MINISYMPOSIUM

Wilms tumour: prognostic factors, staging, therapy

and late effects
Sue C. Kaste & Jeffrey S. Dome & Paul S. Babyn &
Norbert M. Graf & Paul Grundy & Jan Godzinski &
Gill A. Levitt & Helen Jenkinson
Received: 22 May 2007 / Revised: 15 October 2007 / Accepted: 24 October 2007 / Published online: 17 November 2007
# Springer-Verlag 2007
Abstract Wilms tumour is the most common malignant
renal tumour in children. Dramatic improvements in
survival have occurred as the result of advances in
anaesthetic and surgical management, irradiation and
chemotherapy. Current therapies are based on trials and
studies primarily conducted by large multi-institutional
cooperatives including the Socit Internationale dOnco-
logie Pdiatrique (SIOP) and the Childrens Oncology
Group (COG). The primary goals are to treat patients
according to well-defined risk groups in order to achieve
the highest cure rates, to decrease the frequency and
intensity of acute and late toxicity and to minimize the
cost of therapy. The SIOP trials and studies largely focus on
the issue of preoperative therapy, whereas the COG trials
and studies start with primary surgery. This paper reviews
prognostic factors and staging systems for Wilms tumour
and its current treatment with surgery and chemotherapy.
Surgery remains a crucial part of treatment for nephroblas-
toma, providing local primary tumour control and adequate
staging and possibly controlling the metastatic spread and
central vascular extension of the disease. Partial nephrec-
tomy, when technically feasible, seems reasonable not only
in those with bilateral disease but also in those with
unilateral disease where the patient has urological disorders
or syndromes predisposing to malignancy. Partial nephrec-
tomy, however, is frequently not sufficient for an anaplastic
variant of tumour. The late effects for Wilms tumour and its
treatment are also reviewed. The treatment of Wilms
tumour has been a success story, and currently in excess
of 80% of children diagnosed with Wilms tumour can look
forward to long-term survival, with less than 20% experi-
encing serious morbidity at 20 years from diagnosis. The
Pediatr Radiol (2008) 38:217
DOI 10.1007/s00247-007-0687-7
This work was supported in part by grants P30 CA-21765.
S. C. Kaste (*)
Department of Radiological Sciences,
St. Jude Childrens Research Hospital,
332 N. Lauderdale, MS #752,
Memphis, TN 38105-2794, USA
e-mail: sue.kaste@stjude.org
J. S. Dome
Department of Oncology,
St. Jude Childrens Research Hospital,
Memphis, TN, USA
P. S. Babyn
Department of Radiology,
Hospital for Sick Children,
Toronto, Canada
N. M. Graf
Clinic for Pediatric Oncology and Hematology,
University Hospital of the Saarland,
Homburg, Germany
P. Grundy
Division of Pediatric Hematology, Oncology and Palliative Care,
and Northern Alberta Childrens Cancer Program,
University of Alberta,
Edmonton, Canada
J. Godzinski
Department of Oncological Surgery for Children and Adolescents,
Mother and Child Institute,
Warsaw, Poland
G. A. Levitt
Paediatric Oncology,
Great Ormond Street Hospital for Sick Children NHS Trust,
London, UK
H. Jenkinson
Oncology Department,
Birmingham Childrens Hospital NHS Trust,
Birmingham, UK
late complications are a consequence of the type and
intensity of treatment required, which in turn reflects the
nature and extent of the original tumour. Continual inter-
national trial development and participation will improve
matching of treatment needs with prognosis, reducing long-
term complications in the majority. The advent of molecular
markers of disease severity and improved functional
imaging might help.
Keywords Nephroblastoma
.
SIOP
.
COG
.
Staging
.
Surgery
.
Preoperative chemotherapy
.
Children
Introduction
The survival of patients with Wilms tumour (WT) has dra-
matically improved from 30% just several decades ago to
almost 90% of patients now having a 5- to 7-year survival
[13]. This can be attributed to advances in imaging and
histological methods of diagnosis, the development of risk-
adapted therapy and improved staging. More important, this
improved survival reflects the concerted efforts of many
multi-institutional, national and international interdisci-
plinary paediatric cooperative groups including the largest
cooperative groupsthe Childrens Oncology Group
(COG) and the Socit Internationale dOncologie Pdia-
trique (SIOP). This minisymposium reviews the current
status of WT prognostic factors, staging, treatment and
imaging. We highlight some of the differences between the
cooperative oncology groups and illustrate contemporary
controversies and potential new methods for stratifying WT
that could influence management.
Background
WT, also known as nephroblastoma [4], is the most
common paediatric renal tumour in North America,
accounting for approximately 6% of childhood cancer
patients per year. This equates to approximately 500 new
cases per year in the United States, or eight cases per million
children younger than 15 years. The frequency of WT is
slightly higher in blacks than in whites, but is considerably
lower in Asians than in whites. In the United States, the
incidence of WT (either unilateral or bilateral) is slightly
lower in boys than in girls. Affected children most
commonly present with a palpable abdominal mass and less
frequently abdominal pain or haematuria.
The peak incidence of WT occurs between 2 and 5 years
of age, with 95% of children being diagnosed before the
age of 10 years [4], most commonly in the first 2 years of
life [3, 5]. At gross inspection, WT is usually a single
unilateral spherical mass that is well demarcated from
adjacent renal tissue by a fibrous capsule. However, about
5% of children have bilateral disease and 7% have multi-
centric disease. WTs can arise anywhere within the renal
medulla or cortex and can protrude into the calyces and
ureter, and in 6% of patients the tumour extends into the
renal vein or inferior vena cava [4]. Most bilateral tumours
present as bilateral synchronous tumours; however, 1.5%
are bilateral metachronous tumours. These typically occur in
children younger than 1 year who have already been
successfully treated for a unilateral tumour. Bilateral meta-
chronous disease occurs particularly in children whose
resected kidney contained nephrogenic rests [6]. WT most
commonly metastasizes to the lungs followed by lymph
nodes and liver. Rarely, it metastasizes to bone, bone
marrow, or brain [7]. The rate of metastatic WT is as high
as 5% [8].
Histologically, WTs are of a triphasic cell lineage com-
prising blastemal, stromal and epithelial cells. Favourable
or unfavourable histological characterization is a strong
prognostic indicator, as discussed below. Nuclear unrest
might occasionally be seen in favourable-histology WT and
is characterized by nuclear enlargement and hyperchromasia
without enlarged multipolar mitotic figures [4].
Nephrogenic rests, thought to represent precursors of
WT, are present in about 1% of neonates on post-mortem
examination. It is estimated that only 1% of nephrogenic
rests undergo malignant transformation to WT [7, 9]. Two
types of nephrogenic rest have been identified: intralobar
nephrogenic rests develop early in nephrogenesis; perilobar
nephrogenic rests occur later in nephrogenesis and are as-
sociated with Beckwith-Wiedemann syndrome and hemi-
hypertrophy [7]. Although classic WT histologically is a
combination of blastemal, epithelial, and stromal cells, all
three types of tumour cells need not be present for a tumour
to be designated as classic WT [10]. Of classic WTs, 7%
are anaplastic. Anaplasia is defined histologically by cells
with enlarged nuclei, hyperchromasia, and irregular mitotic
figures [4, 11] and might not be adequately detected by
biopsy alone. Patients whose tumours have focal anaplasia
have a better outcome than those with diffuse anaplasia.
