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Journal of Pediatric Urology (2009) 5, 56e65
EDUCATIONAL ARTICLE
Current management of Wilms’ tumor in children
Edmund Y. Ko, Michael L. Ritchey*
Mayo Clinic College of Medicine, Phoenix, AZ, USA
Received 3 August 2008; accepted 18 August 2008
Available online 9 October 2008
KEYWORDS
Nephroblastoma;
Wilms tumor;
Chemotherapy
Abstract Purpose: Wilms’ tumor is the most common renal tumor in children. Outcomes have
improved dramatically over the past few decades, but important treatment questions remain.
These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current
treatment of Wilm’s tumor.
Materials and methods: The medical literature and results of all cooperative group studies
reporting treatment of children with Wilms’ tumor were reviewed.
Results: Overall survival exceeds 90% for most patients with nephroblastoma. However,
outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of
renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral
tumors it continues to be defined.
Conclusions: Current protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to
focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and
mortality rates.
ª 2008 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
Wilms’ tumor (WT) or nephroblastoma is the most common
primary malignant renal tumor in children. More than 90%
of children are now expected to have an excellent outcome
with current treatment modalities. Contemporary issues
involve stratifying children to reduce morbidity and overtreatment of low-risk patients, and providing intensive
treatment for high-risk patients for whom survival remains
* Corresponding author. 1920 E. Cambridge Avenue, Phoenix, AZ
85006, USA. Tel.: þ1 602 279 1697; fax: þ1 602 264 0461.
E-mail address: [email protected] (M.L. Ritchey).
poor [1]. This article reviews the current thoughts on
etiology, diagnosis and management recommendations for
children with WT.
Epidemiology
In children under 15 years of age, the annual incidence rate
of WT is about 7e10 cases per million, and this accounts for
6e7% of all childhood cancers [2]. More than 80% of cases
are diagnosed before 5 years of age, with a median age of
3.5 years [3].
1477-5131/$34 ª 2008 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jpurol.2008.08.007
Wilms tumor in children
57
A family history of WT is present in 1e2% of newly
diagnosed patients, and has been localized to two familial
WT genes (FWT1 at 17q12eq21 and FWT2 at 19q13.4) [4].
These patients usually have an earlier age of onset as well
as an increased frequency of bilateral disease.
Etiology
There are a number of recognized syndromes associated
with an increased predisposition towards developing WT
(Table 1). They can be divided into overgrowth and nonovergrowth syndromes. Common overgrowth syndromes
include BeckwitheWiedemann syndrome (BWS) and isolated
hemihypertrophy. The most recognized non-overgrowth
syndromes include WAGR (WT, aniridia, genitourinary
anomalies, mental retardation) syndrome and DenyseDrash
syndrome (DDS) [5e8].
Aniridia is found in 1.1% of WT patients and is attributed
to a PAX6 gene abnormality. This is located next to the WT1
gene on chromosome 11p13, which contains genes responsible for development of the kidney, genitourinary tract
and eyes. WT1 identification and cloning is a result of the
observations of heterozygous chromosomal deletions noted
in those with WAGR syndrome [9,10]. WT1 encodes transcription factors involved with gene regulation during renal
and gonadal development [11]. It is required for ureteric
bud outgrowth and is important in nephrogenesis. Although
WT1 mutations are present in a minority of WT cases (10e
15%), patients with WT1 abnormalities have a higher
predisposition for developing nephroblastoma [6,12]. WT1
deletions in aniridia patients are associated with a 40% rate
of WT development. Conversely, aniridia patients with
normal WT1 appear to be at low-risk of developing nephroblastoma [7].
DDS is a syndrome associated with WT1 missense mutations. It is characterized by disorder of sexual development
usually with a 46, XY karyotype, renal mesangial sclerosis
and WT. Of patients with nephroblastoma 4.5% have genitourinary abnormalities, including renal fusion anomalies,
cryptorchidism and hypospadias [13]. Although these
disorders are commonly diagnosed in children, a prospective evaluation for WT is not necessary, unless DDS is suspected [14].
The WT2 gene located at 11p15 has been linked to BWS
[15]. There is a 4e10% risk of developing WT in BWS children with hemihypertrophy [16e18]. This gene was identified as a result of finding loss of heterozygosity (LOH) at this
location [15].
LOH at chromosome 16q occurs in 20% of WTs [19].
