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1616
Factors Affecting the Risk of Contralateral Wilms
Tumor Development
A Report from the National Wilms Tumor Study Group
Max J. Coppes, M.D., Ph.D.1
Muoi Arnold, M.D.2
J. Bruce Beckwith, M.D.2
Michael L. Ritchey, M.D.3
Giulio J. D’Angio, M.D.4
Daniel M. Green, M.D.5
Norman E. Breslow, Ph.D.6
1
Children’s Cancer Program, Alberta Children’s
Hospital and Tom Baker Cancer Centre, and Departments of Oncology and Paediatrics, University
of Calgary, Calgary, Alberta, Canada.
2
Department of Pathology and Human Anatomy
and Division of Pediatric Pathology, Loma Linda
University, Loma Linda, California.
3
Department of Surgery, University of TexasHouston Medical School, Houston, Texas.
4
Department of Radiation Oncology, University of
Pennsylvania, Philadelphia, Pennsylvania.
5
Department of Pediatrics, Roswell Park Cancer
Institute, and the School of Medicine, State University of New York at Buffalo, Buffalo, New York.
6
Department of Biostatistics, University of Washington, Seattle, Washington.
Supported in part by research grants CA54498 and
CA42326 from the U.S. Public Health Service.
The authors thank the investigators of the Pediatric
Oncology Group (POG) and the Children’s Cancer
Group (CCG) and the many pathologists, surgeons,
pediatricians, radiation oncologists, nurses, and
other health care professionals who managed the
children entered on the National Wilms Tumor
Study Group trials.
Dr. Max J. Coppes is a Clinical Investigator of the
Alberta Heritage Foundation for Medical Research.
Address for reprints: Max J. Coppes, M.D., Ph.D.,
Children’s Cancer Program, Alberta Children’s
Hospital, 1820 Richmond Road, SW, Calgary, Alberta, Canada T2T 5C7.
Received July 7, 1998; revision received October
15, 1998; accepted December 15, 1998.
© 1999 American Cancer Society
BACKGROUND. Approximately 1% of children with unilateral Wilms tumor develop
contralateral disease. The authors assessed the demographic and histologic features associated with metachronous bilateral Wilms tumor (BWT).
METHODS. Characteristics of all children registered on the first four National Wilms
Tumor Studies (NWTS) were recorded. The primary endpoint for evaluation was
the first appearance of Wilms tumor in the remaining kidney. The cumulative risk
of contralateral disease as a function of time since initial presentation was calculated as 1 minus the Kaplan–Meier estimate of remaining free of contralateral
disease. A matched case control study was conducted to determine whether the
presence and type of nephrogenic rests (NRs) were associated with metachronous
BWT.
RESULTS. Fifty-eight of 4669 registered children developed metachronous BWT; 38
of 2445 females (expected, 30.2) versus 20 of 2224 males (expected, 27.8) (P 5 0.04)
developed BWT. The cumulative incidence of contralateral disease 6 years after
initial diagnosis decreased from greater than 3% in the first NWTS to approximately 1.5% in the three subsequent studies (P 5 0.08). Patients with NRs had a
significantly increased risk of metachronous BWT. This was particularly true for
young children (20 of 206 age , 12 months compared with 0 of 304 age . 12
months). Data from the matched case control study confirmed the increased
relative risk associated with young age and the presence of NRs.
CONCLUSIONS. Children younger than 12 months diagnosed with Wilms tumor
who also have NRs, in particular perilobar NRs, have a markedly increased risk of
developing contralateral disease and require frequent and regular surveillance for
several years. Surveillance is also recommended for those with NRs who are
diagnosed after the age of 12 months. Cancer 1999;85:1616 –25.
© 1999 American Cancer Society.
KEYWORDS: pediatric oncology, kidney, pediatrics, chemotherapy, nephrogenic
rests, risk factors, Wilms tumor.
