Familial Wilms' tumor: a descriptive study.

Among 6,209 patients with Wilms' tumor entered on the National Wilms' Tumor Study (NWTS), 93 patients (1.5%) from 63 families had a positive family history. In 30 of these 63 families a (half) sibling or parent of the NWTS patient was confirmed to have had Wilms' tumor. Fifteen (16.1%) of the familial, but only 7.1% of sporadic cases, had bilateral disease. Mean ages at diagnosis were 15.8 vs. 35.2 months (P = 0.012) for bilateral vs. unilateral familial cases and 32.0 vs. 44.7 months for sporadic cases. Intralobar nephrogenic rests were found twice as frequently in association with the tumors of familial as with those of sporadic cases. Cases of bilateral and metastatic disease tended to cluster within specific families, suggesting heterogeneity in the genetic etiology. The number and age distribution of familial cases transmitted through the father were about the same as those of cases transmitted through the mother. This finding is inconsistent with models of genomic imprinting that involve familial transmission of a tumor-suppressor gene and it casts further doubt on the hypothesis that all bilateral cases are hereditary.

Histological analysis of aggressiveness and responsiveness in Wilms' tumor.

The clinical behavior and outcome for any neoplasm are determined originally by its aggressiveness. As adjuvant therapy becomes increasingly effective for that neoplasm, responsiveness to therapy assumes a larger role in determining outcome. Wilms' tumor (WT) provides instructive examples of the dissociation of aggressiveness from responsiveness. The presence of gigantic nuclei with multipolar mitotic figures (anaplasia) appears to be a marker of resistance to therapy, but not of increased aggressiveness. For this reason, anaplasia in a stage 1 WT and anaplasia confined to discrete foci within the primary tumor have no adverse prognostic significance following surgical resection. The prognostic significance of anaplasia is apparently limited to those patients in whom anaplastic cells remain following attempted surgical resection. WT with predominantly epithelial differentiation usually have a low degree of aggressiveness. In this study, 81.3% of WT with this pattern were stage 1. This feature accounts for the high cure rate associated with this pattern prior to the advent of effective adjuvant therapy. However, epithelial predominant WT that present with advanced stage disease may be quite resistant to therapy, with relapse and death rates higher than for more aggressive WT patterns. In contrast, the diffuse blastemal pattern is associated with marked aggressiveness, but with high survival rates suggesting it is usually responsive to current therapy. These features illustrate the independence of aggressiveness and responsiveness in determining outcome for some patients with cancer. Grading systems must be reevaluated with each significant change in therapy. In order to formulate rational therapy, it is important to determine whether prognostic markers are associated with aggressiveness or responsiveness.

Clinicopathologic correlates of loss of heterozygosity in Wilm's tumor: a preliminary analysis.

Wilms' tumor-specific loss of heterozygosity (LOH) for DNA markers located at chromosomes 11p13, 11p15, 16q, and 1p has been reported to occur in a minority of Wilms' tumors. We hypothesized that tumors classified by region of LOH would exhibit specific clinicopathologic patterns. We have therefore determined the constitutional and tumor genotypes for markers at 11p13, 11p15, 16q, and 1p in a large series of Wilms' tumor patients who were registered on a Pediatric Oncology Group study and on the National Wilms' Tumor Study, to determine whether tumor-specific LOH for any of these regions was associated with any specific phenotype. Of 286 cases, 27% had LOH at both 11p13 and p15 (BOTH), 3% at 11p13 only, 8% at 11p15 only, and 62% at neither. Significant associations were found between younger age at diagnosis and LOH for BOTH, but not for 11p15 only, and between the presence of intralobar nephrogenic rests and LOH for BOTH. The incidence of nephrogenic rests (all types combined) and of bilateral tumors was the same in tumors with or without LOH. There was a negative association between anaplastic histology and LOH for 11p. There was no association between LOH on 11p and outcome as assessed by relapse-free and overall survival. The associations between age at diagnosis and LOH are interpreted as suggesting the existence of a Wilms' tumor locus on 11p in addition to WT1 at 11p13 and the putative WT2 at 11p15. LOH for chromosome 16q was identified in 17% of 204 tumors and was associated with a significantly worse outcome. Outcome for patients with LOH for 1p was also worse but not significantly so.