Favourable-histology tumours have no histological evi-
dence of anaplasia and have an overall better prognosis
than anaplastic tumours. The presence of anaplasia usually
occurs in children older than 2 years and is an indicator of
chemotherapy resistance [1], and is associated with a
marked increase in risk of recurrent disease compared to
tumours with a favourable histology. Blastemal predomi-
nance after completion of chemotherapy [12] is also as-
sociated with increased recurrence.
WTarises from pluripotent embryonic renal precursors. The
identification in 1990 of an association of WTwith disturbances
of WT1 (a tumour-suppressor gene) laid the foundation for the
molecular basis of syndromes predisposing to WT [13], and the
Pediatr Radiol (2008) 38:217 3
loss of heterozygosity (LOH) of tumour tissues characterizes
the majority of syndrome-associated WTs [7]. The WT1 gene,
located on chromosome 11p13, is necessary for renal
development. It is through inactivation of WT1 that most
WTs arise, and intralobar nephrogenic rests occur mainly in
association with WT1 mutations. Germline mutations of WT1
account for the urogenital abnormalities and development of
WT in patients with syndromes associated with chromosome
11 abnormalities including WAGR syndrome, Denys-Drash
syndrome, and Beckwith-Wiedemann syndrome [14]. Inacti-
vating point mutations in the WT1 gene are associated with
Denys-Drash syndrome while Beckwith-Wiedemann syn-
drome has been linked with LOH of the WT2 locus on
chromosome 11p15. A somatic germline deletion of 11p13 has
been identified with WAGR syndrome [4]. Children with
aniridia, hemihypertrophy, cryptorchism, and hypospadias are
more often affected [15]. Only about 2% of patients have a
family history of the disease [4].
Prognostic factors
Histology
The SIOP classification
The SIOP trials and studies largely focus on the issue of
preoperative therapy and have shown the effectiveness of
preoperative chemotherapy. Regarding histology, this ap-
proach changes the size, distribution pattern and prognostic
value of the different histological subtypes compared to
tumours operated upon immediately (Figs. 1 and 2, Table 1).
Furthermore, the use of preoperative chemotherapy is con-
sidered of benefit because it (1) reduces the risk of tumour
rupture during surgery, (2) induces a favourable stage
distribution, with 60% of patients with stage I disease re-
quiring less postoperative therapy, (3) selects good respond-
ers from among patients with stage IV disease, and (4)
provides the opportunity of partial nephrectomy in an
increasing number of patients.
Based on the correlation between the histological features
and survival, three prognostic groups of typical renal
tumours of childhood were discerned in the SIOP trials and
studies: low-risk, intermediate-risk and high-risk tumours.
Mesoblastic nephroma, clear cell sarcoma of the kidney and
rhabdoid tumour of the kidney are separate entities from
nephroblastoma, but are typical renal tumours of childhood.
The SIOP (Stockholm) Working Classification of Renal
Tumours of Childhood has been revised to incorporate the
results of the SIOP 9 and 93-01 trials and studies [16]
(Table 1). Some entities that existed in the previous
classification, such as nephroblastoma with fibroadenoma-
tous structures, and highly differentiated epithelial nephro-
blastoma, have been either excluded or grouped with other
subtypes.
The NWTS/COG classification
Although the composition of WTs varies greatly, the tumour
is assigned a histological type if more than two-thirds of the
tumour sample is of one component. From a review of
National Wilms Tumour Study Group (NWTSG) studies,
favourable and unfavourable histological subtypes of WT
Fig. 1 Distribution of histologi-
cal subtypes in registered patients
from the GPOH subgroup of
SIOP 9 and SIOP 93-01 accord-
ing to the initial treatment
Teaching box: Tumour histology and stage are the two most
significant prognostic factors for patients with Wilms tumour.
4 Pediatr Radiol (2008) 38:217
have been identified [17]. Favourable histology is defined as
the lack of findings of anaplasia. The presence of anaplasia
has been closely linked to decreased tumour responsiveness
to adjuvant therapy. The definition of focal anaplasia is
based on topographical principles, which requires that ana-
plasia be confined to only a few specific regions. Other un-
favourable histological variants identified include rhabdoid
tumour of the kidney and clear cell sarcoma of the kidney.
The identification of histological subtypes is important, for
different subtypes perform differently.
Staging
Stage is one of the most important therapeutic and prog-
nostic criteria for renal tumours. It has been shown in all
multicentre trials that staging still represents a major
problem, partly because renal tumours are usually very large
at nephrectomy and often it is very difficult to assess their
relationship with normal renal anatomical structures such as
the renal capsule and the renal sinus. In SIOP studies, local
(abdominal) staging of primary tumour is done following
surgery after preoperative chemotherapy. Even in those with
stage IV disease, local stage is still a prognostic feature. The
presence/absence of metastases is evaluated at presentation,
on the basis of imaging studies. The criteria for SIOP
staging are given in Table 2. The NWTSG has also
developed an effective staging system that incorporates
clinical, surgical and pathological information that is
gathered at the time of initial surgery, generally before
chemotherapy [17]. This system allows stage-based adju-
vant therapy and the avoidance of unnecessary chemother-
apy for some children. In case of a bilateral WT, a local
stage should be provided for each tumour (Table 3).
The SIOP experience
A retrospective analysis of SIOP 93-01 data has shown that
the histology according to the revised Stockholm classifica-
tion for renal tumours is still most important for prognosis.
Even in the intermediate risk group this is true for histo-
85 470 51 N =
2000
1600
1200
800
400
0
75 382 27 N =
1200
800
400
0
low risk intermediate risk high risk













T
u
m
o
r

v
o
l
u
m
e

[
m
l
]

a
f
t
e
r

c
h
e
m
o
t
h
e
r
a
p
y

















a
t

d
i
a
g
n
o
s
i
s
mean 313 ml 434 ml 457 ml
mean 166 ml 223 ml 423 ml
P < 0.001 P < 0.001 n.s.
