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Characteristics and Outcome of Children With Beckwith-Wiedemann Syndrome and Wilms’ Tumor: A Report From the National Wilms Tumor Study Group

From the Dana-Farber Cancer Institute, Department of Pediatrics and Department of Biostatistics, Harvard Medical School, and Children’s Hospital, Boston, MA; Division of Biology, California Institute of Technology, Pasadena, CA; National Wilms Tumor Study Group and Department of Biostatistics, University of Washington, Seattle, WA; and Department of Pediatrics, Roswell Park Cancer Institute, and School of Medicine and Biomedical Services, Buffalo, NY.

Address reprint requests to Lisa Diller, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email Lisa_Diller@ dfci.harvard.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Children with Beckwith-Wiedemann syndrome (BWS) are at increased risk for developing Wilms’ tumor (WT). We reviewed the National Wilms Tumor Study Group (NWTSG) records to assess clinical characteristics and outcome of patients with WT and BWS.

METHODS: In the NWTSG, treating clinicians were asked to report, for each enrolled patient, whether the patient had BWS. Between 1980 and 1995, 4,669 patients were treated on two consecutive NWTSG protocols (NWTS 3 and NWTS 4). We retrospectively reviewed the clinical characteristics and treatment outcomes of BWS patients compared with patients with WT without BWS.

RESULTS: Fifty-three children enrolled onto NWTS 3 and 4 were reported to have BWS. BWS patients were more likely to present with lower-stage tumors (P = .0001), with more than half (27 of 53) presenting with stage I disease. The overall treatment outcomes for the BWS patients were nearly identical to those without BWS, with overall survival at 4 years from diagnosis at 89% and 90%, respectively. Overall, 21% of the patients with BWS had bilateral disease, either at diagnosis (nine of 53) or as metachronous contralateral recurrence (two of 53). BWS patients enrolled onto NWTS 4 had smaller tumors than those enrolled onto NWTS 3 (P = .02), a trend not seen in the non-BWS patients.

CONCLUSION: Like children without BWS, children with BWS and WT have an excellent prognosis with modern treatment regimens. There is a high risk of bilateral disease, and increasingly smaller tumors are being detected. This suggests that a national trial assessing the role of ultrasound screening followed by nephron-sparing surgery for some patients may be appropriate.

	INTRODUCTION

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BECKWITH-WIEDEMANN syndrome (BWS) is a somatic overgrowth syndrome characterized by neonatal hypoglycemia, abdominal wall defects, macroglossia, organomegaly, hemihypertrophy (HH), and increased birth weight.^1-3 Children with BWS are at an increased risk of developing embryonal tumors, including Wilms’ tumor (WT).⁴ The overall incidence of abdominal tumors in children with BWS is 4% to 7%^1,5-7 The observed tumors include hepatoblastoma, neuroblastoma, rhabdomyosarcoma, and adrenocortical carcinoma, but WT accounts for approximately 60% of the tumors that children with BWS develop.^8,9 DeBaun and Tucker¹⁰ have estimated the relative risk for developing WT in children with BWS to be 816 (95% confidence interval [CI], 359 to 1,156). Conversely, in children with WT, the incidence of BWS is 1% to 2%.^10,11

There is a clear but complex genetic relationship between BWS and WT.¹² BWS is associated with a dysregulation of genomic imprinting at chromosomal locus 11p15. The region of dysregulated imprinting may be as large as several megabases, affecting several different genes. Several genes that may have a role in general somatic overgrowth—including IGF2, p57^KIP2, H19, and KVLQT1—have been shown to have altered imprinting in either BWS, WT from BWS, or WT in general.^13-16 The WT1 gene maps to 11p13 and the putative WT2 gene maps to 11p15. The relationship between the dysregulated imprinting in BWS and the WT1 and WT2 loci continues to be determined.