Renal salvage procedures in patients with synchronous bilateral Wilms' tumors: a report from the National Wilms' Tumor Study Group.

Synchronous bilateral Wilms' tumor accounts for 4% to 6% of all Wilms' tumors. Renal salvage procedures (partial nephrectomy and enucleation) have been recommended to conserve renal parenchyma. The objective of this study was to review the results of renal salvage operations performed in children who had bilateral neoplasms. The authors reviewed the records of 98 children enrolled in the Fourth National Wilms' Tumor Study who had synchronous bilateral tumors and underwent renal salvage procedures. One hundred thirty-four kidneys were managed with renal salvage procedures. Complete excision of gross disease was accomplished in 118 (88%) of the 134 kidneys. Local tumor recurrence in the remnant kidney or tumor bed occurred in 11 cases (8.2%). Overall, 72% of the kidneys were preserved, and the 4-year survival rate was 81.7%. The surgical morbidity after a salvage procedure was comparable to that of a complete nephrectomy in patients with unilateral Wilms' tumor. Although the incidence of positive surgical margins is worrisome, it did not invariably lead to local recurrence in the remnant kidney or the tumor bed.

Treatment of children with stage IV favorable histology Wilms tumor: a report from the National Wilms Tumor Study Group.

The purpose of this study was to evaluate the effect of the sequential addition of doxorubicin and cyclophosphamide to the combination of vincristine and actinomycin D on the relapse-free survival of children with stage IV/favorable histology Wilms tumor. We reviewed the clinical courses of all randomized patients from National Wilms Tumor Study (NWTS)-2 and 3 with stage IV/favorable histology (FH) Wilms tumor. We determined the four-year relapse-free survival percentage for patients treated on NWTS-2 with the combination of vincristine (VCR) and actinomycin D (AMD) with (regimen D) or without (regimen C) doxorubicin (DOX), and for patients treated on NWTS-3 with the combination of VCR+AMD+DOX with (regimen J) or without (regimen DD-RT) cyclophosphamide (CTX). All children received whole lung radiation therapy. The four-year relapse-free survival percentage for children with stage IV/FH Wilms tumor treated with regimen C was 53.3%, compared to 57.7% for those treated with regimen D (P = 0.63). The four-year relapse-free survival percentage for children with stage IV/FH Wilms tumor treated with regimen DD-RT was 79.0%, compared to 80.9% for those treated on regimen J (P = 0.79). The four-year relapse-free survival for children with lung metastases only treated with regimen D on NWTS-2 was significantly lower than that of children treated with the related regimen DD-RT on NWTS-3 (P = 0.03). We conclude that the addition of doxorubicin to the combination of vincristine and actinomycin D and pulmonary irradiation did not clearly improve the four-year relapse-free survival percentage of children with stage IV/FH Wilms tumor, although the benefit may have been masked by the greater frequency of death due to toxicity in NWTS-2. There was no evidence that the addition of CTX to the three-drug treatment regimen improved the four-year relapse-free survival percentage of children with stage IV/FH Wilms tumor. The data with only two drugs derived from NWTS-2 suggest that there is a population of children with stage IV/FH Wilms tumor who can be successfully treated without an anthracycline. The goal of future research will be to identify this subgroup at the time of initial diagnosis.

Renal failure in Wilms' tumor patients: a report from the National Wilms' Tumor Study Group.

This report defines the incidence and determines the etiology of renal failure (RF) in patients undergoing treatment for Wilms' tumor (WT). The database of the National Wilms' Tumor Study (NWTS) was searched to identify all children reported to have developed chronic renal failure. There were 55 patients found to have RF. Of these, 39 patients had bilateral tumors, 15 with unilateral disease and one with a WT in a solitary kidney. The median interval from diagnosis to the onset of renal failure was 21 months. The incidence of RF in bilateral WT was 16.4% for NWTS-1 & -2, 9.9% for NWTS-3, and 3.8% for NWTS-4. The incidence of RF in unilateral WT remained stable. The most common etiologies of RF were: bilateral nephrectomy for persistent or recurrent tumor (24 pts), Drash syndrome (12 pts), progressive tumor in the remaining kidney (5 pts), radiation nephritis (6 pts), and other causes (5 pts). The etiology of renal failure was not reported in three children. Children with unilateral WT and a normal contralateral kidney have a very low incidence of RF, and this review does not support a recommendation for parenchymal sparing procedures in these patients. Children with bilateral WT are at risk for the development of RF, and parenchymal sparing procedures are warranted.

Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: The study was undertaken to determine the incidence of second malignant neoplasms (SMNs) in patients treated for Wilms' tumor and demonstrate how the incidence varied with the initial treatment protocol. PATIENTS AND METHODS: Between October 1969 and December 1991, 5,278 assessable patients were enrolled onto the National Wilms' Tumor Study (NWTS) and by the end of 1993 had contributed 39,461 person-years to a follow-up study. Expected numbers of second cancers were calculated by applying national incidence rates to person-years classified by age, sex, and calendar year. RESULTS: Forty-three SMNs were observed, whereas only 5.1 were expected (standardized incidence ratio [SIR], 8.4; 95% confidence interval [CI], 6.1 to 11.4). Fifteen years after the Wilms' tumor diagnosis, the cumulative incidence of a SMN was 1.6% and increasing steadily. Abdominal irradiation received as part of the initial therapy increased the risk of a SMN (SIR, 1.43/10 Gy; 95% CI, 1.13 to 1.81). Doxorubicin potentiated the radiation effect. Among 234 patients who received doxorubicin and greater than 35 Gy of abdominal radiation, eight SMNs were observed, whereas only 0.22 were expected (SIR, 36; 95% CI, 16 to 72). Treatment for relapse further increased the SMN risk by a factor of 4 to 5. CONCLUSION: These results demonstrate the importance of current efforts to limit the use of intensive chemotherapy and radiation therapy, which are now applied only to patients with the most aggressive disease. Continuing close surveillance of the great majority of Wilms' tumor patients who become long-term survivors is essential for early diagnosis of SMNs and other late sequelae of therapy.

Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms' tumor. A report from the National Wilms Tumor Study Group.

BACKGROUND: Five percent of patients with Wilms' tumor will present with bilateral disease. Recent reports suggest that preoperative imaging studies can exclude contralateral disease reliably, obviating the need for formal surgical exploration of the contralateral kidney. This study was undertaken to determine the accuracy of preoperative imaging in diagnosing bilateral Wilms' tumor. METHODS: The charts of 122 patients with synchronous bilateral Wilms' tumor enrolled in National Wilms Tumor Study-4 were reviewed. With the exception of one child, all had an abdominal computed tomography (CT), ultrasound, or magnetic resonance imaging performed. RESULTS: There were nine patients (7%) in whom the diagnosis of bilaterality was missed by the preoperative imaging studies. All but one of the missed lesions were small, five less than 1 cm and three 1-3 cm. The accuracy of each imaging modality was correlated with tumor size. Computed tomography was more sensitive in detecting bilaterality than ultrasound. However, there was not a single study that was able to detect more than 50% of lesions less than 1 cm in greatest dimension. CONCLUSIONS: This review indicates that even with current advances in imaging technology, synchronous bilateral Wilms' tumor will go unrecognized in 7% of patients if formal exploration of the contralateral kidney is omitted. Although this represents a small percentage of all patients presenting with Wilms' tumor, preoperative diagnosis of bilaterality is essential if parenchymal-sparing procedures are to be performed. Until a more reliable indicator of bilateral disease is found, exploration of the contralateral kidney continues to be recommended.

Relationship between dose schedule and charges for treatment on National Wilms' Tumor Study-4. A report from the National Wilms' Tumor Study Group.

National Wilms' Tumor Study-4 was designed to evaluate the efficacy, toxicity, and cost of administration of different regimens for the treatment of Wilms' tumor. The charges for treatment with dactinomycin and doxorubicin administered by two different schedules were calculated using current charges in Buffalo, N.Y. An annual savings of approximately $779,259 could be achieved by the use of the short, pulse-intensive (i.e., single-dose) treatment regimens for all children with Wilms' tumor of stages I-IV/favorable histology. The pulse-intensive administration schedule for the treatment of children with Wilms' tumor permits administration of chemotherapy at a substantially lower total treatment cost.

Management and outcome of inoperable Wilms tumor. A report of National Wilms Tumor Study-3.