Fig. 2 Tumour volume at diag-
nosis and after preoperative
chemotherapy according to his-
tology (data from the GPOH
subgroup of SIOP 9 and SIOP
93-01)
Table 1 The revised SIOP
working classification of renal
tumours [6]. Mesoblastic
nephroma, clear cell sarcoma
of the kidney and rhabdoid
tumour of the kidney are sepa-
rate entities from nephroblas-
toma, but are typical renal
tumours of childhood
Risk category With pretreatment With primary nephrectomy
Low-risk tumours Mesoblastic nephroma
Cystic partially differentiated
nephroblastoma
Completely necrotic nephroblastoma
Intermediate-risk
tumours
Nephroblastoma epithelial type Nonanaplastic nephroblastoma
and its variants Nephroblastoma stromal type
Nephroblastoma mixed type
Nephroblastoma regressive type
Nephroblastoma focal anaplasia
High-risk tumours Nephroblastoma blastemal type
Nephroblastoma diffuse anaplasia
Clear cell sarcoma of the kidney
Rhabdoid tumour of the kidney
Pediatr Radiol (2008) 38:217 5
logical subtypes (Fig. 3). Focal anaplasia has a better prog-
nosis than diffuse anaplasia, with an event-free survival
lying within the range of other intermediate-risk tumours
(Fig. 4). Finally, blastema-predominant tumours that are
diagnosed after preoperative chemotherapy do worse than
any other intermediate-risk tumour. This is the reason these
tumours are treated as high-risk tumours in SIOP 2001.
The SIOP data for stage and lymph node involvement
are shown in Fig. 5. Because of the impact of lymph node
involvement on prognosis, SIOP did change the staging
classification. In the ongoing SIOP 2001 trial and study, all
tumours with positive lymph nodes are staged as III. This
also helps to better compare SIOP results with the results of
the COG trials and studies.
Table 2 SIOP criteria for nephroblastoma staging
Stage Criteria
I The tumour is limited to the kidney or surrounded with a fibrous pseudocapsule if outside the normal contours of the kidney; the renal
capsule or pseudocapsule may be infiltrated with the tumour but it does not reach the outer surface, and it is completely resected.
The tumour may be protruding (bulging) into the pelvic system and dipping into the ureter, but it is not infiltrating their walls.
The vessels of the renal sinus are not involved.
Intrarenal vessels may be involved.
II The tumour extends beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal fat, but is
completely resected.
The tumour infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma, but it is completely
resected.
The tumour infiltrates adjacent organs or vena cava, but is completely resected.
The tumour has been surgically biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery
III Incomplete excision of the tumour, which extends beyond resection margins (gross or microscopic tumour remains postoperatively).
Any abdominal lymph nodes are involved.
Tumour rupture before or during surgery (irrespective of other criteria for staging).
The tumour has penetrated the peritoneal surface.
Tumour implants are found on the peritoneal surface.
The tumour thrombi present at resection, margins of vessels or ureter transected or removed piecemeal by surgeon.
IV Haematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region.
V Bilateral renal tumours at diagnosis. Each side has to be substaged according to above classifications.
Table 3 NWTSG criteria for nephroblastoma staging
Stage Criteria
I The tumour is limited to the kidney or surrounded with a fibrous pseudocapsule if outside the normal counters of the kidney; the renal
capsule or pseudocapsule may be infiltrated with the tumour but it does not reach the outer surface, and it is completely resected.
The tumour may be protruding (bulging) into the pelvic system and dipping into the ureter, but it is not infiltrating their walls.
The vessels of the renal sinus are not involved.
Intrarenal vessels may be involved.
II The tumour extends beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal, fat but is
completely resected.
The tumour infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma, but it is completely
resected.
The tumour infiltrates adjacent organs or vena cava, but is completely resected.
The tumour has been surgically biopsied (wedge biopsy) or there was spillage of tumour before or during surgery that is confined to the
flank and does not involve the peritoneal surface.
III Residual nonhaematogenous tumour is present and confined to the abdomen.
Any one of: Any abdominal lymph nodes are involved.
The tumour has penetrated through the peritoneal surface.
Tumour implants are found on the peritoneal surface.
Gross or microscopic tumour remains postoperatively.
The tumour is not resectable because of local infiltration into vital structures.
Tumour spill before or during surgery.
IV Haematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region.
V Bilateral renal tumours at diagnosis. Each side has to be substaged according to the above criteria prior to biopsy or treatment.
6 Pediatr Radiol (2008) 38:217
The NWTS/COG experience
Advanced tumour stage at the time of diagnosis is
associated with an increased risk of recurrence [18, 19].
There is recent recognition that tumour rupture at surgery
even if localizedpredisposes the patient to disease
recurrence. These patients should be staged and treated as
having stage III disease [20, 21]. Older patient age is
associated with an increased risk of disease recurrence
[18, 19].
Molecular factors associated with prognosis
Recently identified molecular biological factors associated
with an increased rate of recurrence include a LOH in
chromosomes 1p and 16q in favourable-histology WT [22,
0 6 12 18 24 30 36 42 48
months
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
S
u
r
v
i
v
a
l

P
r
o
b
a
b
i
l
i
t
y
blastemal predom
focal anaplasia
diffuse anaplasia
Fig. 4 Event-free survival of
patients enrolled in SIOP 93-01
with blastema-predominant sub-
types and focal or diffuse ana-
plasia (all stages; diagnosis by
reference pathology)
0 6 12 18 24 30 36 42 48
months
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
S
u
r
v
i
v
a
l

P
r
o
b
a
b
i
l
i
t
y
inter (rest)
epithelial/stromal
blastemal
Fig. 3 Event-free survival for
patients treated according to
SIOP 93-01, including all stages
for the different histological
subtypes of the intermediate risk
group (inter (rest) includes all
intermediate-risk tumours with-
out epithelial, stromal or blaste-
mal predominance; diagnosis by
reference pathology)
Teaching box: Likelihood of disease recurrence is increased with
tumour rupture.
Pediatr Radiol (2008) 38:217 7
23]. This LOH occurred in approximately 20% of 232 WT
patients studied and was associated with a lower 2-year
relapse-free rate and poorer overall survival. A gain of
chromosome 1q [24] and a high telomerase expression level
[25, 26] are also associated with an increased rate of
recurrence. Additional prognostic factors based on ongoing
studies in molecular biology are likely to be identified.
Therapy for Wilms tumour
Current treatment stratification is based on histology, but this
is imperfect in identifying those patients likely to develop
recurrent disease. Tumours with immature renal cells
distributed among normal mature kidney cells are described
as favourable and carry an excellent prognosis. On the
contrary, anaplastic tumour cells, which are both hyperplas-
tic and dysplastic, are associated with a less favourable
outcome [21].
Current therapy depends on staging and comprises multi-
modality chemotherapy and surgery, with or without
radiation therapy. The current scheme for the NWTSG
directs nephrectomy at the time of diagnosis for all resectable
primary tumours. Surgery is then followed by chemotherapy
and radiation therapy to sites of metastatic or residual disease
after surgery [27]. In contrast, SIOP recommends adminis-
tering several weeks of chemotherapy before nephrectomy
[28]. The outcomes of both approaches are similar.
The activity of actinomycin (Act-D) and vincristine
(VCR) against WT was shown in the 1950s and 1960s, and
these drugs have served as the cornerstone of WT therapy
ever since. Doxorubicin was added to WT therapy in the
1970s, followed by carboplatin and etoposide later on.
