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Characteristics and Outcomes of Children With the Wilms Tumor-Aniridia Syndrome: A Report From the National Wilms Tumor Study Group

Norman E. Breslow, Robin Norris, Patricia A. Norkool, Tammy Kang, J. Bruce Beckwith, Elizabeth J. Perlman, Michael L. Ritchey, Daniel M. Green, Kim E. Nichols

From the Department of Biostatistics, University of Washington; the Fred Hutchinson Cancer Research Center, Seattle, WA; the University of Pennsylvania Medical School; the Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA; the Department of Pathology, Loma Linda University, Loma Linda, CA; the Department of Pathology, Children’s Memorial Medical Center and the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; the Division of Urology, University of Texas at Houston Health Science Center, Houston, TX; and the Department of Pediatrics, Roswell Park Cancer Institute and the School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.

Address reprint requests to Norman Breslow, PhD, Department of Biostatistics, Box 357232, University of Washington, Seattle, WA 98195-7232; e-mail: norm{at}u.washington.edu.

	ABSTRACT

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Purpose: Children with the rare Wilms tumor (WT)-aniridia (WAGR) syndrome have not had systematic evaluation of their clinical and pathologic features. We compared demographics, disease characteristics, and treatment outcomes in a large cohort of WT patients who did or did not have the WAGR syndrome.

Patients and Methods: Clinical and pathology records were reviewed for 8,533 patients enrolled between 1969 and 2002 by the National Wilms Tumor Study Group.

Results: Sixty-four patients (0.75%) had the WAGR syndrome. For WAGR and non-WAGR patients, respectively, the average birth weights (2.94 and 3.45 kg), median ages at diagnosis (22 and 39 months), and the percentages with bilateral disease (17% and 6%), metastatic disease (2% and 13%), favorable histology (FH) tumors (100% and 92%), and intralobar nephrogenic rests (ILNR; 77% and 22%) all differed. Survival estimates for WAGR and non-WAGR patients were 95% ± 3% and 92% ± 0.3% at 4 years but 48% ± 17% and 86% ± 1.0%, respectively, at 27 years from diagnosis. Five late deaths in WAGR patients were from end-stage renal disease (ESRD).

Conclusion: The excess of bilateral disease, ILNR-associated FH tumors of mixed cell type, and early ages at diagnosis in WAGR patients all fit the known phenotypic spectrum of constitutional deletion of chromosome 11p13. Despite a favorable response of their WT to treatment, WAGR patients have a high risk of ESRD as they approach adulthood. The renal pathology associated with this apparent late manifestation of WT1 deletion, and the explanation for the abnormally low birth weights in patients with del 11p13, have yet to be determined.

	INTRODUCTION

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CHILDREN WITH the congenital anomaly syndrome consisting of Wilms tumor (WT), aniridia, genitourinary malformations, and mental retardation (WAGR) constitute a small but important group of children with cancer.^1,2 In Denmark, aniridia is diagnosed during childhood in approximately one live-born child in 40,000.³ In contrast, WT affects approximately one in 10,000 white children, with slightly higher rates in Africans and lower rates in Asians.^4,5 The risk of WT is estimated to be 67-fold higher, however, if the child is already known to have sporadic aniridia.³ Cytogenetic study of patients with both WT and aniridia led to the discovery that the syndrome is invariably accompanied by a constitutional deletion of all or part of chromosome 11p13.^6,7 Genetic evaluation of overlapping deletions at 11p13 eventually led to positional cloning of the first WT gene, WT1.^8,9 PAX6, the gene responsible for aniridia, is concurrently deleted with WT1 in patients who have the syndrome.¹⁰ These patients generally have lower birth weights and smaller stature than normal individuals, and their WTs are more frequently bilateral and diagnosed at younger ages.^4,11,12 Those patients who survive their childhood malignancy are at high risk of renal failure once they pass the age of puberty.¹³

We are not aware of any systematic studies evaluating the clinicopathologic characteristics of children with the WAGR syndrome, nor of how their response to treatment compares with that of other patients with WT. The archives of the National Wilms Tumor Study Group (NWTSG) offered the opportunity to investigate these questions using a large and relatively unselected patient population. In operation since 1969, the NWTSG has enrolled during the last two decades an estimated 70% to 80% of all children with renal tumors in North America.