Although the epidemiologic relationship between BWS and WT is established and the genetic relationship between the two is intriguing, the clinical features of WT in BWS patients and the prognostic significance of BWS in WT have not been fully examined. Vaughan et al⁹ reported a 100% event-free survival with a median follow-up of 9 years in 10 patients with WT and BWS, concluding that BWS confers a favorable prognosis. To investigate the possibility that BWS patients have a different clinical course from other children with WT, we analyzed data from the National Wilms Tumor Study Group (NWTSG) protocols to assess the outcome of patients with BWS treated or followed on NWTSG protocols versus those without BWS.

	MATERIALS AND METHODS

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The National Wilms Tumor Study (NWTS) is a multi-institutional study of patients with newly diagnosed WTs. NWTS and the design of NWTS 3 and 4 have been reported elsewhere.^17,18

At the time of enrollment onto NWTS 3 and 4, registering physicians were requested to indicate the presence or absence of specific conditions, including BWS, HH, aniridia, and genitourinary anomalies. Demographic data were also obtained on all patients, as well as specific clinical details, including stage at diagnosis, histologic diagnosis, treatment protocol, and clinical outcome. This information was analyzed to compare clinical features, relapse-free survival, and overall survival of patients who had BWS with those who did not. No systematically collected details about the clinical features of BWS were available, nor was information regarding screening for tumors in BWS patients.

Statistical Analysis
Percentages of patients remaining alive or alive and free of disease at 4 years from diagnosis were estimated using actuarial techniques. Differences in rates of relapse and death between BWS patients and non-BWS patients were compared using the log-rank test.¹⁹ Statistical adjustment for differences between BWS and non-BWS patients in stage and histology was accomplished by stratification of the sample into six strata (shown in "Stage distribution," Table 1). Comparison of proportions was made with the Fisher’s exact and Cochran-Armitage trend tests, and comparison of means was made using the t test, as described in standard statistical texts.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

There were significant differences in the stage distribution of patients with favorable-histology WT with and without BWS (Table 1). The stage distribution suggests that BWS patients are more likely to present with early-stage disease (P = .0001 Cochran-Armitage test for trend). Overall, 50.9% of the BWS patients presented with stage I disease, compared with 33.9% in the non-BWS population. None of the BWS patients presented with metastatic disease, compared with 12% of the non-BWS group. BWS patients, however, had a higher incidence of favorable histology instead of bilateral disease (17% v 5.8%; P = .005, Fisher’s exact test) at presentation.

In addition to the differences in stage, children with BWS were more likely to have WT with favorable histology than non-BWS children, but this trend did not reach statistical significance (P = .18, Fisher’s exact test). Only one (1.9%) of 53 BWS tumors showed anaplasia (stages II to IV) on histologic examination compared with 6% in the general population. In the single BWS patient with unfavorable histology, the anaplasia was focal rather than diffuse.

Nephrogenic rests (NRs) were seen in the kidneys of 44 of 53 of the BWS patients. Fourteen of 53 BWS patients had only perilobar NR, nine of 53 had only intralobar NR, and 21 of 53 had both types of rests. Of the 11 patients who had bilateral disease at some point in their course, only two had no NR, with five of 11 having both perilobar and intralobar NR and four of 11 having only perilobar NR.

Management of BWS Patients With WT
The surgical approach for patients with BWS and WT in the NWTSG was not different from that for the non-BWS population. Of the 44 patients with non–stage V disease, 96% (42 of 44) underwent complete nephrectomy; the other two received nephron-sparing surgery. The two patients who received nephron-sparing surgery were relapse-free survivors at 5 and 11 years’ follow-up. Stage V patients with BWS primarily underwent initial biopsy followed by chemotherapy or combined chemotherapy and radiotherapy.

Radiotherapy was used in nine (17%) of 53 patients with BWS and WT. Fifty-two (98%) of 53 patients in the NWTS BWS cohort received adjuvant chemotherapy. The regimen was determined by the study (NWTS 3 or 4), stage, and histologic diagnosis and was comparable to that received by non-BWS patients.

Outcome of BWS Patients With WT
Patients with BWS and WT have similar outcomes when compared with patients with WT but without BWS, stratifying the analysis for stage and histologic results. The 4-year relapse-free survival and overall survival rates for BWS patients were 81% and 89%, respectively, and 84% and 90% for non-BWS patients (no significant difference; Table 2). Of note, patients with contralateral recurrences were excluded from the outcome analysis and are discussed below.