P
atients with bilateral Wilms tumor (BWT) present a therapeutic
challenge to clinicians. Unlike those with unilateral Wilms tumor,
the incidence of renal insufficiency following otherwise successful
therapy is high in patients with bilateral disease. Recently, investigators from the National Wilms Tumor Study Group (NWTSG)
reported that 30 of 391 (7.7%) children with bilateral disease at
onset (synchronous BWT) registered on the first four NWTSG studies ultimately developed renal failure, most often because bilateral
nephrectomy became necessary.1 The risk of renal failure increases
with time. The use of effective preoperative chemotherapy seems
to have decreased the risk of renal failure by facilitating parenchymal sparing surgery, as illustrated by a decreased frequency of
Risk Factors for Metachronous Bilateral Wilms Tumor/Coppes et al.
renal failure in successive NWTSG studies, a function of time: 8 of 65 (12.3%) patients in NWTS study
1 (NWTS-1) and NWTS-2 together, 15 of 158 (9.5%)
patients in NWTS-3, and 7 of 168 (4.2%) patients in
NWTS-4 registered up to July of 1993.1
In contrast to children with synchronous BWT,
patients with metachronous BWT initially present
with unilateral Wilms tumor and subsequently develop contralateral disease. A recent literature review indicates overall survival rates of 49.1% and
47.2% at 5 years and 10 years, respectively.2 In these
patients, treatment is dictated by the extent of disease and histopathologic characteristics at initial
presentation and invariably includes unilateral nephrectomy, which is followed by adjuvant chemotherapy with or without radiation therapy.3 Parenchymal sparing surgery is then limited to salvaging
nephrons of the second affected kidney, because the
first kidney is removed at the time of initial diagnosis. The incidence of renal failure for this group of
children, 6 of 20 (30%) patients in NWTS-1 and
NWTS–2 and 3 of 23 (13%) patients in NWTS-3,1 is
higher than that observed in children with synchronous BWT. The reported incidence of renal failure
for the 17 metachronous BWT patients registered on
NWTS-4 was zero, but the duration of follow-up was
short.
Initial parenchymal sparing surgery could be justified in a group of children with unilateral Wilms
tumor if “. . . we could accurately predict which patients with unilateral disease are at risk for subsequent
contralateral tumors.”1 One of the features associated
with metachronous BWT is the presence of nephrogenic rests (NRs) in the normal tissue of the kidney
with Wilms tumor.4 Previously, the presence of NRs
usually was discovered during histopathologic examination following nephrectomy. In the past few years,
however, we have come to better recognize the radiologic appearance of NRs.5,6 On magnetic resonance
imaging, for example, NRs are best visualized evident
on T1-weighted images post-gadolinium. Unlike
Wilms tumors, which typically show inhomogeneous
enhancement, NRs generally remain homogeneously
hypointense.7 Because magnetic resonance imaging is
not readily available for all patients with Wilms tumor,
at present, histopathologic examination following nephrectomy remains an important tool to assess the
presence of NRs.
It would be helpful if additional clinicopathologic
features associated with metachronous BWT could be
identified. Here, we report on such factors: the combination of young age and the presence of NRs, gender, and initial chemotherapy.
1617
PATIENTS AND METHODS
Study Population
All children registered between October 1969 and December 1992 in the randomized or followed categories, as defined elsewhere,8,9 on the first four NWTSG
studies were included in this review. Tumor specimens were reviewed centrally to confirm the diagnosis
of Wilms tumor of either favorable or anaplastic histology. Patients with clear cell sarcoma, rhabdoid tumor of the kidney, renal cell carcinoma, and other
renal neoplasms were excluded. Also excluded were
those with bilateral disease at onset (synchronous
BWT), those with a fused kidney or tumor originating
from an extrarenal site, those diagnosed after age 15
years, and patients who received preoperative treatment with chemotherapy and/or radiation therapy. A
total of 4669 children were eligible for analysis. According to the inclusion criteria, all had unilateral
disease at diagnosis and were treated with nephrectomy and adjuvant chemotherapy with or without additional radiation therapy.
Follow-Up and Evaluation
Most patients (4643; 99.4%) were treated according to
one of the standard NWTS regimens,3,8 –10 which included either single (dactinomycin [AMD] or vincristine [VCR]), double (AMD 1 VCR), triple (AMD 1
VCR 1 doxorubicin[DOX]), or quadruple (AMD 1
VCR 1 DOX 1 cyclophosphamide [CMD]) chemotherapy. Therefore, only 26 patients (0.6%), all of whom
had been treated other than with one of the standard
NWTS regimens, were excluded from analyses that
used chemotherapy as a variable. Clinical details at
diagnosis and information on treatment outcome
were reported on check lists, narratives, and flow
sheets submitted by the pediatric oncologist, surgeon,
and pathologist involved in the actual care of the
patients. Patients were followed on study indefinitely
from the time of initial diagnosis. Median follow-up
for the 4669 children was 6.8 years from initial diagnosis. All but 209 of the 4149 surviving patients were
followed for at least 2 years.
