rare occasions, be responsible for sudden death following manipulation and embolization of the tumor at laparotomy.63,64 Plain chest radiographs, preferably including both oblique views, should be obtained to determine if pulmonary metastases are present. The role of computed tomography of the lungs in the evaluation of children with Wilms tumor is controversial.65 Lesions are rarely identified using computed tomography in patients with a negative plain chest radiograph.66,67 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, suggesting that the added information is of limited, if any, value.68 Clear cell sarcoma of the kidney, classical pattern. Cords and nests of pale-stained tumor cells are separated by a delicate but distinct network of fine vascular septa. Nuclei are vesicular, with poorly stained chromatin and inconspicuous nucleoli (hematoxylin-eosin, original magnification × 200). A radionuclide bone scan and skeletal survey should be obtained postoperatively on all children with CCSK. A magnetic resonance image of the brain should be obtained on all children with RTK or CCSK. The treatment of children with Wilms tumor begins with abdominal exploration, using the transabdominal approach. The goal of abdominal exploration is radical or modified radical nephrectomy. Upon entering the abdomen, the opposite kidney should be inspected on all its surfaces for evidence of a synchronous bilateral tumor or evidence of nephrogenic rests. These may not be identified on preoperative imaging studies, especially if they are small and/or flat. The tumor, kidney, renal hilar structures, 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. After the primary tumor has been removed, the liver should be inspected. Biopsies should be obtained from areas that are grossly suspicious for tumor. The para-aortic lymph nodes should be inspected. If enlarged nodes are present, these should be biopsied. If all of the para-aortic lymph nodes appear to be normal, then a random biopsy should be obtained. 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.69 A biopsy should be obtained from the kidney in this situation only if a tumor nodule cannot be identified at some other site, such as the peritoneal surface or the liver. In addition, attempts at primary surgical excision of the tumor and caval extension are associated with increased surgical morbidity.69 Preoperative chemotherapy should be administered to patients who have intracaval and atrial extension of the tumor.70 Tumor shrinkage usually follows, making the standard transabdominal approach feasible. 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. The staging system employed by the NWTSG is detailed in Table 1. 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. 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, if treatment includes combination chemotherapy with vincristine and dactinomycin.71,72 Rhabdoid tumor. Most nuclei have a large, single nucleolus, imparting an "owl's eye" appearance to the nucleus. Several cells, including one near the center, have hyaline globular cytoplasmic inclusions. Ultrastructurally the latter inclusions consist of whorled masses of intermediate filaments, usually composed of vimentin (hematoxylin-eosin, original magnification × 600). Wilms tumor sonogram. Prone sagittal scan of right renal fossa demonstrates a large, complex, mainly solid intrarenal mass. Analyses also indicate that flank irradiation is sufficient for children with tumor spill confined to the flank, but that whole abdomen irradiation is advisable when contamination of the entire peritoneal cavity has occurred.73 The use of dactinomycin for the adjuvant treatment of children with Wilms tumor was pioneered by Farber and his colleagues. These investigators reported that such therapy improved the survival rate of patients compared with that observed when nephrectomy was followed only by abdominal irradiation.74 Others have demonstrated that multiple courses of dactinomycin decrease the frequency of recurrence compared with a single course.75,76 Computed tomography scan of the abdomen showing a right renal tumor and a normal appearing left kidney. Vincristine was evaluated as single-agent adjuvant chemotherapy by investigators at the MD Anderson Hospital and the Pediatric Division of the Southwest Oncology Group, the NWTSG, and the Medical Research Council. Patients with nonmetastatic, locally advanced tumors in the NWTS-1 trial were randomized to receive dactinomycin, vincristine, or the combination, in addition to postoperative abdominal irradiation. The relapse-free survival rate for children treated with vincristine was 54.4 percent at four years compared with 56.0 percent at four years for children treated with dactinomycin. The relapse-free survival rate for children treated with the combination of vincristine and dactinomycin was 77.5 percent, significantly better than for either single agent.77,78 In the trial by the Medical Research Council, children were randomized to therapy with multiple courses of dactinomycin or vincristine after receiving a postoperative course of dactinomycin. Thus, children randomized to therapy with vincristine actually received combination chemotherapy. The relapse-free survival rate for children treated with vincristine was 78 percent compared with 54 percent for children treated with dactinomycin.79 In NWTS-2, children with group I tumors were randomized to six or fifteen months of adjuvant chemotherapy with vincristine and dactinomycin. None of these patients received postoperative abdominal irradiation. The relapse-free survival rate after randomization for those children who received six months of chemotherapy was 97.4 percent compared with 91.1 percent for those who were treated for 15 months,71,78 a difference that was not statistically significant. In NWTS-2, the combination of vincristine and dactinomycin was compared with the same two agents plus doxorubicin in children with stage II to IV, FH or anaplastic Wilms tumor, CCSK, or RTK. 