Impact of HH on the Outcome of WT in BWS
Twenty-four BWS cases (45%) were associated with reported HH. In five cases of HH/BWS (21%), the patients presented with bilateral WT. In five patients with unilateral tumors, the side of either the tumor or the HH was not reported and no correlation could be determined. In the remaining 14 unilateral tumors in patients with HH/BWS, 10 (71%) occurred on the same side as the HH. The outcome for patients with HH and BWS was not statistically different from that for those with BWS without HH, although small numbers preclude a definitive conclusion. Among the 24 BWS patients with HH, there were six cases (25%) of relapsed disease, compared with five cases (17%) of relapse among 29 BWS patients without HH. Similarly, the overall survival in children with BWS, HH, and WT was indistinguishable from that in children with BWS and WT but without HH.

Comparison of NWTS 3 and NWTS 4
We compared BWS patients enrolled onto NWTS 3 with those enrolled onto NWTS 4 and found several interesting trends (Table 4). First, the percentage of patients with stage I tumors rose from 44.4% in NWTS 3 to 54.3% in NWTS 4. Tumors from NWTS 4 had an average weight that was substantially smaller (334 g ± 359 g) than that of the NWTS 3 tumors (916 g ± 693 g) (two-sided t-test, P = .02). The trend downward in tumor size was not seen in the non-BWS cohort, in which tumor sizes were nearly identical in the two studies (NWTS 3, 608 g; NWTS 4, 605 g). Finally, there was a suggestion that BWS patients on NWTS 4 may have a better overall survival (92% v 83%), but this did not reach statistical significance.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

Overall, our analysis suggests that children with BWS and WT present with lower-stage disease, less metastatic disease, and fewer anaplastic tumors. The propensity toward low-stage disease may represent a potential biologic difference in the growth potential of WTs that children with BWS develop and/or the role of increased surveillance for abdominal tumors given to children with BWS.²⁰

Children with BWS received essentially the same treatment for their tumors as those without BWS, in terms of the type of surgery, radiation, and chemotherapy. Further, the overall survival and relapse-free survival were excellent in both groups. In contrast to the 100% event-free survival in the 10 BWS patients reported by Vaughan et al,⁹ the event-free survival of children with BWS and WT was 81% in the NWTSG cohort. This difference probably reflects the larger size of the NWTSG cohort. The sites of relapse were different in the BWS and non-BWS groups, with fewer lung recurrences in the BWS patients but more subdiaphragmatic recurrences. Patients with BWS had a significant chance of having both kidneys involved by WT, with a total of 21% developing bilateral disease at some time in their course (17% with synchronous bilateral disease at diagnosis and 4% with metachronous recurrence after initial presentation with unilateral disease).

The relatively high percentage of bilateral disease may reflect an underlying biologic mechanism. NRs are thought to be precursor lesions to some WTs, and BWS is associated with bilateral NRs.¹² Thus, the bilateral disease in BWS probably reflects a predisposition to developing independent bilateral disease (as in hereditary retinoblastoma). We cannot conclude, however, that adjuvant chemotherapy completely prevents the transformation of the premalignant lesion to WT, as nearly 20% of all observed recurrences in BWS patients occurred in the contralateral kidney after adjuvant chemotherapy.

In a case series from the BWS registry, DeBaun et al²¹ reported that WTs occur primarily, if not exclusively, in kidneys that are two or more SDs larger than those of age-matched controls. In their study, DeBaun et al found that in 11 of the 13 cases of WT, the BWS patient had bilateral nephromegaly. The relationship, however, between nephromegaly and HH is unclear. We were unable to evaluate kidney size from the NWTSG data. In our series, nearly 30% of the tumors occurred on the side opposite the extremity HH, suggesting that extremity overgrowth and the development of WT are not necessarily linked by laterality. Several case series have reported the presence of HH as an independent positive predictor for the development of WT.^5,8,10 In our series, 45% of the BWS patients had HH, which is higher (P = .002) than the 25% incidence of HH in BWS patients reported in the literature and thus supports the observation that HH may be a risk factor for developing WT.^1,6,10 We did not find, however, that HH was a poor prognostic factor for WT in the setting of contemporary combined-modality therapy.