Through successive trials, the combination, length, and
mode of administration of these drugs have been refined.
The main objectives of todays trials and studies are to treat
patients according to well-defined risk groups in order to
achieve the highest cure rates, to decrease the frequency and
intensity of acute and late toxicity and to minimize the cost of
therapy [29]. A summary of the most important studies is
given below.
Trials and studies
SIOP
The SIOP trials and studies largely focus on the issue of
preoperative therapy. The concept of neoadjuvant chemother-
apy plays an important role in the treatment of most paediatric
solid tumours today. The complete surgical removal of a
shrunken tumour is facilitated, mutilation caused by surgical
procedures is minimized or avoided and micrometastases, not
visible at diagnosis, are treated as early as possible. Besides
that, response to treatment can be measured individually by
tumour volume reduction and percentage of therapy-induced
necrosis at the time of surgery in the histological specimen.
This might give an early individual prognostic indication and
can be used for further stratifying and individualizing post-
operative treatment as in other paediatric cancers. Neverthe-
less, there is a well-known risk of unnecessarily administering
chemotherapy to children preoperatively without a histolog-
ically proven diagnosis. This risk is avoided by primary
surgery. Using molecular biological findings, a very-low-risk
group of patients can be cured by surgery alone.
The first SIOP study (SIOP 1) opened in 1971 and
showed that pretreatment reduces the number of ruptures and
months
48 42 36 30 24 18 12 6 0
S
u
r
v
i
v
a
l

P
r
o
b
a
b
i
l
i
t
y
1,0
,8
,6
,4
,2
0,0
stage I
stage II N-
stage II N+

stage III
Fig. 5 Event-free survival of
patients enrolled in SIOP 93-01
by stage done by the panel of
pathologists
8 Pediatr Radiol (2008) 38:217
favours the stage distribution after surgery. There was no
evidence in that study that prolonged treatment with Act-D
for six courses after surgery contributes to a better survival or
disease-free survival [30]. These data were confirmed by
SIOP 2. It was also shown that the risk of tumour rupture is
independent of tumour volume. Even small tumours have a
higher risk of rupture if the primary treatment is surgery
(5% vs. 20%). The next SIOP trial (SIOP 5) showed that
chemotherapy is comparable to radiotherapy in efficacy of
preparing the tumour for surgery. Because there are fewer
late effects, chemotherapy is used instead of radiation
therapy [31] in the preoperative phase of treatment. SIOP 6
focused on the postoperative treatment. After pretreatment
and surgery only a short postoperative treatment is ne-
cessary in stage I patients. In stage II without lymph node
involvement (II N) it was decided to intensify treatment
because of the higher number of relapses. In the more
advanced stages doxorubicin proved to be an effective su-
pplement to VCR and Act-D [32]. SIOP 9 showed that the
prolongation of preoperative treatment from 4 to 8 weeks in
those with unilateral disease without metastasis was not
necessary [28]. Shortening the duration of chemotherapy
was shown to reduce acute and late toxicity while
maintaining effectiveness, and it is beneficial in terms of
health costs [33]. Furthermore, it was shown that patients
with blastema-predominant histology have a poorer out-
come than those with other subtypes of nephroblastoma.
In the ongoing SIOP 2001 such patients are treated as high-
risk patients. In this study postoperative chemotherapy is
tailored according to histological features, as defined by a
new classification system. Another aim of this study is to
decrease late cardiac toxicity in patients with stage II or III
and histologically intermediate-risk disease. These patients
are randomly assigned to treatment with or without
doxorubicin.
NWTS
NWTSG has sought to refine adjuvant therapy, with each
study intensifying the therapy provided to high-risk patients
and decreasing or modifying the therapy to low-risk patients.
The first NWTS study was open for registration from
October 1969 until December 1973. It showed that radio-
therapy is unnecessary for stage I patients and that the
combination of VCR and Act-D is better than either drug
alone [34]. The results of the next study (NWTS 2) were
that the addition of doxorubicin improves survival of
patients with higher-stage disease and that in patients with
stage I disease receiving VCR plus Act-D, 6 months is as
efficacious as 15 months of therapy [35]. The treatment
duration could be further reduced for those with stage I to
11 weeks after NWTS-3. In this trial and study doxorubicin
was shown to be unnecessary for stage II but not for stage
III disease, if the dose of radiation is lowered to 10 Gy.
Only in those receiving 20 Gy local irradiation can
doxorubicin be avoided. This study also demonstrated that
cyclophosphamide is without benefit for patients with stage
IV disease [36]. The next study (NWTS 4) evaluated the
efficacy, toxicity and costs of the administration of different
regimens for the treatment of WT. Pulse-intensive chemo-
therapy was shown to be as effective, less toxic, and less
expensive in those with stage IIV disease. In those with
stage II, III and IV a total duration of 6 months of
chemotherapy is sufficient [37]. Between August 1995 and
June 2002 previously untreated children with favourable-
histology or anaplastic WT, clear cell sarcoma of the kidney
or malignant rhabdoid tumour of the kidney were treated
with stage- and histology-specific therapy in NWTS 5.
Their tumours were assayed for polymorphic DNA markers
on chromosomes 1p and 16q. Tumour-specific LOH for both
chromosomes 1p and 16q identified a subset of patients with
favourable-histology WTwho have a significantly increased
risk of relapse and death. LOH for these chromosomal
regions is now used as an independent prognostic factor
together with disease stage to target intensity of treatment to
risk of treatment failure [38]. The treatment approach of
NWTS 5 provides a reasonable standard of care for WTwith
favourable histological features. NWTS 5 patients with stage
I diffuse or focal anaplasia were treated with VCR and Act-D
because of the good results of earlier studies for this group of
patients. However, preliminary analysis yielded an unex-
pectedly low 4-year event-free survival of 69.5%. Hence,
further COG studies will intensify the therapeutic regimen
by adding doxorubicin and irradiation [39].
Bilateral Wilms tumour
Synchronous bilateral WTs occur in approximately 5% of
patients. Treatment of these tumours is characterized by the
challenge of establishing local tumour control while preserving
renal function. One needs to spare as much renal parenchyma
as possible in order to avoid significant renal insufficiency or
place the patient in need of renal transplant. Typically, patients
receive preoperative chemotherapy to reduce the tumour bur-
den and facilitate surgery. Approximately 40% of tumours are
reduced more than 50% in size by chemotherapy [40]. The
duration of preoperative chemotherapy should not exceed
12 weeks. In patients without tumour regression during pre-
operative chemotherapy, intensification of treatment is not
Teaching box: A primary distinction between SIOP and NWTS
trials is that patients typically receive preoperative chemotherapy
in SIOP trials. In NWTS trials, surgical resection generally
precedes chemotherapy.