Estimation of the Cumulative Incidence of Contralateral
Kidney Disease
The primary endpoint for evaluation was the first appearance of Wilms tumor in the remaining kidney. In
most cases, this was the first and only appearance of
recurrent disease in an otherwise healthy child. In a
few instances, however, the appearance of disease in
the contralateral kidney followed earlier relapse in
another site.
The cumulative risk of contralateral disease as a
function of time since initial presentation was calcu-
1618
CANCER April 1, 1999 / Volume 85 / Number 7
lated as 1 minus the Kaplan–Meier estimate11 of remaining free of contralateral disease. This estimate
accounted for incomplete follow-up due to a patient’s
death, loss to follow-up, or the end of the study. Contralateral disease incidence rates in different patient
subgroups were compared by using the log-rank test
statistic.12 Multiple regression analysis was conducted
by using the Cox proportional hazards model.13
control study. All surgical records from the first surgery were reviewed, and contralateral exploration was
recorded as “no exploration of the contralateral kidney,” “exploration without visualization,” and “visualization of the posterior surface.” Relative risk of contralateral involvement according to the degree of
surgical exploration subsequently was calculated by
using conditional logistic regression.15
Matched Case-Control Study
Prior to 1980, renal lesions thought to be potential
precursors of Wilms tumor, which are found in 30 –
40% of kidneys removed for Wilms tumor,4 were recorded as “blastemal rests.” Starting with NWTS-3, the
term for these lesions changed to nephrogenic rests
(NRs).4 In addition, the NWTSG Pathology Center
started to recognize the importance of the localization
of NRs in the renal lobe. Consequently, NRs were
categorized as being perilobar (PLNRs) if they occurred at the surface of the renal lobe or intralobar
(ILNRs) if the they occurred in the deep medulla,
medullary cortex, renal sinus, or pelvicalyceal wall.4
NWTSG investigators have suggested previously that
the presence of ILNRs or PLNRs is associated with a
risk of subsequent tumor development in the contralateral kidney.4 Hence, a substudy of slides archived
at the NWTSG Pathology Center was conducted to
ensure a uniform evaluation of the NRs in tumor specimens collected throughout all four NWTSG studies.
For each metachronous BWT case, four controls were
selected at random from among children registered on
the same NWTSG study. Each control had to have
survived at least as long as it took for the corresponding case to develop contralateral disease. In other
words, the four controls were selected at random from
“risk sets” created during a Cox proportional hazards
regression analysis with stratification on study.14 The
list of metachronous BWT cases and randomly selected controls, identified only by NWTSG identification number, was submitted to the NWTSG Pathology
Center for histopathologic reevaluation of the corresponding diagnostic slides. For the matched case-control study, odds ratios, which approximate relative
risks of contralateral disease, were estimated from the
matched sets by using conditional logistic regression.15 This produced estimates of relative risk comparable to those that would have been obtained from
Cox proportional hazards analysis of the entire data
set had the slides been reevaluated for all patients.
Although there is some loss of efficiency, we nevertheless obtained 80% efficiency for testing the null hypothesis,15 having selected four controls for each
study case.
We also analyzed the extent of surgical exploration of the contralateral kidney in our nested case-
RESULTS
Among the 4669 children, 58 (1.2%) developed metachronous Wilms tumor. Thirty-eight were female, and
20 were male. In 50 patients, contralateral tumor development occurred prior to or simultaneously with
any other relapse, whereas eight occurred after relapse
to another site. Thirteen cases occurred in the first
year following initial nephrectomy, 18 in the second
year, 12 in the third year, 5 in the fourth year, 4 in the
fifth year, and 5 in the sixth year. The last case occurred 13.1 years from diagnosis of the initial Wilms
tumor. The actuarial percentage of patients who developed contralateral disease was 1.5% 5 years after
initial diagnosis. However, the cumulative incidence
of contralateral disease at 6 years from initial diagnosis decreased from greater than 3% in NWTS-1 to
approximately 1.4% in NWTS-2 and remained in that
same range in NWTS-3 and NWTS-4 (Fig. 1).