Similarly, 10% of cases have been found to have LOH at
chromosome 1p [20]. These have been shown to be associated with an increased risk of tumor relapse and
mortality. One of the major objectives of the National
Wilms’ Tumor Study (NWTS)-5 was to confirm the utility of
LOH at chromosome 16q and 1p to predict an adverse
prognosis. Among patients with Stage IeII FH tumors, the
relative risk of relapse and death was increased for LOH of
either 1p or 16q in comparison with patients lacking LOH at
either locus [20]. The risk of relapse and death for patients
with Stage IIIeIV favorable histology (FH) tumors was
increased only with LOH for both regions. In the current
Children’s Oncology Group (COG) protocols, there is an
intensification of treatment for children whose tumors
demonstrate LOH for these chromosomal regions.
Recently, a previously uncharacterized tumor suppressor
gene otherwise known as the ‘Wilms tumor gene on the X
chromosome’, or WTX, was found to be inactivated in up to
one third of WT cases [21]. WTX is inactivated by a monoallelic, or ‘single-hit’ event rather than by the classical
biallelic ‘two-hit’ Knudson model. It targets the single X
chromosome in males and the active X chromosome in
females with tumors, and occurs at comparable frequencies
in both sexes. Tumors that are caused by WTX mutations
lack WT1 mutations.
Presentation
Over 90% of children will present with an asymptomatic
abdominal mass. Most WTs are solitary lesions, although 6%
present with bilateral disease and 12% may present with
multifocal disease within a single kidney [22]. Presenting
symptoms can include abdominal pain that should alert the
surgeon to the risk of preoperative rupture and bleeding.
Gross hematuria may be a sign of tumor extension into the
collecting system or ureter [23].
Atypical presentations occur in less than 10% of patients.
They are a result of compression of surrounding organs or
vascular invasion. Vascular extension into the renal vein or
inferior vena cava occurs in up to 4% of WT patients [24].
Patients with vascular extension can present with ascites,
congestive heart failure, hepatomegaly and varicocele [25].
Paraneoplastic syndromes can result from tumor production
of hormonal substances, and include hypertension, hypercalcemia, erythrocytosis and von Willebrand’s disease
[26,27].
Pathology
Table 1
Wilms’ tumor: syndromes and genetic loci
Syndrome
Genes
Locus
BeckwitheWiedemann
DenyseDrash
WAGR
Bloom
LieFraumeni
Neurofibromatosis
SimpsoneGolabieBehmel
Sotos
WT2
WT1
WT1
BLM
p53
NF1
GPC3
NSD1
IGF2, H19, p57, KIp2
11p13
11p13
15q26
17q13
17q11
Xq26
5q35
Histology is the most important prognostic indicator for WT.
The majority of WT patients have tumors with FH. Several
tumor types are associated with an increased risk of tumor
recurrence, or resistance to standard WT chemotherapy.
These include patients with anaplastic WT, which can be
focal or diffuse. Two other renal tumors, rhabdoid tumor of
the kidney and clear cell sarcoma of the kidney, were once
considered to be WT. They were identified to have a higher
risk of recurrence and therefore receive different therapy.
Histologic classification has been very important for stratifying patients into treatment groups and protocols.
58
Classic WT includes three histological cell types in varying
proportions: (1) blastemal; (2) epithelial; and (3) stromal
components [28]. Tumors with predominantly epithelial
differentiation have low aggressiveness and are mostly Stage
I if diagnosed early. When diagnosed at an advanced stage,
these tumors tend to be more resistant to therapy. Tumors
with blastemal predominance are highly aggressive,
although they are responsive to chemotherapy [29].
Anaplasia is a marker for chemoresistance representing
up to 10% of unilateral WTs. Anaplasia may be focal or
diffuse. The incidence of anaplasia in children less than
2 years old is about 2%, increasing significantly to 13% in
children diagnosed at ages greater than 5 years [29].
Although tumors with unfavorable histology carry a poor
prognosis and are the greatest challenge to cure across all
stages, when the anaplastic component is surgically removed
in its entirety, the outcome is generally good [29e31].
Nephrogenic rests (NRs) are precursor lesions that are
found in 25e40% of kidneys with WT [32e34]. They are
found in 1% of infants at autopsy [35]. Most NRs do not
develop into malignancy. Rather, they can undergo maturation, sclerosis, or disappear completely. An increased
incidence of NRs is found in syndromic patients with BWS,
DDS and sporadic aniridia [36].
There are two types of NR, intralobar (ILNR) and perilobar (PLNR) [32]. ILNRs are associated with the 11p13 WT
locus, and are found with an increased incidence in children with aniridia and DDS. ILNR-associated tumors also
have an earlier onset. PLNRs, developing later in renal
embryogenesis, are associated with the 11p15 WT locus and
are noted to have an increased incidence in children with
BWS [36].