	PATIENTS AND METHODS

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Patients
Between October 1969 and June 2002, 9,460 patients with a childhood renal tumor were enrolled on one of five protocol studies undertaken by the NWTSG. From this total, 838 patients, including many with clear-cell sarcoma or rhabdoid tumor of the kidney, were excluded because they did not have a diagnosis of Wilms tumor according to the NWTSG Pathology Center.¹⁴ An additional 69 patients were excluded because the tumor occurred in a single, fused, or horseshoe kidney or in an extrarenal site. This left 8,533 patients eligible for this investigation, of whom 5,983 (70%) had treatment regimens assigned by randomization and 2,570 (30%) were observed. Those who were observed were eligible patients who were treated with protocol regimens and had the same requirements for submission of records as did patients who were assigned randomized treatments, but were not assigned randomized treatments for various reasons.

Details of the diagnostic criteria, staging systems, and treatment regimens used in the first four studies (NWTS-1 through NWTS-4) have been published.^15–18 With the exception of a trial using no adjuvant therapy for patients with the most favorable prognosis, the treatments used for disease of favorable histology in NWTS-5 were identical to those used in NWTS-4.¹⁹ Patients with stage V disease (bilateral WT at diagnosis), those who received preoperative treatment with chemotherapy or irradiation, and those older than age 15 years at diagnosis were not eligible for the randomized trials. They were included as observed patients, however, and generally received the same drugs and the same doses and schedules of radiation therapy that were used for other patients at the time of their diagnosis.

The NWTSG protocols and informed consent documents were approved by the institutional review board of each institution registering patients, and informed consent was obtained from the parents of all patients before participation in the study.

Sources of Data
Slides of tumor tissue and adjacent kidney were reviewed by the NWTSG Pathology Center. Tumors were classified according to the presence or absence of anaplasia, which could be focal or diffuse.²⁰ They were assigned a histologic pattern according to the predominant cell type among blastemal, epithelial, and stromal components, with most tumors being assigned the pattern mixed WT because of the presence of all three cell types.^14,21 Patients enrolled onto NWTS-3, -4, or -5 were evaluated for the presence in adjacent kidney of the precursor lesions known as intralobar and perilobar nephrogenic rests (ILNR and PLNR, respectively), which are often used to distinguish tumors according to pathogenesis.^22–24

Stage of disease was assigned by the institution on the basis of surgery and pathology findings, often after consultation with the NWTSG Pathology Center. Sites of progressive, recurrent, or metastatic disease and causes of death were abstracted from clinical records by staff of the NWTSG Data and Statistical Center and reviewed by NWTSG oncologists. Patients were identified as having renal failure if the clinical record or patient report mentioned persistent or chronic renal failure or end-stage renal disease (ESRD). Deaths caused directly or indirectly by such renal failure were ascribed to ESRD. Information on congenital anomalies including aniridia was specifically requested on registration forms submitted by the oncologist and checklists submitted by the surgeon. In a few instances the presence of aniridia was abstracted by staff from other clinical records. Presence of aniridia was the sole criterion accepted as evidence for the WAGR syndrome. For most such patients, aniridia or WAGR syndrome was mentioned repeatedly in the clinical record. With the exception of one cytogenetic report from 1975, before the WAGR-11p13 deletion association was recognized, all 34 WAGR patients for whom a cytogenetic report was available had evidence of deletion at chromosome locus 11p13.