Pediatr Radiol (2008) 38:217 9
indicated, for it is most likely that histology will showa stroma-
predominant subtype and not anaplasia. This subtype is closely
related to mutations of the WT1 gene and is unresponsive to
chemotherapy. Nevertheless, outcome is excellent if the tumour
can be totally excised. In a series of 90 patients treated
according to the SIOP 93-01 study in Germany, relapse-free
survival was as high as 75%, with an overall survival of 84%
after 5 years. In 50% of patients, bilateral kidney-sparing sur-
gery was possible. Only in two patients were bilateral neph-
rectomies necessary. Most important for outcome was a local
stage III, anaplasia or metastatic disease at the time of
diagnosis. PET scanning has been reported to differentiate
viable germ-cell tumour from mature teratoma and tissue
necrosis [41], and therefore it might also help in distinguishing
between proliferating and nonproliferating bilateral WT.
Patients at greatest risk of metachronous WT include
those with aniridia, overgrowth syndromes, and WT in
association with nephrogenic rests [42]. Children younger
than 12 months with perilobar nephrogenic rests in the
kidney have an increased risk of contralateral disease [6].
Though these patients might well benefit from nephron-
sparing procedures, the reported increased risk of recurrent
disease (reported in up to 8.1% of patients following partial
nephrectomy) using this procedure is of considerable
concern regarding disease control [42, 43]. Disease recur-
rence portends treatment with intensive chemotherapy and
possibly radiation therapy, both of which can further
compromise renal function. A much needed prospective
study of nephron-sparing surgery is ongoing in large clinical
trials to assess its utility and outcomes in children with WT.
Role of surgery
Historically, surgery was the first effective treatment for
WT, with cure possible in selected patients with localized
disease [44, 45]. Disease control remains contingent upon
surgical resection, whether at the time of diagnosis or after
several courses of chemotherapy. Transperitoneal radical
nephrectomy is the mainstay of treatment for most patients
with WT [3]. From the SIOP perspective, before preoper-
ative chemotherapy was introduced, intraoperative tumour
ruptures had been the major problem. A 32% rupture rate
after primary surgery was found in the SIOP 1 trial. Pre-
operative radiotherapy reduced that rate to 4%. According
to SIOP protocols, the primary staging allocates patients to
one of three pretreatment groups: localized unilateral
nephroblastoma (regardless of regional lymph node status
on imaging), metastatic nephroblastoma, or bilateral neph-
roblastoma. Precise local-regional staging is performed
after preoperative chemotherapy and takes into account
the extent of the disease at that time only [46]. From the
surgical point of view, adequate exploration of the ab-
dominal cavity and biopsy or excision of all suspicious
structures is essential. Biopsy of lymph nodes at the level of
renal vessels is obligatory even if they seem not to be
invaded [20, 47]. It is not clear how many lymph nodes
should be sampled to achieve reliable staging but extensive
lymph node dissection is thought unnecessary [48]. A child
is at increased risk of under-staging and inadequate
treatment in the absence of lymph node sampling [20]. In
contrast, tumour spillage preceding or at the time of surgery
upstages the disease [1]. Pretreatment tumour ruptures have
traditionally implied staging the patient as stage III, even if
there were no traces of that event after preoperative che-
motherapy [46]. Recently, that question has been reas-
sessed. It seems that the arguments in favour of the classic
policy are limited [49, 50]. For more solid conclusions a
better imaging criterion for rupture will be necessary, as
discussed elsewhere in this Minisymposium. Surgical
exploration of the contralateral kidney is no longer
recommended [20, 51, 52].
Surgery for vascular extension of the disease
In 410% of patients, WT thrombus extends into the in-
ferior vena cava; rarely, it extends into the right atrium. In
such patients, chemotherapy preceding definitive surgery
has been shown to facilitate surgical resection of intravas-
cular tumour by decreasing the size of the tumour thrombus
[1, 53, 54]. Those patients have a high risk (20%) of lung
metastases. The aim of surgical treatment is to remove the
primary tumour and thrombus during the same session.
Difficulties are created mainly by infiltration of the wall of
the vena cava. The choice between resection-reconstruction
of the vena cava and other treatments (radiotherapy for
residual disease) must be made. Incomplete resection does
not always imply a fatal outcome. Radiotherapy and
chemotherapy still offer a chance to those patients. Three
such patients from SIOP 9 are long-term survivors [5558].
The survival of children with cavoatrial tumour extension
does not differ from that of those with intrarenal tumours of
the same histology and stage [1].
Partial nephrectomy
Partial nephrectomy is the recommended treatment for
bilateral tumours and tumours within a solitary kidney. It
may consist of polar heminephrectomy or wedge resection of
smaller tumours. In more difficult cases, with multifocal
tumour and low- or intermediate-risk pathology, enucleating
the tumour nodules might be of benefit. Partial nephrectomy
can be oncologically successful in unilateral nephroblastoma
[5962]. It should be taken into account that low-stage
tumours currently have an excellent prognosis (90100%)
and taking the risk of relapse versus the low potential of
hyperperfusion nephropathy in the remaining kidney might
10 Pediatr Radiol (2008) 38:217
not be justified. Partial nephrectomy in unilateral nephro-
blastoma can be applied when there is an extremely fa-
vourable location of small tumours and possibly when
patients have contralateral urological and nephrological
disorders or syndromes predisposing to further renal malig-
nancies. The SIOP 2001 suggests the following contra-
indications to partial nephrectomy i n unilateral
nephroblastoma: preoperative tumour rupture or biopsy,
tumour infiltrating extrarenal structures, intraabdominal
metastases or lymph nodes seen on preoperative imaging,
thrombus in the renal vein or vena cava, tumour involving
more than one-third of the kidney (at least 50% of renal
tissue should be spared after the tumour resection with a
margin of healthy tissue, to give any worthwhile protection
against hyperperfusion), multifocal tumour, central location,
involvement of calyces, haematuria, and little experience in
partial nephrectomy [46]. Preliminary data are quite
acceptable for low-risk and intermediate-risk tumours but
discouraging for anaplastic ones. Possibly, examination of a
frozen section of the operative specimen to make possible
immediate conversion to total nephrectomy is the solution
[60, 62]. A weak response to the pretreatment might be
another guide to consider anaplastic nephroblastoma. On
the other hand, a similar reaction might be observed in low-
risk tumours. The pretreatment needle puncture is not
reliable enough in heterogeneous tumours.
Metastasectomy
Historically, a cure of disseminated nephroblastoma was un-
usual until the 1970s [8, 45, 55, 63]. Currently, these
patients have a good chance of cure. Patients with the most
favourable prognosis are those in whom pulmonary (the
most frequent location) metastases disappear with pretreat-
ment chemotherapy [8, 64]. It is not clear whether the
prognosis is the same for those in whom the response is not
complete but makes possible complete metastasectomy.
Patients with stable or progressing metastases are not good
candidates for surgery. The technique of metastasectomy is
wedge resection in the majority of patients. Lobe resection or
pneumonectomies are rarely justified. The classic recom-
mendation has been that only a chest radiograph was
required to diagnose or exclude initial pulmonary stage IV
disease [46, 60, 65]. On the other hand, CT facilitates the
surgical choice between a classic thoracotomy and mini-
mally invasive techniques. Extrapulmonary locations of
metastases are rare (20% of all those with stage IV disease)
[55, 66]. The SIOP 6 and 9 experience has shown that
metastases located in the liver or in the liver and lungs
might have an acceptable prognosis but patients with
metastases in other locations have a poorer prognosis. The
importance of the anaplastic variant of pathology outweighs
both location and treatment modalities [55, 66].