There was some evidence that patients with an
initial tumor localized to the kidney and completely
resected, i.e., Stage I disease, had a higher incidence of
contralateral kidney involvement than children with
more advanced disease at diagnosis (Table 1). Further
analysis, however, suggested that this was explained
largely by treatment following initial diagnosis and by
the association of stage and NRs rather than disease
extent per se. Among 265 children treated with a single
chemotherapeutic agent (AMD or VCR), 9 developed
contralateral disease (expected, 3.6) compared with 38
of 2808 patients treated with VCR 1 AMD (expected,
35) and 10 of 1570 children treated with AMD 1
VCR 1 DOX (expected, 19.84; P 5 0.002). The cumulative incidence for children treated with four drugs
(AMD 1 VCR 1 DOX 1 CMD) also appeared to be
intermediate, although this result was based on only
three cases occurring among 152 patients and therefore is statistically unreliable. Finally, children receiving radiation therapy to the flank as part of their
treatment for the initial Wilms tumor were not found
to have an incidence of subsequent contralateral tumor involvement that was significantly different from
those who did not receive radiation therapy after initial nephrectomy: 22 of 2170 patients who received
radiation therapy as part of treatment for their initial
Wilms tumor developed metachronous BWT (expect-
Risk Factors for Metachronous Bilateral Wilms Tumor/Coppes et al.
1619
FIGURE 1. Probability of contralateral tumor development for patients with unilateral Wilms tumor registered on the first four National Wilms Tumor Studies as
a function of time. The total number of patients included per study, the number of patients who actually developed metachronous bilateral Wilms tumor, the number
expected, and the relative risk (RR) with 95% confidence interval (CI) also are provided (P 5 0.08).
TABLE 1
Observed versus Expected Number of Patients who Developed Contralateral Wilms Tumor and Estimated Relative Risk with 95% Confidence
Intervals in Relation to Stage at Initial Diagnosisa
Stage
N
Observed
Expected
RR
95% CI
I
II
III
IV
1813
1254
1026
576
33
12
9
4
23.6
15.8
12.5
6.1
1.0
0.54
0.51
0.47
0.28–1.05
0.25–1.07
0.17–1.33
N: number; RR: relative risk; CI: confidence interval.
a
P 5 0.03.
ed, 26.6) versus 36 of 2499 children who did not receive radiation therapy (expected, 31.4; P 5 0.23).
There was no evidence that the incidence of metachronous BWT was associated with histopathologic
features of the initial Wilms tumor. Fifty-six of 4378
patients with favorable histology at initial diagnosis
developed metachronous BWT (expected, 55.4) versus
2 of 291 with anaplastic histology at first presentation
(expected, 2.6; P 5 0.71). Similarly, there was no indication that ethnicity influenced the occurrence of contralateral disease. Gender, however, was found to be a
factor. The incidence was significantly higher in girls
compared with boys: 38 of 2445 females developed
contralateral disease (expected, 30.2) versus 20 of 2224
males (expected, 27.8; P 5 0.04).
There was a pronounced decline in the risk of
contralateral Wilms tumor development with increasing age at diagnosis (Fig. 2). The risk was particularly
elevated among children ages , 1 year when the initial
Wilms tumor was found. Such children accounted for
21 of 58 cases of metachronous BWT. The cumulative
incidence of contralateral tumor development in this
particular age group was 4% at 6 years from diagnosis
(Fig. 2).
Several syndromes predispose to the development
of Wilms tumor. These include aniridia, Beckwith–
1620
CANCER April 1, 1999 / Volume 85 / Number 7
FIGURE 2. Probability of contralateral tumor development for patients with unilateral Wilms tumor in each age group as a function of time. The total number of
patients included in each age group, the number of patients who actually developed metachronous bilateral Wilms tumor, the number expected, and the relative
risk (RR) with 95% confidence interval (CI) also are provided (P , 0.001).
Wiedemann syndrome, Denys–Drash syndrome, and
hemihypertrophy. We therefore determined whether
the incidence of metachronous BWT was higher
among patients with these syndromes compared with
children without congenital anomalies. Children with
Beckwith–Wiedemann syndrome, hemihypertrophy,
or congenital aniridia appeared to be at higher risk for
metachronous BWT, whereas children with other congenital anomalies were not. Fifty-three of the 4602
children without aniridia or Beckwith–Wiedemann
syndrome developed metachronous BWT (expected,
57.14), as did 2 of 32 children with aniridia (expected,
0.41) and 3 of 35 patients with Beckwith–Wiedemann
syndrome (expected, 0.45). Similarly, 5 of 144 children
with hemihypertrophy developed metachronous BWT
(expected, 1.83) compared with 53 of 4525 who did not
have hemihypertrophy (expected, 56.17). The numbers of patients with anomalies were judged to be too
small for reliable statistical inference. Thus, specific
congenital anomalies were not among the predictors
considered in the multiple regression analysis.