Statistical Methods
Frequency distributions of age at diagnosis and birth weight were estimated nonparametrically.²⁵ Comparisons of frequency distributions between subgroups were evaluated using t tests and exact tests for categoric data (StatXact 3 for Windows, CYTEL Software Corp, 1995). Overall survival (OS) and relapse-free survival (RFS) proportions and SEs were estimated using actuarial techniques.^26,27 The end point for RFS was the first occurrence of relapse, metastasis, new disease in the contralateral kidney, or death in the absence of disease. The statistical significance of the association of WAGR syndrome with RFS and OS was evaluated using both the log-rank test and a test for interaction between WAGR status and time in the Cox model.^28–30 The Cox model was also used to estimate relative relapse rates.

	RESULTS

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Demographics of the WAGR Syndrome in NWTSG Patients
Sixty-four patients with WAGR syndrome (0.75%) were identified among the 8,553 patients included in this investigation. Excluding patients with bilateral disease, who were ineligible for random assignment, the fraction of patients whose treatment assignment was randomized was similar for WAGR (42 of 64; 65%) and non-WAGR patients (5,914 of 8,489; 69%; P = .57). The prevalence of WAGR syndrome among NWTSG patients was remarkably stable over time; percentages of patients with aniridia were 11 of 1,311 (0.84%) during 1969 to 1979, 22 of 2,939 (0.75%) during 1980 to 1989, and 31 of 4,303 (0.72%) during 1990 to 2002 (P =.70 for the trend).

Twenty-seven of the WAGR patients (42%) were clinically female (some may have had ambiguous genitalia from WT1 deletion), whereas non-WAGR patients had a slight female preponderance (4,588 of 8,489; 54%; P = .02). The mean age at diagnosis of WAGR patients was 30.8 v 45.1 months for non-WAGR patients (P = .001). The WAGR age at diagnosis distribution (Fig 1) had a single mode at approximately 22 months. Relatively few (10 of 64; 16%) WAGR patients were diagnosed after 4 years of age in comparison with non-WAGR patients (3,253 of 8,489; 38%).

View larger version (18K): [in this window] [in a new window]   Fig 1. Frequency distributions of age at diagnosis for patients with and without Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome.

View larger version (14K): [in this window] [in a new window]   Fig 2. Frequency distributions of birth weight for patients with and without Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome.

Because of the absence of anaplasia in tumors obtained from WAGR patients, comparison of the stage distributions and evaluation of treatment outcomes was restricted to include only non-WAGR patients with a similar favorable histology. Patients with WAGR syndrome were more likely to have bilateral disease (stage V) at diagnosis (nine of 64; 14%) when compared with non-WAGR patients (6%; P = .01). Apart from this difference, however, the stage distribution of WAGR patients was extremely favorable, with 27 of 55 (48%) of those patients with unilateral tumors having stage I disease and only one patient (2%) having metastases (stage IV) at diagnosis (P = 0.002 for the trend; Table 1). The average weight of the tumor-bearing specimen for WAGR patients was 175 g less (29% less) than that for non-WAGR patients (P < .00001). The 13 WAGR patients whose clinical record suggested they had not been screened before WT diagnosis had less favorable stage (six stage I, two stage II, and five stage III), age (38.3 ± 48.2 months), and specimen weight (644.2 ± 364.5 g) distributions than those of WAGR patients who had been screened, but only the difference in specimen weight (P = .006) was statistically significant.

Nephrogenic Rests
The tumors of patients with and without WAGR syndrome differed remarkably in the nature and extent of their association with precursor lesions (P < .00001; Table 1). The majority (81%) of kidney specimens from WAGR patients showed evidence of nephrogenic rests, whereas only 42% of non-WAGR tumors had such evidence. Furthermore, the rests discovered in WAGR patients were almost invariably ILNR or a combination of ILNR plus PLNR, whereas PLNR was found more frequently than ILNR in non-WAGR patients.

Treatment Outcomes
Table 2 lists the estimated percentages of patients surviving (OS) and surviving without prior relapse (RFS) at 4 and 27 years after diagnosis. Four years was selected for display because virtually all relapses in patients with favorable histology disease will have occurred by this time. At 27 years, just after the last WAGR death, three WAGR and 250 non-WAGR patients remained alive and under observation. Table 3 lists relevant features of the 15 patients with WAGR syndrome who experienced treatment failure or died.