METHODS: The authors reviewed 131 children enrolled in National Wilms Tumor Study-3 (NWTS-3) who received preoperative treatment for tumors unable to be resected at surgery or judged inoperable by imaging evaluation. Preoperative biopsies were performed on 103 patients. Patients were assigned a pretreatment stage: stage II (11 patients), stage III (39 patients), stage IV (66 patients), and unknown (15 patients). The chemotherapy regimen included dactinomycin and vincristine (81 patients), dactinomycin, vincristine, and doxorubicin (30 patients), dactinomycin, vincristine, doxorubicin, and cyclophosphamide (10 patients), and other (8 patients). Preoperative radiation therapy was started concurrently with chemotherapy (27 patients) or because of lack of response (14 patients). Two patients were given preoperative irradiation without chemotherapy. RESULTS: Response to therapy was assessed after the first trial of chemotherapy. Partial responses were noted in 110 patients (85%), 3 had complete responses, 13 had no response or progression of disease, and 5 patients were not able to be evaluated. There were no significant differences in preoperative response to the different chemotherapy regimens. Median time interval from diagnosis to nephrectomy was 58.5 days. When compared with NWTS-3 patients not receiving preoperative treatment, survival was reduced for patients treated preoperatively (88% vs. 74%, respectively, 4-year survival), which was only partially explained by differences in stage distribution. Median duration of follow-up was 5.9 years. Lack of response to the preoperative treatment was associated with a poor prognosis. Eight children died before removal of the primary tumor. All eight had either progressive disease or no response to the preoperative treatment. CONCLUSIONS: The use of preoperative treatment can facilitate subsequent surgical resection in selected patients with inoperable Wilms tumors. Although these very large tumors--judged unable to be resected--have a somewhat worse prognosis, nephrectomy was completed in 93% of patients after preoperative treatment. However, preoperative treatment will lead to less accurate surgical and pathologic staging, and undertreatment should be avoided in these high-risk patients.

Treatment of children with stages II to IV anaplastic Wilms' tumor: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the combination of vincristine, dactinomycin, and doxorubicin with (regimen J) or without (regimen DD-RT) cyclophosphamide on the relapse-free survival of children with stages II to IV Wilms' tumor and focal or diffuse anaplasia. PATIENTS AND METHODS: We reviewed the clinical courses of all randomized patients from National Wilms' Tumor Study (NWTS)-3 and NWTS-4 with stages II to IV anaplastic Wilms' tumor, and determined the 4-year relapse-free survival rate separately for those with focal or diffuse anaplasia. Anaplasia was evaluated using newly developed topographic definitions for focal and diffuse anaplasia. RESULTS: The 4-year relapse-free survival rate for five children with focal anaplasia who received regimen DD-RT was 80.0%, compared with 100.0% for eight children who received regimen J (P = .68). The 4-year relapse-free survival rate for 29 children with diffuse anaplasia treated with regimen DD-RT was 27.2%, compared with 54.8% for 30 children treated with regimen J (P = .02). CONCLUSION: We conclude that children with focal anaplasia have an excellent prognosis when treated with vincristine, doxorubicin, and dactinomycin. The addition of cyclophosphamide to the three-drug treatment regimen improved the 4-year relapse-free survival rate of children with stage II to IV diffuse anaplasia. This result suggests that further intensification of the treatment regimen for children with diffuse anaplasia may result in an additional improvement in prognosis.

Treatment of children with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of the sequential addition of doxorubicin (DOX) and cyclophosphamide (CTX) to the combination of vincristine (VCR) and dactinomycin (AMD) on the relapse-free survival of children with clear-cell sarcoma of the kidney (CCSK). PATIENTS AND METHODS: We determined the 6-year relapse-free survival rate for patients with CCSK treated on National Wilms' Tumor Study (NWTS)-1, NWTS-2, or NWTS-3 with the combination of VCR and AMD, with or without DOX, and for patients treated on NWTS-3 with the combination of VCR, AMD, and DOX with (regimen J) or without (regimen DD-RT) CTX. RESULTS: The 6-year relapse-free survival rate for the eight children with CCSK treated with VCR, AMD, and radiation therapy was 25.0%, compared with 63.5% for the 58 children treated with VCR, AMD, DOX, and radiation therapy (P = .09). The 6-year relapse-free survival rate for children with CCSK treated on regimen DD-RT was 64.6%, compared with 58.2% for those treated on regimen J (P = .79). CONCLUSION: We conclude that the addition of DOX to the combination of VCR plus AMD appeared to improve the 6-year relapse-free survival rate of children with CCSK. The addition of CTX in the dose and schedule used in NWTS-3 did not improve the 6-year relapse-free survival rate of children with CCSK. Because 30% of relapses occurred more than 2 years after diagnosis, prolonged follow-up evaluation of patients with CCSK is necessary.