Because the coding of NRs changed in 1980, as
explained above, the association between NRs and
metachronous BWT was determined separately for patients registered on NWTS-1 and NWTS-2 and those
registered on NWTS-3 and NWTS– 4 (Table 2). Only in
the latter group were we able to determine the incidence of metachronous BWT for those with intralobar
nephrogenic rests (ILNRs) only or with perilobar
nephrogenic rests (PLNRs) only (Table 2B). Regardless
of the NWTSG study, patients with unilateral Wilms
tumor and NRs had a significantly increased risk of
developing metachronous BWT.
In a further evaluation of the joint effects of NRs
and age at diagnosis on predicting the occurrence of
contralateral disease, patients were simply classified
with regard to whether or not NRs had been noted.
Patients who had inadequate tissue submitted for NR
determination were classified as “unknown.” Table 3
shows the high risk of contralateral tumor development in patients with NRs whose Wilms tumor was
diagnosed under the age of 12 months. Among those
with NRs, 20 cases of metachronous BWT were reported, whereas no cases were observed among 304
children that did not have NRs at diagnosis (Table 3).
The relative risk estimate in this group of patients is
infinite (Table 4). Beyond 1 year of age, the relative risk
associated with positive rest status stabilized at about
5. The actuarial estimate at 6 years was 15% for those
with both PLNRs and ILNRs, 10% for those with PLNRs
only, 5% for those with ILNRs only, and 0% for those
without NRs (Fig. 3).
Risk Factors for Metachronous Bilateral Wilms Tumor/Coppes et al.
1621
TABLE 2
Observed versus Expected Number of Patients with Metachronous Bilateral Wilms Tumor in Relation to Nephrogenic Rest Status with Estimated
Relative Risk and 95% Confidence Intervalsa
Rest status
N
Observed
Expected
RR
95% CI
Negative
Positive
841
231
3
15
14.1
3.9
1.0
18.3
5.3–63.4
Negative
PLNR
ILNR
Both
1855
512
423
110
7
11
8
8
21.8
5.9
4.9
1.4
1.0
5.82
5.06
18.54
2.25–15.0
1.83–14.0
6.72–51.1
A
B
N: number; RR: relative risk; CI: confidence interval; PLNR: perilobar nephrogenic rest; ILNR: intralobar nephrogenic rest.
a
(A) Patients registered on National Wilms Tumor Study 1 (NWTS-1) and NWTS-2 (P , 0.0001). Thirty-seven patients were excluded from this particular analysis because their rest status was unknown. (B) Patients
registered on NWTS-3 and NWTS-4 (P , 0.0001). Six hundred and sixty patients were excluded because their exact rest status could not be determined.
TABLE 3
Observed versus Expected Number of Patients with Metachronous
Bilateral Wilms Tumor in Relation to Nephrogenic Rest Status and
Age at Diagnosis (P < 0.0001)
Rest status
Age (yrs)
N
Observed
Expected
Negative
Negative
Negative
Negative
,1
$1 and ,2
$2 and ,4
$4
304
407
887
1098
0
2
4
4
3.98
5.34
11.04
13.38
Positive
Positive
Positive
Positive
,1
$1 and ,2
$2 and ,4
$4
206
292
408
370
20
8
8
6
2.61
3.67
5.13
4.33
Unknown
Unknown
Unknown
Unknown
,1
$1 and ,2
$2 and ,4
$4
106
124
241
226
1
0
4
1
1.23
1.57
3.02
2.69
4669
58
58
Total
N: number.
In an attempt to ascertain those factors that were
most important in predicting contralateral Wilms tumor development, a multiple regression analysis using
the Cox proportional hazards model was conducted
among the 3949 patients who were treated with a
standard NWTSG chemotherapy regimen for whom
rest status was known. Fifty-one of 58 metachronous
BWT cases occurred in this subgroup. The association
between metachronous BWT and age at initial diagnosis noted in Table 3 was accommodated by including an interaction term for the logarithm of the age in
months 1 1. Extrapolation from this model suggests
that children whose Wilms tumor is diagnosed at birth
in the presence of NRs would have 15 times the
chance of developing metachronous BWT compared
with those who do not have NRs. According to the
model, the relative risk falls to 6 by age 4 years and to
TABLE 4
Relative Risk for Metachronous Bilateral Wilms Tumor by Age Group
in Patients who were Rest Positive at First Presentation
Age (yrs)
<1
>1 and <2
>2 and <4
>4
RR
`
5.7
4.5
4.6
RR: relative risk.