If NRs are present on one kidney they are also likely to
be present on the contralateral kidney, and frequent
surveillance of the contralateral kidney is recommended
after surgery to monitor for metachronous tumors [37].
Children, less than 1 year of age, with WT and PLNRs have
a markedly increased risk of developing metachronous
tumors after undergoing nephrectomy [38]. Distinguishing
hyperplastic, large NRs from a WT can be challenging. WT
can be differentiated pathologically by observing an intrarenal pseudocapsule that is composed of compressed,
atrophic renal tissue. NRs lack this capsule with the cells
interfacing with the normal renal parenchyma.
Imaging
Ultrasound (US) is often the initial study obtained in children presenting with abdominal masses. Doppler studies
can be used to evaluate the inferior vena cava (IVC) for
patency and the presence of tumor extension, occurring in
4% of WT patients [24,39]. CT and MRI are also used to
evaluate extent of the tumor, involvement of the contralateral kidney, venous involvement, invasion of surrounding
structures, lymph node involvement, metastases to other
organs, and treatment response [40]. CT of the chest is
recommended to assess metastatic pulmonary disease [41].
The improved imaging has now obviated the need for
exploration of the contralateral kidney [42]. However, one
limitation of imaging is the ability to determine resectability. These are large lesions relative to the size of the
E.Y. Ko, M.L. Ritchey
patient, but determination of inoperability must be at
surgical exploration.
Screening
Syndromic patients with a known increased risk for WT
undergo periodic screening renal US for early detection.
The Wilms Tumor Surveillance Working Group from the UK
recommended conducting screening when a condition has
a WT incidence of greater than 5% [43]. US surveillance is
performed from time of diagnosis until 5 years of age, with
a frequency of every 3e4 months. Those that have BWS,
SimpsoneGolabieBehmel and familial WT histories should
continue to 7 years [43,44]. A CT or MRI should be performed if US demonstrates a suspicious lesion.
The potential benefits of WT screening are detecting
lower stage tumors and thereby improving patient survival.
Overall there is no compelling evidence that screening
children at high-risk for WT has improved survival [46e47].
Two retrospective studies demonstrated a difference in
stage distribution with unscreened children having more
late-stage disease compared to unscreened cases [45,46].
Early detection can provide an opportunity for nephronsparing surgery (NSS), since these children are at an
increased risk for bilateral disease [17]. The smaller tumors
found on screening studies are more amenable to renal
sparing surgery either before or after preoperative
chemotherapy.
Staging
Stage and histopathology are the most important determinants of outcome in children with WT. There are currently
two staging systems available reflecting treatment differences (Tables 2 and 3). The current system used by the COG
reflects staging at primary surgery. Alternatively, the
system used by the International Society of Paediatric
Oncology (SIOP) is performed after preoperative chemotherapy. Tumors with favorable histology are more likely to
Table 2
System
Children’s Oncology Group Wilms’ Tumor Staging
Stage I
Tumor confined to kidney and completely
resected; no capsular breach, tumor spillage
or renal sinus extension
Extracapsular penetration (including iatrogenic
via biopsy prior to resection) or renal sinus
extension with vascular involvement; complete
resection with negative margins and no lymph
node involvement
Non-hematogenous spread beyond the kidney
(abdominal lymph nodes, transected renal vein,
IVC tumor thrombus); macroscopic/microscopic
residual tumor after resection; peritoneal
spillage during resection
Hematogenous metastases (lung, liver, bone,
brain) or extra-abdominal lymph node spread
Bilateral renal involvement at diagnosis
Stage II
Stage III
Stage IV
Stage V
Wilms tumor in children
Table 3 International Society of Paediatric Oncology
Staging System
Stage I
Stage II
Stage III
Stage IV
Stage V
Tumor limited to kidney; fibrous pseudocapsule
surrounds tumor if outside of contours of kidney;
clear resection margins; no renal sinus vessel
involvement
Tumor extends beyond kidney into perirenal fat,
renal sinus, adjacent organs or IVC; complete
resection with clear margins
Incomplete excision of tumor; positive
abdominopelvic lymph nodes, tumor penetration
through peritoneal surface, tumor thrombi
at vascular resection margins
Hematogenous metastases; extra-abdominopelvic
lymph node metastases
Bilateral tumors at diagnosis
be of lower stages versus anaplastic tumors, which are
twice as likely to have Stage IV disease [29].