Surgery-related complications
Recently, three important studies have dealt with this
problem. The first, that from NWTS evidenced a high rate
(19.6%) of surgery-related complications in patients operat-
ed on primarily. That study excluded intraoperative ruptures
[67]. Experience of the SIOP 9 (pretreated patients only)
revealed much lower rates of complications despite includ-
ing the intraoperative ruptures (8%) [68]. To better explore
this subject, the common NWTS-SIOP study was conducted.
The complication rate (intraoperative tumour ruptures
excluded) in the NWTS study were much lower than in their
previous study and the difference from the SIOP study was
not significant. Intraoperative ruptures were compared
separately and their rate was significantly higher in the
NWTS than in the SIOP study. The most common com-
plications found were bowel obstruction (4.5%) and exten-
sive haemorrhage (2.3%) in patients who were not pretreated.
In pretreated patients, bowel obstructions were less frequent
(0.08%) and extensive haemorrhage was not reported [69].
Minimally invasive techniques
Laparoscopic nephrectomy is feasible but currently gener-
ally considered inadequate for malignant conditions. This
opinion will probably evolve in coming years. The
improving sensitivity and specificity of imaging techniques
will decrease the value of extensive surgical explorations at
tumour nephrectomy, which is easy with the classic surgical
approach and difficult with minimally invasive techniques.
Pulmonary chemoresponsive subpleural metastatic spread,
well-defined on good-quality CT scans, is probably the best
indication for thoracoscopy. It has a good chance of
assuring control in such metastases and has been confirmed
successful in seven of seven such patients [70]. A large-
scale evaluation would be important.
The role of nephron-sparing surgery is controversial.
Published reports present conflicting results of outcomes
associated with this procedure [42, 43, 65, 66, 71, 72]. The
premise upon which this technique is based is that sparing
as much renal parenchyma as possible is beneficial for
preservation of renal function. This is particularly important
in patients at greatest risk of renal insufficiency and the
development of metachronous WT and those in whom more
than 50% of total renal mass is resected [66, 73, 74]. How-
ever, as reported by the NWTSG, renal failure is extremely
rare (0.25%) in patients with unilateral WT; most patients in
whom renal failure occurs are those with significant pre-
existing risk of renal failure, such as those with Denys-
Drash syndrome [73, 74]. Breslow et al. and the NWTSG
later found a 38% incidence of renal failure at 14 years
from diagnosis in patients who had aniridia and genitouri-
nary abnormalities [75].
Pediatr Radiol (2008) 38:217 11
Although nephron-sparing surgery benefits the patient
in preserving renal function, there are concerns. There is a
potential for limited lymph node dissection that could lead
to understaging of tumour burden. In reports from both
the United States and Europe, almost half of patients who
underwent nephron-sparing surgery for bilateral WT still
lost more than 50% of functioning renal tissue, placing
them at increased risk of renal failure during a long-term
follow-up [66]. Such risk of renal failure has not been
reported in patients with multicentric unilateral WT [76].
However, nephron-sparing surgery does have an increased
likelihood of positive resection margins and thus, of local
recurrence [40, 76]. Currently, it seems that nephron-
sparing surgery is most appropriate in patients with
unilateral low-risk WT; other indications for its use remain
controversial [77].
Role of radiation therapy
Radiation therapy serves as an important adjuvant treatment
modality for WT, based on tumour histology and stage [3].
Treatment of disease relapse
Disease relapse in WT is associated with a mortality rate of
57% as reported by Shamberger et al. [20] in children who
develop local recurrence after nephrectomy. Clearly defined
prognostic factors at the time of relapse include tumour
histology (diffuse anaplasia has a 4.7 times greater relative
risk of recurrence), initial stage of disease (stage III disease
has a 3.2 times greater relative risk of recurrence), time
from diagnosis to relapse of less than 12 months, the site of
relapse, tumour spillage during surgery (3.7 times greater
relative risk of recurrence) and previous treatment [20].
With the availability of new drugs and new drug combina-
tions, the salvage rate for patients with relapsed disease is
estimated at 5060%; 4050% of patients still succumb to
their disease. Promising results have been shown using high-
dose chemotherapy with stem cell rescue, but studies have
shown intensive chemotherapy alone to be equally effective
[78]. Abu-Ghosh et al. [79] reported an overall response rate
of 82% in 11 patients treated with ifosfamide-carboplatin-
etoposide chemotherapy for poor-risk relapsed WT. A simi-
lar collaborative study between the French Society of
Pediatric Oncology and the United Kingdom Childrens
Cancer Study Group found a promising role for etoposide
but with significant haematological toxicity [80]. Using
high-dose chemotherapy followed by autologous haemato-
poietic stem-cell rescue, Campbell et al. [81] reported an
estimated 4-year event-free survival rate of 60% (95% CI,
0.406.88) and overall survival of 73% (95% CI, 0.40
6.86) at 4 years.
Late consequences of treatment
The successful treatment of WT unfortunately comes at a
cost, as cancer treatment is not cell-specific. In addition to
killing malignant cells, damage occurs to normal organs and
tissues. This is particularly true of cancers occurring in the
very young, such as WT, where cytotoxic therapy can have
profound effects on growth and development. Childhood
cancer survivor studies have shown that at least 60% of
young adults have chronic health problems, with a small
minority dying as a result of their treatment [82, 83]. The
treatment of WT has been one of paediatric oncologys
success stories, with a 5-year survival in excess of 85%
during the last two decades [84]. This has enabled late
effects to be studied into adulthood. With this information,
subsequent treatment trials have endeavoured to reduce
morbidity, particularly in low-stage disease. In present-day
treatment protocols for low-stage disease where patients
receive two-drug chemotherapy with VCR and Act-D and
nephrectomy, the late effects are minimal [85]. In the higher
stages and when the disease has relapsed, anthracyclines are
likely to be required, in addition to radiotherapy (abdominal
and lung), alkylating agents, etoposide and carboplatin.
These patients are at much greater risk of late sequelae. In
addition, patients with bilateral disease who require more
than 50% reduction in renal mass or have associated chro-
mosomal anomalies might have significant renal problems.
The clinically significant late sequelae occurring in
survivors of WT are predominantly cardiotoxicity, reproduc-
tive problems, renal dysfunction and the development of
benign and malignant second tumours.
Anthracyclines, principally doxorubicin, have been used
successfully for stage III and IV disease since the 1970s.
Since their inception there has been an appreciation of their
preferential myocytic toxicity resulting in a reduction in
myocardial mass and myofibril dysfunction which leads to
reduced contractility and cardiomyopathy. Clinical heart
failure is the commonest presentation and can occur acutely
or many years following treatment. The most important risk
factor is total cumulative dose, although all dose levels can
cause some degree of myocyte damage [86]. Sorensen et al.