3 by age 16 years. Even accounting for these strong
effects, girls still have twice the risk of boys.
Matched Case-Control Study
The main purpose of the matched case-control study
was to determine systematically whether the presence
of NRs was correlated with the development of metachronous BWT. With four controls matched to each
case of metachronous BWT, there were 5 3 58 5 290
patients, one of whom was excluded later because the
initial Wilms tumor originated from an extrarenal site.
The presence of PLNRs or ILNRs both increased the
risk of contralateral Wilms tumor development (Table
5). Patients with NRs of both types had the most
dramatic risk of metachronous BWT (matched odds
ratio for PLNRs 1 single ILNR 5 8.23; for PLNRs 1
multiple ILNRs 5 7.56). Data from this substudy confirmed our previous observation regarding the interactive effect of age at initial diagnosis and the presence of NRs. The diagnosis of PLNRs in very young
children (,12 months of age) carried the most dramatic risk of contralateral disease (Table 5B).
Evaluation of the degree of surgical exploration at
the time of initial surgery (Tables 6 and 7), demonstrated a clear temporal change in surgical practice.
Relatively few patients in NWTS-1, whether metachronous BWT patients or controls, had visualization of
the posterior surface (Table 6). By contrast, virtually all
1622
CANCER April 1, 1999 / Volume 85 / Number 7
FIGURE 3.
Probability of contralateral tumor development by nephrogenic
rest status and type for children less than 12 months of age with unilateral
Wilms tumor. PLNR: perilobar nephrogenic rest; ILNR: intralobar nephrogenic
rest; NEG, negative.
patients registered on NWTS-4 had such visualization.
Because the case control analysis automatically adjusted for study number, the data shown in Tables 6
and 7 provide no reason to believe that surgical exploration of the contralateral kidney affected the risk of
subsequent contralateral tumor involvement.
Finally, Table 8 shows the results of the conditional logistic regression analysis. The model contained terms for the presence of PLNRs, age at initial
diagnosis, the interaction between age and positive
PLNRs, gender, and the number of chemotherapeutic
agents used in the treatment of the first Wilms tumor.
Once again, age was treated as a continuous variable
by taking the logarithm of age in months 1 1. The
relative risk estimated for the presence of PLNRs associated with Wilms tumor diagnosed at age 0 was 8.8
relative to that for a child without PLNRs. According to
the model, the relative risk associated with positive
PLNRs declines with increasing age to the point that
there is no excess risk associated with positive rests for
tumors diagnosed at age 16 years. There continued to
be some suggestion of a reduction in risk associated
with increasing amounts of chemotherapy, although
this reduction was not statistically significant. Effects
of study number on risk were accounted for through
the formation of the matched sets. The slightly increased risk associated with female gender (Table 8)
was not significant for the matched case-control
study.
DISCUSSION
This study identified several demographic features associated with an increased risk for developing metachronous BWT that can be ascertained prior to surgery. For example, children diagnosed with Wilms
tumor prior to their first birthday have an increased
risk for developing contralateral disease. However,
further analysis reveals that this is only true if these
patients also have NRs, in particular, PLNRs (Table
5B). NWTSG pathologists previously reported that PLNRs were more commonly associated with synchronous BWT, whereas ILNRs were more preponderant in
patients with metachronous BWT.4 This study confirms the association of metachronous BWT and NRs
in general (Table 2), but the matched case-control
study (Table 5A) suggests a particularly high risk for
developing metachronous BWT in children ,12
months of age who are found to have PLNRs in the
renal tissue removed for unilateral Wilms tumor. Because the NWTSG has demonstrated that the median
age at diagnosis for children with Wilms tumor and
PLNRs is substantially higher (36 months) than that of
those with Wilms tumor and ILNRs (16 months),16 the
occurrence of PLNRs in children ,12 months is rare.
Nevertheless, it is precisely this combination that
seems to carry the highest risk of contralateral disease
development (Table 8).