Treatment
Surgery maintains an important role in treatment, although
the improved prognosis for this malignancy during the 20th
century is attributed primarily to advances in chemotherapy. Overall survival rates reach 90% with current
treatment regimens. COG and SIOP treatment protocols are
now focusing not only on maximizing cure, but also minimizing treatment side effects and associated morbidity [1].
Surgery
Transperitoneal radical nephrectomy is the standard operative procedure for unilateral WT. If preoperative CT or MRI
demonstrates a normal contralateral kidney, exploration of
the contralateral kidney is not needed [42]. During
nephrectomy, careful dissection and surgical technique
must be observed to ensure en-bloc resection of the tumor
without contamination of the operative field. Tumor
spillage results in a six-fold increase in local abdominal
recurrence. The risk factors for local tumor recurrence
include unfavorable histology, incomplete removal of
tumor, any tumor spillage and absence of lymph node
sampling [48]. Although formal lymph node dissection is not
needed, sampling of hilar and ipsilateral para-aortic or
caval lymph nodes is mandatory. Absence of lymph nodes in
the specimen will mandate treatment as Stage III disease.
As noted above, many WTs look quite massive on
preoperative imaging. Right-side tumors may appear to be
invading the liver, particularly if only viewed on coronal CT
views. Determination of resectability should be based on
findings at exploration. One exception is the diagnosis of
extension into the IVC above the level of the hepatic veins
[25]. A patient determined to have an inoperable tumor is
considered Stage III and treated accordingly [49].
NSS is advocated for children with a solitary kidney and
bilateral WT. The greatest concern is the increased risk of
positive surgical margins and local tumor recurrence.
NWTS-4 demonstrated that patients with bilateral WT
59
undergoing NSS had an 8% incidence of local recurrence
[50]. Those with unilateral tumors and FH undergoing
primary nephrectomy only had a 3% incidence of local
recurrence [48]. The differences in local recurrence may be
due to the increased aggressiveness in NSS technique for
patients with bilateral disease to preserve renal function.
The role of laparoscopic removal of renal tumors in
children has been explored. Duarte et al. reported on eight
patients with unilateral non-metastatic WT who underwent
preoperative chemotherapy prior to nephrectomy [51]. In
this small series, there were no conversions to open
surgery, no tumor ruptures and no postoperative complications. Currently, the role of laparoscopy is limited to the
removal of tumors that have been pretreated with
chemotherapy. For the untreated tumor, this approach is
likely not feasible due to concerns regarding removal of an
intact tumor, risk of tumor spill and accurate surgical
staging.
Performing NSS in children with unilateral WT remains
controversial [52]. Most tumors at the time of diagnosis are
too large for NSS, thus making it difficult to obtain negative
margins to decrease recurrence. Partial nephrectomy may
be considered if the tumor involves one pole of the kidney,
if there is no evidence of collecting system or vascular
involvement, if clear margins exist between the tumor and
surrounding structures, if there is a solitary kidney, and if
the involved kidney demonstrates appreciable function.
Less than 5% of patients with unilateral WT would be
candidates for partial nephrectomy at diagnosis [53].
Preoperative chemotherapy can be used to decrease tumor
burden to a size that is amenable to NSS [54,55]. It is
unclear if this approach can decrease the incidence of renal
failure, which is less than 1% in patients with unilateral WT
undergoing nephrectomy [56]. More importantly, it will
have to be shown that the benefit of NSS outweighs the
potential for increased local recurrence and mortality.
Surgical removal of a large renal mass in a small child has
inherent risks. The most common intraoperative complication is bleeding. Following surgery the most common
complication is small bowel obstruction occurring in >5% of
patients [57]. Chylous ascites is a less common but significant event [58]. Tumor risk factors for surgical complications include tumor diameter >10 cm, and tumor or
thrombus extension into the IVC or atrium. The overall
surgical complication rate of nephrectomy for WT appears
to have declined over time. In a comparison of the
complication rates from NWTS-3 (1979e1987) to NWTS-4
(1986 and 1994), National Wilms’ Tumor Study Group
(NWTSG) investigators found the complication rate
decreased from 19.8% to 12.7% (P < 0.001) [59].