The relationship between microsubstaging variables, age at diagnosis, and tumor weight of children with stage I/favorable histology Wilms' tumor. A report from the National Wilms' Tumor study.

BACKGROUND: The purpose of this study was to determine the relationship between histologic microsubstaging variables, patient age, and tumor specimen weight in patients with Stage I/favorable histology Wilms' tumors. METHODS: The authors reviewed all randomized patients from the Fourth National Wilms' Tumor Study, who had Stage I/favorable histology Wilms' tumors evaluated for one or more of the microsubstaging variables: (1) the presence of an inflammatory pseudocapsule, (2) renal sinus invasion, (3) tumor in the intrarenal vessels, and (4) tumor capsule invasion. The authors determined the correlation between microsubstaging variables and age at diagnosis or tumor specimen weight. RESULTS: Patients who were younger than 2 years of age at diagnosis were significantly more likely to have all negative microsubstaging variables. Patients who had tumors weighing less than 550 g were more likely to have all negative microsubstaging variables. However, neither renal sinus invasion nor tumor in the intrarenal vessels was more frequent in tumors weighing more than 550 g. CONCLUSIONS: An age at diagnosis of younger than 2 years and a tumor specimen weight of less than 550 g are highly correlated with the absence of adverse microsubstaging variables. The clinical variables of age at diagnosis and tumor specimen weight, compared with the assessment of microsubstaging variables, have the practical advantage of being more objectively determined and not requiring a central pathologic review for confirmation.

The effect of chemotherapy dose intensity on the hematological toxicity of the treatment for Wilms' tumor. A report from the National Wilms' Tumor Study.

PURPOSE: To determine the relationship between hematological toxicity and actual dose intensity of treatment of patients randomized to therapy during the first 28 months of the National Wilms' Tumor Study-4. METHODS: The mean minimum white blood cell count (WBC), platelet count (PLT), hemoglobin, and absolute neutrophil count (ANC) during the first two courses of chemotherapy and the mean number of days of hospitalization for toxicity were compared between standard and "pulse-intensive" regimens for all randomized patients entered on National Wilms' Tumor Study-4 between August 6, 1986 and December 31, 1988. The mean dose intensity of dactinomycin, vincristine, and doxorubicin received during the first two courses and the entire course of treatment was compared between standard and "pulse-intensive" regimens. RESULTS: The mean minimum WBC, PLT, and ANC were all significantly lower during the first two courses of chemotherapy for stage I patients treated with the standard regimen, compared with the "pulse-intensive" regimen. The mean dose intensity of dactinomycin and doxorubicin was significantly higher for patients treated with the "pulse-intensive" regimens, compared with the appropriate standard regimen. CONCLUSIONS: The "pulse-intensive" administration schedule for the treatment of children with Wilms' tumor permits administration of chemotherapy at a higher dose intensity without an increase in hematological toxicity.

Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome.

We have prospectively analyzed Wilms' tumors from 232 patients registered on the National Wilms' Tumor Study for loss of heterozygosity (LOH) on chromosomes 11p, 16q, and 1p. These chromosomal aberrations were found in 70 (33%), 35 (17%), and 21 (12%) of the informative cases, respectively. LOH for two of these regions occurred in only 25 cases, and only one tumor harbored LOH at all three sites. There was no statistically significant association between LOH at any of the three regions and either the stage or histological classification of the tumor. Patients with tumor-specific LOH for chromosome 16q had relapse rates 3.3 times higher (P = 0.01) and mortality rates 12 times higher (P < 0.01) than patients without LOH for chromosome 16q. These differences remained when adjusted for histology or for stage. Patients with LOH for chromosome 1p had relapse and mortality rates three times higher than those for patients without LOH for chromosome 1p, but these results were not statistically significant. In contrast, LOH for chromosome 11p had no effect on measures of outcome. These molecular markers may serve to further stratify Wilms' tumor patients into biologically favorable and unfavorable subgroups, allowing continued use of the clinical trial mechanism in the study of Wilms' tumor.