[87] performed a detailed echocardiography study in 98
survivors of WT whose treatment included doxorubicin
(mean total anthracycline dose of 300 mg/m
2
) at a mean
follow-up of 5 years. Subclinical cardiac abnormalities
were found in 25% of the patients either as increased end-
systolic wall stress, a measure of afterload, or decreased
Teaching box: Clinically significant late sequelae include
cardiotoxicity, reproductive problems, renal dysfunction and the
development of benign and malignant second tumours.
12 Pediatr Radiol (2008) 38:217
contractility. By contrast, an analysis of cardiac function by
echocardiogram and ECG in WT patients treated on SIOP
9/GPOH and SIOP 93-01/GPOH with a shorter mean
follow-up of 2.9 years demonstrated abnormalities in only
2.5% of patients [88]. More recent work suggests that the
damage is progressive; therefore there is an increasing
lifelong risk of developing clinical cardiac dysfunction that
could necessitate a cardiac transplant [89]. It is anticipated
that this is not such a problem in survivors receiving a total
dose of <250 mg/m
2
[90, 91]. Recent protocol designs have
attempted to reduce the total anthracycline dose to 250 mg/m
2
.
An additive effect might occur with radiation involving the
heart, as in patients needing lung radiotherapy and those
requiring left flank radiotherapy for upper pole WT. Regular
monitoring with echocardiograms is recommended.
Radiation treatment in young children is particularly
detrimental to growth and development of normal tissues,
and the degree of damage is dependent on total dose, frac-
tionation and field. A classic example is the practice of flank
irradiation in the era before 1960 in which only part of
the vertebral column (up to the midline) was included in the
field, resulting in differential growth of the spine with the
development of severe scoliosis. The treatment of the whole
vertebral body has prevented the severe deformities, but
despite this recent studies have shown occurrence rates of
spinal deformities of between 10% and 70% [9294], the
variability in part resulting from differences in the method
of evaluation (clinical vs. radiological). Most patients are
asymptomatic and require no surgery or bracing.
Fertility and a successful pregnancy outcome are impor-
tant issues for survivors. Unfortunately, gonads are particu-
larly sensitive to radiation. The majority of WTsurvivors are
not at risk, but girls who have abdominal radiation in which
both ovaries or the uterus are within the field are at sig-
nificant risk of poor fertility outcome. Predicting the
outcome is made more complicated by the variable position
of the infantile ovaries and uteri, as they are not necessarily
in a fixed position but generally lie below the pelvic brim
[95]. Reports both in America and the UK have shown a
high incidence of infertility, spontaneous miscarriages and
intrauterine growth retardation, probably due to the radia-
tion damage to the uterine vasculature and ovaries [9698].
US imaging of female WT survivors who received
abdominal radiation has shown small or absent ovaries
within the radiation field and in some patients the uteri are
small despite hormone replacement therapy [99]. Wallace
[96] followed survivors of WT treated from 1940 to 1972.
Only 1 out of 25 females who had received whole abdo-
minal radiation had normal ovarian function, with 20 ex-
periencing primary ovarian failure and 4 developing
premature menopause at younger than 36 years [96].
Hawkins and Smith [97] performed a general practitioners
post-study investigating pregnancy outcome in British
childhood cancer survivors [97]. Patients treated for WT
with abdominal irradiation were compared with patients
who had no abdominal irradiation. The spontaneous
abortion rate was increased in the irradiated group (22%
vs. 6%). Live birth outcome was also affected, with the
birth-weight significantly lower (by a mean of 500 g) com-
pared with the nonirradiated group.
There is a known association between patients with WT
and with genitourinary abnormalities including mullerian
duct anomalies and septated or unicornate uteri [100, 101].
Male fertility is generally not at risk except when alkylating
agents such as cyclophosphamide, ifosfamide and melpha-
lan, to which males are particularly sensitive, are used.
Renal function is a question all families are concerned
about as this tumour arises from the kidney. Unilateral
nephrectomy is usually the surgery of choice, although there
is controversy whether nephron-sparing surgery is an option
[42]. Evidence from a number of long-term studies has
rarely shown renal dysfunction in the majority of unilateral
event-free survivors [85]. A study using the NWTSG
database between 1969 and 1994 identified a cumulative
incidence of end-stage renal failure at 20 years in unilateral
disease to be 0.6% in those with no evidence of WT1
mutation or genitourinary anomalies, but 74% in those with
accompanying Denys-Drash syndrome, 36% in those with
WT-aniridia syndrome (WAGR), and 7% in those males
with cryptorchidism or hypospadias. Among those with
bilateral disease either synchronously or metachronously,
end-stage renal failure occurred in 12%, with a higher
incidence of 90% in patients with WAGR and 20% in males
with associated genitourinary anomalies [102]. Life-long
renal monitoring is a requirement for bilateral and unilateral
tumours in association with abnormalities known to
predispose to renal dysfunction.
The occurrence of second tumours, either benign or
malignant, is a well-recognized late sequela of therapy in
survivors of childhood cancer, and WT survivors are no
exception. The less-serious occurrence of osteochondromas,
benign bone tumours, is associated with radiation of the
epiphysis of growing bone, although, interestingly, these
tumours have been reported in WT patients who have not
been irradiated, and indeed some of these patients have a
family history of multiple exostoses [105, 104]. Patients
exposed to radiotherapy or certain chemotherapy agents or
who have a known familial cancer predisposition syndrome
have all been demonstrated to have an increased risk of
second cancers. The NWTSG in the United States reported
43 second cancers in a population of 5,278 patients diag-
nosed with WT between 1969 and 1991, giving a standard-
ized incidence ratio (SIR) of 8.4 and a cumulative risk within
15 years of diagnosis of 1.6% [105]. A European study of
WT survivors based on 1,988 patients treated on the SIOP
WT trials and studies 1, 2, 5 and 6 describe eight second
Pediatr Radiol (2008) 38:217 13
cancers, giving an SIR of 4.15 and a cumulative risk within
15 years of diagnosis of 0.65% [106]. The types of second
cancers reported vary and include bone and soft-tissue sar-
comas, breast cancer, lymphoma, tumours of the digestive
tract, melanoma and acute leukaemias [105109]. Radiation
therapy used to treat childhood cancer has been consistently
shown to be an important contributory factor in the excess
risk of subsequent cancers observed in long-term survivors
of all childhood cancers [107, 110, 111]. Within a cohort of
WT survivors, Breslow et al. [105] describe 73% of second
solid tumours occurring within the radiotherapy field and
clear evidence of an increase in the risk of second cancer
with increasing dose of radiation. An interaction between
radiotherapy and doxorubicin, a known radiation sensitizer,
has been postulated and suggestive evidence of this
interaction can be found in a number of reports, although
small numbers prevent solid statistical analysis to support
this [105, 109]. In the NWTSG study, among 234 patients
who received doxorubicin and greater than 35 Gy abdom-
inal radiation, 8 second cancers were observed where only
2.22 were expected [105]. The type and distribution of
second cancers following WT would indicate that patients
exposed to radiotherapy during their primary treatment are
at the greatest risk of developing subsequent malignancies.