Preoperative chemotherapy may influence surgical
complication rates by producing tumor shrinkage. A report
from SIOP, where nephrectomy was performed after 4 or
8 weeks of chemotherapy, showed an overall surgical
complication rate of 5% [60]. A prospective comparison of
complications (Table 4) in patients enrolled in the NWTS-5
and SIOP-93-01 trials demonstrated that the overall
complication rate for the SIOP patients was 6.4% compared
to 9.8% in NWTSG patients (P Z 0.12) [61]. There was
a markedly decreased incidence of intraoperative tumor
spill in the SIOP patients, 2.2%, compared to the NWSTG
patients, 15.3% (P < 0.001). There was also a statistically
60
E.Y. Ko, M.L. Ritchey
Table 4 Comparison of complication rates from SIOP and
NWTSG trials
SIOP-93-01 NWTS-5
No. of patients
Complication rate
Intraoperative tumor spill
Small bowel obstruction
Stage III tumors
Resection of other organs
360
6.4%
2.2%
1.1%
14.2%
6.9%
326
9.8%
15.3%
4.3%
30.4%
15.0%
(P Z 0.12)
(P < 0.001)
(P Z 0.002)
(P < 0.001)
(P < 0.001)
significantly decreased incidence of Stage III tumors in the
SIOP group (14.2%) compared to NWST-5 (30.4%).
Chemotherapy
The clinical course of children with WT was altered in the
1960s with the application of the chemotherapeutic agents
dactinomycin (AMD) and vincristine (VCR). Survival was
dramatically improved even for patients with high-stage
tumors compared to prior treatment with surgery and
radiation therapy alone. The NWTSG, SIOP and others have
conducted randomized clinical trials to determine the most
effective combinations of treatment for these patients.
The primary goals have been to improve overall survival but
they are continually adjusting treatment protocols to
prevent late effects from these treatments. Stratification
of treatment is primarily based on stage and tumor
histology, although the biologic features of the tumor are
also a consideration. The difference between NWTSG and
SIOP treatment protocols is that SIOP recommends treatment to begin with preoperative chemotherapy.
National Wilms’ Tumor Study Group (NWTSG)
and Children’s Oncology Group (COG)
The early NWTSG studies showed that the combination of
VCR and AMD was more effective than the use of either drug
alone. The addition of doxorubicin (DOX) resulted in
improved survival for Stage III and IV patients. Postoperative flank irradiation was eliminated for Stage I and II
patients and the dose for Stage III patients decreased to
1000 cGy [62,63]. A major accomplishment was identification of prognostic factors that allowed stratification of
patients into high-risk and low-risk treatment groups.
Patients with positive lymph nodes and tumor spill have an
increased risk of abdominal relapse and are therefore
considered Stage III and given abdominal irradiation. One of
the most important findings of the NWTSG was the identification of unfavorable histologic features that have a very
adverse impact on survival [63]. These patients continue to
be a challenge as standard WT chemotherapy is ineffective
for patients with high-stage anaplastic tumors or rhabdoid
tumor [64,30]. Children with clear cell sarcoma of the
kidney have a good outcome if treated with DOX and
postoperative radiation [65]. Overall, the 4-year survival
for patients with all stages of FH WT now exceeds 90%.
The last NWTS trial (NWTS-5 1995e2001) was a singlearm therapeutic trial. As noted above, one of the major
findings of the trial was that LOH for chromosomes 16q and
1p is predictive for increased risk of tumor relapse and
death [20]. In NWTS-5, children less than 2 years of age
with Stage I FH tumors weighing less than 550 g did not
receive chemotherapy after nephrectomy. This portion of
the study was closed when the number of tumor relapses
exceeded the limit allowed by the design of the study [66].
However, the 2-year overall survival of this cohort was 100%
due to the high rate of retrieval of the relapsed patients.
The COG has assumed the role of the NWTSG in conducting WT clinical trials. The current studies are outlined
in Table 5. This will also be a single-arm therapeutic trial
comparing outcomes to historic controls. Patients are
stratified into low-risk, standard risk and high-risk categories. The low-risk study will again evaluate the feasibility
of omitting postoperative chemotherapy for infants with
small Stage I tumors. Low-stage patients with LOH of 1p and
16q will be treated with more intensive treatment. Patients
with pulmonary metastases will be monitored for response
of the pulmonary lesions to chemotherapy. Patients with
complete resolution of the pulmonary lesions after 6 weeks
of chemotherapy will not receive pulmonary irradiation. A
new chemotherapy regimen has been designed for treatment of patients with diffuse anaplastic WT and malignant
rhabdoid tumor of the kidney.