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.78 The relapse-free survival rate following randomization among group II, FH patients treated with two agents was 78.4 percent compared with 87.7 percent for those who received three agents. The relapse-free survival rate following randomization for group III, FH patients treated with two agents was 65.4 percent compared with 88.5 percent for those treated with three agents,71,78 a difference that was statistically significant. The addition of doxorubicin did not improve the relapse-free survival rate of those patients with an unfavorable histology tumor or group IV disease. The benefit reported in NWTS-2 from the addition of doxorubicin may be due to the greater intensity of the three-drug regimen, rather than the addition of a third agent. This hypothesis was tested in NWTS-3 (Fig. 7). The results of this trial demonstrated that (1) intensive treatment with vincristine and dactinomycin was equivalent to therapy with these two drugs plus doxorubicin; (2) postoperative abdominal irradiation does not improve the relapse-free survival rate of children with stage II Wilms tumor; and (3) 1,000 and 2,000 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).72 Treatment randomization for patients entered on National Wilms Tumor Study-3. DACT = dactinomycin; VCR = vincristine; DOX = doxorubicin; CPM = cyclophosphamide. Early NWTS-3 analyses suggested that patients with stage II to IV, anaplastic Wilms tumor, who all received radiation therapy, benefited from the addition of cyclophosphamide to the combination of dactinomycin, vincristine, and doxoru-bicin.72 This result for patients with diffuse anaplasia (stages II to IV) has been confirmed with additional patient accrual on NWTS-4.80 There is no beneficial effect of adding cyclophosphamide in patients with tumors having only focal anaplasia. All NWTS-3 patients with CCSK received abdominal radiation therapy and were randomized to the same three- versus four-drug comparative regimens. The four-year, relapse-free survival rate for CCSK patients treated with three drugs was 70.6 percent, and the four-year overall survival rate was 74.8 percent. There was no statistically significant improvement in those given the fourth drug (cyclophosphamide).52 Patients with RTK have responded poorly to all the treatments used in the NWTS. The four-year, relapse-free survival rate for all NWTS-3 patients with RTK randomized according to Figure 7 was about 25 percent, and the overall four-year survival rate was the same.72 Wilms tumor occurs simultaneously in both kidneys in about seven percent of cases. Most children with bilateral Wilms tumor are not diagnosed on the basis of the physical examination. In the NWTS-1, only nine of 30 children (30 percent) with bilateral disease had bilateral, palpable abdominal masses. Bilateral disease was identified in only 17 of 30 children (56.6 percent) by intravenous urography, and only about 10 percent of those found at laparotomy to have bilateral disease were previously identified using computed tomography.81 These data emphasize the importance of contralateral renal exploration at the time of laparotomy. The treatment of children with bilateral Wilms tumor must be individualized. The goal of therapy is to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the frequency of chronic renal failure among these children.82–84 The approach presently recommended is initial bilateral renal biopsy with staging of each kidney. Initial treatment is with the combination of vincristine and dactinomycin. A reevaluation is performed to determine if there has been sufficient response of the tumors to allow tumor resection, with preservation of a substantial amount of normal renal tissue. Additional chemotherapeutic agents, such as doxorubicin, with or without radiation therapy, may be necessary for the management of children whose tumors respond poorly to the combination of vincristine and dactinomycin. Wilms tumor has a tendency to recur in several sites, including lung, liver, opposite kidney, original tumor bed, and other intra-abdominal sites. Bone, brain, and other sites are only occasionally involved. The most frequent site of recurrent disease is the lung.85 Although most first relapses are diagnosed within the first two years after nephrectomy, initial relapse has been diagnosed as long as eleven years after diagnosis.86 Those factors that favorably affect the success of further therapy include initial treatment with only vincristine and dactinomycin, relapse to the lungs only, relapse in the abdomen of a patient who received no prior abdominal irradiation, and relapse more than twelve months after diagnosis. The treatment that children receive for Wilms tumor may cause damage to other structures or organs, such as the bones and heart. In addition both chemotherapeutic agents and radiation therapy can induce second malignant neoplasms. Congestive heart failure is a known complication of therapy with an anthra-cycline.87 