View larger version (14K): [in this window] [in a new window]   Fig 3. Survival curves for patients with and without Wilms tumor, aniridia, genitourinary malformations, and mental retardation (WAGR) syndrome.

	DISCUSSION

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The prevalence of WAGR syndrome (64 of 8,533; 0.75%) observed in this study of WT patients agrees with the prevalence reported for a 1982 to 1989 French hospital series (four of 501; 0.80%), but is substantially lower than the prevalence found for a 1971 to 1977 population-based British series (12 of 549; 2.19%).^31,32 Because of the severe phenotype and its repeated mention in patient records, we believe our ascertainment of WAGR patients is complete for the vast majority of patients with complete baseline and moderate follow-up data. We cannot rule out, however, the possibility that some WAGR patients were selectively excluded from enrollment onto NWTSG trials. Hence, 0.75% may best be regarded as a lower bound on the true population prevalence.

Except for their predisposition to bilateral disease, patients with the WAGR syndrome generally had more favorable prognostic features than non-WAGR patients. All had favorable histology and thus, a priori, a greater responsiveness to therapy. They also had a lower percentage of tumors with the blastemal predominant histologic patterns associated with increased tumor aggressiveness and a poorer prognosis.^21,33 Consistent with the lack of anaplastic histology, WAGR patients were on average younger at diagnosis. Their tumors were smaller and fewer were diagnosed with high-risk stage III or IV disease. As suggested by the clear difference in specimen weight and suggestive differences in stage and age between WAGR patients who had and had not been screened, these characteristics could well be related to the fact that most patients with aniridia are screened for WT.³⁴ Hence, it is not surprising that WAGR patients fared at least as well as non-WAGR patients during the 4- to 6-year period after diagnosis, during which patients with WT are most at risk for relapse and tumor-related death.

In contrast to their positive response to treatment, the longer-term outcomes for these patients are less favorable. As shown in Table 3 and Figure 3, WAGR patients experienced relatively large numbers of deaths as a result of ESRD, which started approximately 10 years after WT diagnosis. The two decreases after 20 years in the survival curve for the WAGR patients in Figure 3 were due to ESRD-associated deaths that occurred, respectively, when only five and four WAGR patients remained in follow-up. Consequently, there is a high degree of statistical imprecision in the estimates of mortality. Furthermore, given that news of death may reach the statistical office sooner than routine follow-up information, there could be some downward bias. It seems clear, nonetheless, that WAGR patients are subject to unusual risks not shared by non-WAGR patients.

Our earlier report estimated the risk of chronic renal failure in WAGR patients to be 38% at 20 years from diagnosis on the basis of 10 events that were observed in 46 patients.¹³ We ascertained 14 patients with renal failure among the 64 patients in the current study and now estimate the risk to be 53% at 20 years. Five of these 14 patients have died as a result of ESRD (Table 3). Currently, little is known to explain the histopathology underlying WAGR-associated renal failure. Patients with the Denys-Drash syndrome, generally caused by a point mutation in WT1, also experience renal failure but at much younger ages.^13,35–37 It would be of great interest to examine the failing kidneys of WAGR patients to determine if they display the same mesangial sclerosis of the glomeruli that typifies the renal pathology seen in Denys-Drash syndrome patients.³⁸ Interestingly, WT1 is expressed throughout life in podocytes, renal epithelial cells that surround the capillaries comprising glomeruli. Podocytes are thought to contribute to the viability and function of glomeruli by maintaining the glomerular basement membrane. Consistent with this function, abnormalities in podocytes are often associated with glomerulopathies leading to ESRD. Although the role played by WT1 in podocytes is not completely understood, recent genetic experiments using Wt1-deficient mice, and mice expressing an inducible Wt1 transgene, have demonstrated that decreased expression levels of wild-type Wt1 can result in crescenteric glomerulonephritis or mesangial sclerosis, depending on Wt1 gene dosage.³⁹ Moreover, diseased kidneys in these mouse models expressed reduced levels of the genes podocalyxin and nphs1 (nephrin), suggesting that they act downstream of Wt1 in maintaining podocyte survival and function. Taken together, these mouse genetic experiments suggest that decreased WT1 expression levels may be responsible for the pathogenesis underlying WAGR-associated renal disease.