International Society of Paediatric Oncology
(SIOP)
Beginning in 1971, the SIOP treatment protocols have
examined the role of therapy prior to surgery. The SIOP
protocols have the same goal of maximizing cure while
minimizing toxicity. They have demonstrated that this
approach is effective in reducing tumor volume in most
patients and reduces the risk of tumor rupture [60,67]. The
preoperative treatment also leads to a ‘downstaging’ of the
tumor. The SIOP trials report a higher percentage of Stage I
tumors and a lower percentage of Stage III tumors
compared to the NWTSG trials. This reflects the inherent
differences in staging a tumor after the effects of chemotherapy. Clearly, there are patients with extra-renal tumor
extension that is eradicated by the preoperative chemotherapy and cannot be detected on pathology after the
tumor is resected. In SIOP-6 (1980e1986), Stage II patients
with negative lymph nodes that did not receive postoperative abdominal irradiation had a higher recurrence
rate compared to those with radiation [68]. In SIOP-9
(1987e1993), they demonstrated that the relapse rate for
Stage II patients with negative lymph nodes without radiation therapy was reduced with epirubicin. However, the
addition of an anthracycline has increased the risk of late
effects for these children [69,70]. This study also demonstrated that treatment with VCR and AMD for 4 weeks
versus 8 weeks gave comparable rates of stage distribution
and tumor shrinkage in patients with Stage IeIII disease.
More recently, SIOP investigators have studied the
usefulness of histologic changes in the tumor after preoperative therapy to guide postoperative treatment decisions
[71,72]. This approach places more emphasis on the
response of the tumor to chemotherapy than on the
apparent aggressive behavior of the tumor as reflected by
Wilms tumor in children
Table 5
protocols
61
Recommended therapy according to COG
Stage/histology
Radiotherapy
Chemotherapy
Stage I FHWT
<2 years, <550 g
Stage 1 FHWT, >2 years
or >550 g
Stage II FHWT
Stage I, II, FHWT and
LOH 1p, 16q
Stage III FHWT no LOH
1p, 16q
Stage IeIII focal AHWT
Stage I diffuse AHWT
Stage III, IV FHWT and
LOH 1p, 16q
Stage IV FHWT
pulmonary metastases
Lesions resected at
diagnosis
Lesions resolve after 6
weeks chemo
Lesions persist after 6
weeks chemo
Stage IV FHWT nonpulmonary metastases
Stage IIeIII diffuse AHWT
Stage IV diffuse AHWT
(no measurable
disease)
Stage IV focal AHWT
Stage I CCSK
Stage IIeIII CCSK
Stage IV CCSK
Stage IeIII MRT
Stage IV MRT
Stage IV AHWT
(measurable disease)
None
None
None
Regimen EE-4A
None
None
Regimen EE-4A
Regimen DD-4A
Yes
Regimen DD-4A
Yes
Yes
Yes
Regimen DD-4A
Regimen DD-4A
Regimen M
Yes
Regimen DD-4A
None
Regimen DD-4A
Yes
Regimen M
Yes
Regimen M
Yes
Yes
Regimen UH-1
Regimen UH-1
Yes
None
Yes
Yes
Yes
Yes
Yes
Regimen
Regimen
Regimen
Regimen
Regimen
Regimen
Regimen
UH-1
I
I
UH-1
UH-1
UH-2
UH-2
Regimen EE-4A: Pulse-intensive AMD plus VCR (18 weeks).
Regimen DD-4A: Pulse-intensive AMD, VCR and DOX (24 weeks).
Regimen M: VCR, AMD, DOX, alternating with CYCLO and ETOP
(24 weeks). Regimen UH-1: CYCLO, Carboplatin, ETOP alternating with VCR, DOX, CYCLO (30 weeks). Regimen I: VCR, DOX,
CYCLO alternating with CYCLO, ETOP (24 weeks). Regimen UH2: VCR, DOX, CYCLO alternating with CYCLO, Carboplatin, ETOP
and VCR, Irinotecan (30 weeks). FHWT, favorable histology
Wilms’ tumor; AHWT, anaplastic histology Wilms’ tumor; CCSK,
clear-cell sarcoma of the kidney; MRT, malignant rhabdoid
tumor of the kidney; AMD, dactinomycin; VCR, vincristine; DOX,
doxorubicin; CYCLO, cyclophosphamide; ETOP, etoposide.
the tumor’s clinical stage at diagnosis. The relative
proportions of histologic subtypes of WT differ following
preoperative chemotherapy when compared to those
reported following primary surgical resection [71,72].
Stromal and epithelial predominant tumors are found more
often after chemotherapy. These histologic subtypes may
demonstrate a poor clinical response to therapy but have
an excellent prognosis if the tumor is completely excised
[71]. The proportion of blastemal predominant tumors is
decreased after chemotherapy, indicating some response of
this tumor type to the preoperative chemotherapy.