A second characteristic identified with increased
risk of metachronous BWT is gender. The 1:2 male:
female ratio found in this study was similar to that
reported by investigators of the International Society
of Paediatric Oncology.17 In the current study, however, we demonstrate that the risk of contralateral
Wilms tumor development is higher in females even
taking other risk factors into account. Our current
knowledge of the molecular genetics of Wilms tumor
does not provide an explanation for this observation,
despite the recent implication of chromosome X in
Wilms tumorigenesis. Some investigators have suggested that a locus on chromosome X might control
parental allele specific imprinting (a genetic phenomenon affecting gene expression and therefore function) of genes on chromosome 11p15, a region that
includes WT2, a putative second Wilms tumor suppressor gene. If WT2 function is indeed regulated by a
gene or gene complex on the X chromosome, then the
same locus might help explain the high incidence of
BWT in females. To date, however, no “imprintor”
gene has been identified on the X chromosome.
The incidence of metachronous BWT decreased
by half after the first NWTSG study (Fig. 1). A previous
NWTSG report indicated that only 7 of 18 patients
with metachronous BWT registered on NWTS-1 and
NWTS-2 had adequate contralateral kidney exploration at the time of initial surgery.18 Therefore, we
considered the possibility that a higher incidence of
failure to recognize synchronous BWT at the time of
first surgery during the first NWTSG study might explain the higher incidence of metachronous BWT in
NWTS-1. The case-control study, however, provided
no evidence for this. The extent of surgical exploration
of the contralateral kidney at the time of initial surgery
Risk Factors for Metachronous Bilateral Wilms Tumor/Coppes et al.
TABLE 5
Number of Cases, Controls, and Estimated Relative Risk with 95%
Confidence Interval According to the Presence of Perilobar or
Intralobar Nephrogenic Rests and Age at Diagnosis
Number
Group
A. PLNR/ILNRa
Negative/negative
Negative/single
Negative/multiple
Positive/negative
Positive/single
Positive/multiple
Unknown/unknown
B. Age (mos)/PLNR
0–11b
Negative
Positive
$12c
Negative
Positive
Unknown
C. Age (mos)/ILNR
0–11d
Negative
Single
Multiple
$12e
Negative
Single
Multiple
Unknown
Cases
Controls
TABLE 6
Degree of Surgical Exploration of the Contralateral Kidney
for Cases of Metachronous Bilateral Wilms Tumor and Matched
Controls by Study
Matched set analysis
RR
Degree of exploration
95% CI
Study
10
10
4
16
6
10
2
88
51
15
39
7
12
19
1.0
1.87
2.66
3.61
8.23
7.56
1.11
6
15
23
3
1.0
`
18
17
2
132
55
18
1.0
2.18
1.02
1.01–4.68
0.20–5.10
4
6
11
9
13
4
1.0
0.31
2.65
0.03–3.16
0.25–27.5
22
10
3
2
118
46
23
18
1.0
1.22
0.95
0.65
0.72–4.91
0.71–10.0
1.50–8.70
2.05–33.1
2.59–22.0
0.22–5.53
1.66–`
1623
NWTS-1
Case
Control
NWTS-2
Case
Control
NWTS-3
Case
Control
NWTS-4
Case
Control
Total
Case
Control
None
Exploration without
visualization of
posterior surface
Visualization of
posterior surface
Total
3
15
6
21
2
6
11
42
3
15
4
8
1
8
8
31
0
7
5
28
16
46
21
81
2
5
4
7
10
46
16
58
8
42
19
64
29
106
56
212
NWST: National Wilms Tumor Study.
0.52–2.90
0.25–3.60
0.14–3.08
RR: relative risk; CI: confidence interval; PLNR: perilobar nephrogenic rest; ILNR: intralobar nephrogenic rest.
a
P 5 0.001.
b
P 5 0.01.
c
P 5 0.11.
d
P 5 0.22.
e
P 5 0.89.
did not affect the frequency of contralateral involvement (Tables 6 and 7). Moreover, review of the
NWTSG data indicates that the incidence of synchronous BWT has not changed significantly over the years
(5.8 %, 4.6%, 6.9%, and 6.6% for NWTS-1, NWTS-2,
NWTS-3, and NWTS-4, respectively). Thus, there is
nothing to suggest that the decrease in incidence of
metachronous BWT can be attributed to more accurate diagnosis of contralateral tumor due to better
visualization at the time of initial surgery.
Following NWTS-1, the incidence of metachronous BWT has remained stable despite a dramatic
increase in patient accrual and improved outcome for
patients with unilateral Wilms tumor. Perhaps a fixed
proportion of patients with Wilms tumor is biologically predisposed to develop contralateral disease despite receiving chemotherapy adequate to cure the
TABLE 7
Relative Risk with 95% Confidence Interval of Contralateral
Involvement According to the Degree of Surgical Exploration of the
Opposite Kidney Estimated from the Matched Set Analysis
Degree of exploration
RRa
95% CI
None
Exploration without visualization
Visualization of posterior surface
1.0
1.60
1.44
—
0.62–4.11
0.53–3.77
RR: relative risk; CI: confidence interval.
a
P 5 0.62.
initial tumor. In other patients, however, chemotherapy may not only contribute to the patient’s ultimate
cure but, in addition, obliterate cells that otherwise
would have developed into macroscopic Wilms tumor.