The exceptionally high proportion of WAGR patients whose tumors occur in conjunction with ILNR, confirmed here in Table 1, was one of the features of ILNR that led to its suggested role as an indicator of pathogenesis.²² ILNR serves as a phenotypic marker of WTs that are associated with WT1 mutations.²⁴ This is in contradistinction to WT associated with loss of imprinting or loss of heterozygosity of the insulin growth factor gene IGF2, for which PLNR serves as a marker.⁴⁰ The histologic patterns of tumors of WAGR patients (Table 1) are more like those observed in association with ILNR than with PLNR.²² The age at diagnosis distribution of WAGR patients (Fig 1), with a single peak at the median of 22 months, is nearly identical to that for the much larger group of non-WAGR patients whose tumors occur in conjunction with ILNR.⁴

Not explained by the ILNR-WAGR association, however, are the strikingly low birth weights of WAGR patients (Fig 2). Overall, WT patients are heavier at birth when compared with the general population.⁴¹ An earlier NWTSG study found heavier birth weights particularly for patients with PLNR, which seemed to corroborate PLNR as a marker for WT caused by alterations in IGF2 expression.^12,24 This earlier report revealed that birth weights for patients with ILNR were also higher than expected. The only subgroup whose birth weights were lower than normal consisted of 10 WAGR patients whose average birth weight was 2.99 kg, approximately 0.38 kg less than expected on the basis of US population rates specific for sex, race, and year of birth. This observation has been confirmed in this investigation, on the basis of an average birth weight of 2.94 kg for 33 WAGR patients (Table 1). We have no data on gestational age and hence cannot determine whether this is simply the result of earlier births of WAGR patients. Their small stature persists at least until WT diagnosis, however, as indicated by their shorter average height (Table 1). Because small stature affects only the WAGR patients, and not patients without aniridia whose tumors occur in association with ILNR, one might speculate that alteration in WT1 expression is not responsible for this feature. It is conceivable that deletion or alteration of a neighboring gene at chromosome 11p13 leads to the growth retardation observed in WAGR patients, but we have no data on the extent of interstitial deletions to investigate this issue. Curiously, three atypical WAGR patients have been reported with severe obesity and del(11)(p12p14).⁴²

A recent report from Denmark estimated the prevalence of sporadic aniridia at 1.2 per 100,000 based on 68 patients with disease in a population of approximately 6 million live births.³ If one accepts that the cumulative incidence of WT is 1 in 10,000 births, and that the prevalence of sporadic aniridia among WT patients is 7.5 per 1,000, as found in this study, the risk of WT in patients with sporadic aniridia may be calculated as (0.0075 x 0.0001)/0.000012 = 6.3%. This is remarkably close to the risk of two in 44 (4.5%; 95% CI, 0.6% to 15.5%) actually observed in the population-based Danish study.³

We conclude that the frequency of WAGR in the NWTSG population has remained remarkably constant during the period of the studies conducted by the NWTSG. Children with WAGR have a lower birth weight, are shorter at the time of WT diagnosis, and have tumors that demonstrate ILNR more frequently than non-WAGR WT patients. The outcome of WT treatment does not differ between WAGR and non-WAGR patients. However, late mortality as a result of ESRD is significantly more frequent in WAGR survivors. Long-term surveillance of renal function of WAGR patients should be performed to facilitate appropriate timing for intervention with dialysis and renal transplantation.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	ACKNOWLEDGMENTS

 
We thank investigators of the Children’s Oncology Group and the health professionals who managed the care of children entered onto the National Wilms Tumor Group Studies.

	NOTES

 
Supported in part by United States Public Health Service grant Nos. CA 42326 and CA 54498.

	REFERENCES

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Submitted June 23, 2003; accepted September 22, 2003.

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