However, patients with blastemal predominant tumors
after chemotherapy had a 31% relapse rate in SIOP-9 [71].
In SIOP-9, approximately 10% of all tumors resected after
preoperative chemotherapy were completely necrotic (with
<1% of viable tumor) [72]. Of these patients, 98% had no
evidence of disease at 5 years (one non-tumor death). The
SIOP now classifies tumors with complete tumor necrosis
following preoperative chemotherapy as ‘low-risk’, and
tumors with diffuse anaplasia and blastemal predominance
after chemotherapy (because of the high rate of recurrence
in these patients) as ‘high-risk’. SIOP ‘intermediate-risk’
tumors comprise all other histologies [71]. In the most
recently concluded study, SIOP 93-01, as well as in the
current SIOP 2001 study, children with Stage I low-risk
tumors following post-chemotherapy nephrectomy receive
no further chemotherapy [73]. The ongoing SIOP 2001 study
treats patients with Stage I intermediate risk-tumors with
AMD and VCR. The most important study question of this trial
is whether patients with Stage II and III intermediate-risk
tumors can be safely treated without DOX. Patients with
Stage II or higher high-risk tumors will receive intensified
postoperative chemotherapy with a combination of cyclophosphamide, carboplatin, etoposide and DOX.
Bilateral Wilms’ tumor
Synchronous bilateral WT (BWT) occurs in 4e6% of patients
with WT [50]. Children with BWT should not undergo initial
radical nephrectomy. Rather, these children should receive
preoperative chemotherapy with the goal of tumor
shrinkage and renal preservation. This is important because
the risk of renal failure in patients with BWT approaches
15% at 15 years post treatment [74].
The proposed COG protocol for patients with BWT
recommends 6 weeks of chemotherapy prior to surgery.
Tumor response is evaluated with CT or MR after 6 weeks.
Patients with tumors amenable to renal sparing procedures
can proceed with surgery. If there has not been a good
response, biopsy of the tumor(s) is recommended to
determine the histology. SIOP has reported that patients
with unilateral tumors not responding to chemotherapy
have a worse prognosis [75]. Additional chemotherapy is
then given, but all patients should proceed to surgical
resection within 12 weeks of starting therapy. Continuing
treatment beyond 12 weeks will not likely provide any
additional reduction in tumor burden.
Partial nephrectomy or wedge excision of the tumor is
preferred, but only if it will not compromise tumor resection and negative margins can be obtained. The kidney with
the lower tumor burden is addressed first. If complete
excision of tumor from this kidney can be performed
leaving a viable and functioning kidney, then radical
nephrectomy of the contralateral kidney with more
extensive tumor involvement is done. Tumor enucleation
may be considered in lieu of a formal partial nephrectomy.
This will usually be considered for large centrally located
tumors where removal of a margin of renal tissue would
compromise the vascular supply to the kidney. Even when
large bilateral masses remain after initial chemotherapy,
a high percentage of children can be successfully managed
62
with renal sparing surgery [76]. It is easy to underestimate
the amount of renal parenchyma that can be salvaged due
to compression by the tumor, therefore NSS should be
entertained in all patients.
Late effects of Wilms’ tumor treatment
Normal tissues and organs are damaged as a consequence of
the non-specific nature of WT anticancer therapy. This is
a particular problem in the very young, in whom cytotoxic
therapy can severely affect future growth and development. Clinicians must monitor these children as they
mature and be aware of potential future problems. Studies
demonstrate that at least 60% of young adult cancer
survivors manifest chronic health problems [77,78]. The
major sequelae in WT survivors are cardiotoxicity, musculoskeletal problems, reproductive issues and the development of secondary tumors.
Anthracyclines, such as DOX, have been known to have
preferential myocytic toxicity, which reduces myocardial
mass and causes myofibril dysfunction [69,70]. This results
in reduced contractility and cardiomyopathy, with congestive heart failure as the presenting problem occurring
acutely or many years after treatment [79]. A preliminary
review of NWTS-1e4 by Green et al. demonstrated a heart
failure frequency of 4.4% in patients who received DOX as
a part of their initial chemotherapy [69,70]. Total cumulative dose is the most important risk factor associated with
cardiac dysfunction, although any amount of DOX exposure
can lead to myocardial injury [80].
Radiation treatment has detrimental consequences upon
growing and developing tissues. Children receiving radiation therapy in early NWTSG trials had significant musculoskeletal conditions, such as scoliosis [81]. Height
reductions were noted to be dependent upon total radiation dose, age of treatment, fractionation and field [82].