The frequency is directly proportional to the cumulative dose of doxorubicin received, with a reported incidence of congestive heart failure of about five percent in patients who received a cumulative dose of 400 to 500 mg/m2.88 Subclinical effects are observed in up to 57 percent of patients,89 with impairment of diastolic function clearly related to dose.90 Although the initial reports of congestive heart failure were limited to the first year after completion of therapy,91 reports of cardiac failure and dysrythmias, leading in some cases to sudden death, are now appearing for patients treated four to 20 years earlier92,93 and may be precipitated by a physiologic stress such as pregnancy.94 In a preliminary analysis of the frequency of and risk factors for congestive heart failure in patients entered on NWTS-1, NWTS-2, and NWTS-3, 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. All eight patients received doxorubicin as part of their chemotherapy regimen. The cumulative frequency of congestive heart failure was 1.7 percent among doxorubicin-treated patients. Additional statistically significant risk factors included prior whole lung irradiation and concurrent therapy with cyclophosphamide.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.96,97 Further follow-up of the NWTSG cohort is needed to define more accurately the magnitude of the risk for late congestive heart failure.95 The late effects of trunk irradiation—scoliosis and soft tissue underdevelopment—are still being seen since the advent of megavoltage irradiation.98–101 Heaston et al100 reported the frequency of spinal abnormalities in patients treated with megavoltage irradiation following nephrectomy. Scoliosis was diagnosed in six of 16 patients (38 percent) who had entered the adolescent growth spurt, but no patient had a curve that exceeded 25 degrees. Eight patients (50 percent) had kyphosis, including five who did not have scoliosis.100 Other investigators identified scoliosis in seven of 12 patients (58 percent)99 and 35 of 57 patients (61 percent)102 treated with mega-voltage irradiation following nephrectomy. These data suggest that the frequency of spinal deformity may not decrease with the use of megavoltage radiation sources. 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. One would expect the least deformity in nonirradiated patients. That expectation has been documented by the NWTSG, 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.102 Second malignant neoplasms can develop in Wilms tumor survivors.103–105 Most of these, such as bone,106 breast,107 and thyroid cancers,108 have occurred in irradiated areas. The most significant risk factor for the occurrence of a second malignant neoplasm in the NWTSG cohort was treatment with radiation therapy. Initial treatment that included doxorubicin increased this risk. Significantly, even those patients whose therapy included only dactinomycin and vincristine, without radiation therapy, had an increased risk of cancer compared with the US population.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, should they occur, and not vitiate what has been gained from so many years of successful clinical research. 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. Careful palpation of the abdomen is essential to detect local tumor recurrence or tumor growth in the liver or contralateral kidney. The indicated radiographic examinations depend upon the original stage of the tumor. Local tumor recurrence and recurrence at other intra-abdominal sites is very uncommon among children with stage I or II Wilms tumor. The first site of disease recurrence in these patients is most frequently the lung. Children who have gross residual abdominal disease (stage III and stage IV) have a greater risk of local tumor recurrence. These patients should have frequent, careful palpation of the abdomen. Suspicious findings on physical examination may be clarified using abdominal ultrasonography or computed tomography (Table 4).85 Patients who present with hematogenous metastases (lung, brain, bone, and/or liver) require regular evaluation of these sites. The brain is most easily evaluated using magnetic resonance imaging. The liver should be palpated at each follow-up visit. Evidence on physical examination of enlargement and/or nodularity of the liver should be confirmed with computed tomography. 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. A radionuclide bone scan should be obtained when the plain radiographs are negative and the symptoms are highly suggestive of a bone metastasis. The tumor bed of patients who present with hematogenous metastases and patients without metastases should be evaluated (Table 4).85 The purpose of the AACR's 1996 Research Fellowship in Clinical Translational Research, sponsored by Amgen, Inc., 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. 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). Academic faculty holding the rank of assistant professor or higher, graduate or medical students, government employees, and employees of private industry are not eligible. Both fellowships provide a one-year grant of $30,000. Candidates must be nominated by a member of the AACR and submit a detailed application. The deadline is February 15. For application information, contact Jenny Anne Horst-Martz, American Association for Cancer Research, Public Ledger Building, Suite 816, 150 South Independence Mall West, Philadelphia, PA 19106–3483; telephone 215–440–9300; fax 215–440–9313.