Univariate analysis suggests that triple chemotherapy
with AMD, VCR, and DOX is more effective in inhibiting the transformation of a NR into a Wilms tumor
(or, alternatively, eradicating an indolent Wilms tumor) than double agent therapy with AMD and VCR.
Single chemotherapy regimens utilizing either VCR or
AMD are even less effective. This could explain the
higher incidence of metachronous BWT observed in
NWTS-1. On the first NWTSG study, all patients with
Group I disease and 60% of those with Group II and
Group III disease were treated with a single chemotherapeutic agent (VCR or AMD) with or without radiation therapy, which did not include the contralat-
1624
CANCER April 1, 1999 / Volume 85 / Number 7
TABLE 8
Conditional Logistic Regression Analysis of Contralateral Kidney
Involvement
Variable
Coefficient 6 SE
Relative risk
P value
PLNR (age 5 0)
PLNR 3 log (age 1 1)
Female gender
Chemotherapya
2.17 6 0.47
20.75 6 0.24
0.35 6 0.38
20.58 6 0.44
8.80
0.48
1.42
0.56
0.0
0.02
0.36
0.18
PLNR: perilobar nephrogenic rest; SE: standard error.
a
Code 0 for dactinomycin (AMD) or vincristine (VCR); code 1 for AMD 1 VCR; code 2 for AMD 1 VCR 1
doxorubicin 6 cyclophosphamide.
eral kidney.8 In the three ensuing NWTSG studies, all
patients received at least two chemotherapeutic
agents, i.e., both AMD and VCR, as adjuvant therapy.
Certain congenital syndromes known to predispose to the development of Wilms tumor (aniridia,
Beckwith–Wiedemann syndrome, and hemihypertrophy) appeared to be at higher risk, but the number of
patients identified with such anomalies were judged
too small for reliable statistical inference. Children
with Denys–Drash syndrome were not found to have
an increased risk at developing metachronous BWT
(data not shown). This is likely due to the fact that
most if not all of these patients undergo bilateral nephrectomy once the disease is recognized.
The follow-up recommendations that follow are
based on the data presented. We recommend that
children with NRs in the nephrectomy specimen undergo regular abdominal ultrasonography following
surgery, with particular attention to the remaining
kidney. For children ,48 months of age at initial
diagnosis, abdominal ultrasonography should be
performed at least every 3 months for 6 years. For
children .48 months of age at initial diagnosis, we
suggest abdominal ultrasonography at least every 3
months for 4 years.2 Because this study has not
addressed specifically the risk of either contralateral
disease or local relapse in children who do not
have NRs in their nephrectomy specimens, we suggest
that they be monitored as previously recommended.19
Briefly, for those with Stage I and II favorable histology Wilms tumors, abdominal ultrasonography
yearly 3 3 is recommended. For those with Stage III
favorable histology disease, abdominal ultrasonography 6 weeks and 3 months postoperative, then every 3
months 3 5, every 6 months 3 3, and finally yearly 3
2 is recommended. The latter group of patients requires additional surveillance to monitor for local relapse rather than contralateral disease. The use of
abdominal ultrasonography for follow-up has two advantages: it is readily available and is relatively inexpensive.19
Finally, with regard to parenchymal sparing surgery, the low incidence of metachronous BWT in
children .12 months of age with NRs does not
support such an approach, and these children
should be treated with nephrectomy up front.
Nephron conserving surgery might be considered
for a very selected group of infants with NRs demonstrated pre- or intraoperatively, given the higher
frequency of metachronous disease in such children. However, pilot studies have shown that there
are very few tumors located at one pole of the kidney that are circumscribed so clearly that sharp and
complete separation from the remaining kidney is
possible.20 Incomplete removal after injudicious attempts is a danger. In short, we have no data to
support such a policy, nor do we have a specific
treatment or series of treatments that might be appropriate if such an attempt were to be made. We
feel strongly that such an approach should be studied formally, and the NWTSG recommendations for
managing children with synchronous BWT might be
consulted for guidance.21
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