The current recommended radiation doses should not have
clinically significant height sequelae [83].
Fertility and pregnancy are two areas that can be
detrimentally affected by WT treatment. Radiation to the
testes can result in hypogonadism and temporary azoospermia in males [84]. Inadequate testosterone production
can result in delayed sexual maturation. Females who have
their ovaries or uterus located within the radiation field are
at a significant risk of adverse fertility outcomes [85]. Postradiation females have been found to have small or absent
ovaries, primary ovarian failure and even premature
menopause. There is also a high incidence of infertility,
spontaneous miscarriages and intrauterine growth retardation [86,87]. The offspring are at risk for premature
birth, intrauterine growth retardation resulting in low birth
weight, as well as congenital malformations.
Children treated for WT have also been noted to have an
increased risk of developing subsequent malignant tumors.
Most of these occurred in children who received radiation,
and most tumors occurred within the radiation field. WT
survivors have been noted to have a 1% cumulative incidence
of developing second neoplasms 10 years after diagnosis
with an increasing incidence thereafter [88]. The cumulative
risk within 15 years of diagnosis reached 1.6% [89]. Second
cancers include bone and soft-tissue sarcomas, breast
E.Y. Ko, M.L. Ritchey
cancer, hepatocellular carcinoma, lymphoma, gastrointestinal tract tumors, melanoma and leukemias [90,91]. Children who are exposed to radiation during their primary
treatment are at the greatest risk of developing subsequent
secondary malignancies.
Despite the potential late effects from treatment for
WT, the success rate is in excess of 80% with long-term
survival. Along with this, less than 20% experience serious
morbidity at 20 years from diagnosis [92]. The increased
risk of late effects is in direct correlation to the aggressiveness of therapy for high-stage disease. Current treatment protocols focus on reducing the aggressive nature of
treatment while decreasing morbidity especially for lowstage disease [93].
There is concern about late occurrence of renal
dysfunction after unilateral nephrectomy. Some studies
have noted proteinuria and a decrease in creatinine
clearance, but other investigators have failed to confirm
these findings. The incidence of renal failure following
treatment for unilateral WT is low. Only 0.25% of NWTSG
patients have developed renal failure after nephrectomy
for unilateral tumors [56]. Most of those were children with
DDS who have intrinsic renal disease and often progress to
end-stage renal disease. Patients with the WAGR syndrome
are at increased risk of renal failure: 38% at a median of
14 years from diagnosis [94]. NWTSG investigators have
noted an increased risk of renal failure in children presenting with genitourinary anomalies and WT. The renal
dysfunction in these patients may be due to mutation of
WT1 which is necessary for normal renal development. As
noted above, the children with the highest rate of renal
failure are those with bilateral tumors [56].
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65
Review of Wilms’ tumor e multiple choice questions
1. A 5-year-old boy presents with a solid abdominal mass
noted on ultrasound. The child is found to have
a palpable right-sided abdominal mass as well as an
ipsilateral varicocele on physical examination. The next
step in evaluation is:
a. CT scan of abdomen and pelvis
b. intravenous pyelogram
c. MRI scan of abdomen and pelvis
d. ultrasound of scrotum
2. A 6-year-old boy undergoes radical nephrectomy for an
asymptomatic palpable abdominal mass confirmed to
be a solid right renal mass on imaging. The worst
prognostic indicator would be:
a. diffuse anaplasia
b. diffuse tumor spill
c. pulmonary metastases
d. positive surgical margins
3. A 1-year-old girl is found to have a left-sided renal mass
consistent with Wilms’ tumor. The histologic finding
associated with an increased risk for a metachronous
tumor is:
a. blastemal predominant pattern
b. diffuse anaplasia
c. nephrogenic rests
d. renal sinus invasion
4. A 3-year-old boy is found to have bilateral Wilms’
tumor. The right kidney has >50% involvement with
tumor and the left kidney has a 3.0 cm lower pole mass.
The next step in management is:
a. bilateral partial nephrectomy
b. chemotherapy
c. radiation
d. right nephrectomy and left partial nephrectomy
5. A 4-year-old girl has been diagnosed with Stage III
Wilms’ tumor. While undergoing chemotherapy, she
develops dyspnea on exertion, orthopnea, as well as
edema. The chemotherapeutic agent most likely
responsible for these findings is:
a. dactinomycin
b. doxorubicin
c. etoposide
d. vincristineAnswer Key