Interestingly, there were differences in the clinical characteristics of BWS patients treated on NWTS 3 and NWTS 4, with a tendency toward smaller tumors, less radiotherapy, and lower stage at diagnosis in the BWS patients treated on NWTS 4 compared with those on NWTS 3. We cannot, given available data, define the reason for these differences. This trend to smaller and lower-stage tumors and the resultant decrease in the use of radiotherapy might represent a temporal trend in which pediatricians, pediatric oncologists, and geneticists are recommending radiographic screening of the kidneys of children with BWS and early detection of tumors. Alternatively, increased screening could also result in detection of large NRs, interpreted as small WTs, and therefore a shift in the stage distribution and improved outcome.

Prior studies assessing the role of screening have shown variable results. Green et al²² reported from the NWTSG that screening increased the percentage of low-stage tumors in patients with aniridia but was used inconsistently in other children with a higher risk of developing WT. They concluded that a prospective study of the screening of such individuals should be performed. Craft et al,²³ in their review of the United Kingdom Children’s Cancer Study Group database, concluded that regular screening with abdominal ultrasonography did not improve outcome. Choyke et al,²⁰ however, found that regular screening with abdominal ultrasonography at least every 4 months reduced the percentage of stage III and IV disease. The cost of regular screening was that several patients underwent laparotomies and nephrectomies for nonmalignant disease.²⁰ NRs and WT can have distinct appearances with magnetic resonance imaging; thus, follow-up imaging of suspicious lesions on ultrasonography might eliminate some unnecessary surgeries.^7,24 Although we cannot determine from our review of the database whether screening was more comprehensive during the period of NWTS 4 than during that of NWTS 3, the trend to smaller and lower-stage tumors is consistent with Choyke et al’s data.²⁰ Finally, Clericuzio and Johnson²⁵ suggest that screening of BWS patients should be done until 84 months of age, but our data support the notion that screening ultrasonography, if performed, should continue until 96 months of age, as three patients were diagnosed with WT at greater than 84 months of age.

For patients with an initial diagnosis of WT and BWS, screening for the occurrence of contralateral disease should be performed regularly. Coppes et al²⁶ analyzed risk factors for contralateral WT in patients presenting initially with unilateral WT and found that NRs are associated with an increased risk of metachronous WT. On the basis of that comprehensive analysis of patients with a variety of risk factors, the authors (representing NWTSG opinion) recommend that patients with NRs be screened with ultrasound every 3 months for 6 years, if the original diagnosis of WT occurs before age 4. If initial diagnosis occurs after age 4, the screening should be performed for 4 years. Although too few BWS patients were included in the Coppes et al study to determine whether BWS is an independent predictor of metachronous recurrence, the close association of BWS and NRs suggests that the same recommendations for screening the contralateral kidney in BWS/WT patients should be followed. Of note, Coppes et al found that 2.5% of the patients on NWTS 3 and 4 who had rests noted in their nephrectomy specimen developed contralateral WT. In our cohort, contralateral recurrence occurred in two (4.5%) of 44 patients, and both patients with contralateral recurrence had rests in their initial nephrectomy specimen.

Overall, we make the following three conclusions. First, the presentation of WT in BWS patients may be quite distinct from that in non-BWS patients, with a different pattern of stage and histologic diagnosis. Second, the outcome for BWS patients with WT is as excellent as that for WT patients without BWS, but we find no evidence that the outcome is improved, as has been suggested in a smaller cohort. Finally, the high risk of bilateral disease in the setting of a trend toward detecting smaller tumors may result in more use of partial nephrectomy. A national study of the safety of this approach should be considered before it becomes clinical practice.

	ACKNOWLEDGMENTS

 
Supported in part by the Dyson Scholar Award (to L.D.).

	REFERENCES

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Submitted December 2, 1999; accepted February 9, 2000.

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