These patients should be counselled appropriately and of-
fered advice to minimize future carcinogenic risks such as
smoking and sun exposure.
Although there are many potential late effects for WTand
its treatment, it is important to view these within the context
of the wider clinical picture. The treatment of WT has been a
success story and currently in excess of 80% of children
diagnosed with WT can look forward to long-term survivor-
ship, with less than 20% experiencing serious morbidity at
20 years from diagnosis [112]. The late complications are a
consequence of the type and intensity of treatment required,
which in turn reflects the nature and extent of the original
tumour. Continual international trial development and
participation will enable improved matching of treatment
needs with prognosis, thereby reducing long-term complica-
tions in the majority. The advent of molecular markers of
disease severity and improved functional imaging might help.
Long-term follow-up programmes for young adult
survivors of childhood cancer are being developed around
the world and targeted, individual follow-up plans designed
to optimize the patients understanding and knowledge of
the long-term risks in addition to providing specific clinical
surveillance to achieve early diagnosis of late sequelae have
been established [113, 114].
Treatment controversies and concerns
As discussed above, staging methods and treatment regi-
mens vary internationally, though outcomes have been very
similar [115]. Contemporary cure rates exceed 85%. Thus,
current tumour management efforts focus on minimizing
therapy and associated toxicities without compromising
cure rates [116]. Upcoming clinical trials through the COG
will address several issues including how to minimize ra-
diation exposure of children and adolescents and its
associated potential for inciting second malignant neo-
plasms as well as the sensitivity, specificity, and role of
imaging methods particularly for the identification of
pulmonary metastases by chest radiography versus detec-
tion by CT. Other goals include minimizing therapy-related
acute and late toxicities such as anthracycline-related car-
diac dysfunction, radiation-induced pulmonary compro-
mise, chemotherapy-induced nephrotoxicity, radiation
pneumonitis, second malignant neoplasms, orthopaedic
sequelae such as scoliosis and decreased bone mineral
density, and gonadal failure [115, 117119].
References
1. Kim S, Chung DH (2006) Pediatric solid malignancies: neuro-
blastoma and Wilms tumor. Surg Clin North Am 86:469487, xi
2. Breslow N, Olshan A, Beckwith JB et al (1993) Epidemiology of
Wilms tumor. Med Pediatr Oncol 21:172181
3. Gommersall LM, Arya M, Mushtaq I et al (2005) Current
challenges in Wilms tumor management. Nat Clin Pract Oncol
2:298304; quiz 291 p following 324
4. Hartman DJ, MacLennan GT (2005) Wilms tumor. J Urol
173:2147
5. National Cancer Institute (2004) Surveillance Epidemiology and
End Results (SEER) Pediatric Monograph. National Cancer
Institute, Bethesda, MD
6. Coppes MJ, Arnold M, Beckwith JB et al (1999) Factors affecting
the risk of contralateral Wilms tumor development: a report from
the National Wilms Tumor Study Group. Cancer 85:16161625
7. Pritchard-Jones K, Vujanic G (2006) Multiple pathways to Wilms
tumor: how much is genetic? Pediatr Blood Cancer 47:232234
8. de Kraker J, Lemerle J, Voute PA et al (1990) Wilms tumor with
pulmonary metastases at diagnosis: the significance of primary
chemotherapy. International Society of Pediatric Oncology Neph-
roblastoma Trial and Study Committee. J Clin Oncol 8:11871190
9. Beckwith JB (1998) Nephrogenic rests and the pathogenesis of
Wilms tumor: developmental and clinical considerations. Am J
Med Genet 79:268273
10. Qualman SJ, Bowen J, Amin MB et al (2003) Protocol for the
examination of specimens from patients with Wilms tumor
(nephroblastoma) or other renal tumors of childhood. Arch Pathol
Lab Med 127:12801289
11. Bonadio JF, Storer B, Norkool P et al (1985) Anaplastic Wilms
tumor: clinical and pathologic studies. J Clin Oncol 3:513520
12. Weirich A, Leuschner I, Harms D et al (2001) Clinical impact of
histologic subtypes in localized non-anaplastic nephroblastoma
treated according to the trial and study SIOP-9/GPOH. Ann Oncol
12:311319
13. Pritchard-Jones K (1997) Malignant origin of the stromal
component of Wilms tumor. J Natl Cancer Inst 89:10891091
14. Rivera MN, Haber DA (2005) Wilms tumour: connecting
tumorigenesis and organ development in the kidney. Nat Rev
Cancer 5:699712
14 Pediatr Radiol (2008) 38:217
15. Green DM, Beckwith JB, Breslow NE et al (1994) Treatment of
children with stages II to IVanaplastic Wilms tumor: a report fromthe
National Wilms Tumor Study Group. J Clin Oncol 12:21262131
16. Delemarre JF, Sandstedt B, Harms D et al (1996) The new SIOP
(Stockholm) working classification of renal tumours of child-
hood. International Society of Paediatric Oncology. Med Pediatr
Oncol 26:145146
17. Neville HL, Ritchey ML (2000) Wilms tumor. Overview of
National Wilms Tumor Study Group results. Urol Clin North
Am 27:435442
18. Pritchard-Jones K, Kelsey A, Vujanic G et al (2003) Older age is
an adverse prognostic factor in stage I, favorable histology Wilms
tumor treated with vincristine monochemotherapy: a study by the
United Kingdom Childrens Cancer Study Group, Wilms Tumor
Working Group. J Clin Oncol 21:32693275
19. BreslowN, Sharples K, Beckwith JBet al (1991) Prognostic factors
in nonmetastatic, favorable histology Wilms tumor. Results of the
Third National Wilms Tumor Study. Cancer 68:23452353
20. Shamberger RC, Guthrie KA, Ritchey ML et al (1999) Surgery-
related factors and local recurrence of Wilms tumor in National
Wilms Tumor Study 4. Ann Surg 229:292297
21. Wilimas JA, Dome JS, Metzger M (2006) Wilms tumor. www.
oncopedia.org
22. Grundy PE, Telzerow PE, Breslow N et al (1994) Loss of
heterozygosity for chromosomes 16q and 1p in Wilms tumors
predicts an adverse outcome. Cancer Res 54:23312333
23. Grundy RG, Pritchard J, Scambler P et al (1998) Loss of
heterozygosity on chromosome 16 in sporadic Wilms tumour. Br
J Cancer 78:11811187
24. Hing S, Lu YJ, Summersgill B et al (2001) Gain of 1q is
associated with adverse outcome in favorable histology Wilms
tumors. Am J Pathol 158:393398
25. Dome JS, Chung S, Bergemann T et al (1999) High telomerase
reverse transcriptase (hTERT) messenger RNA level correlates
with tumor recurrence in patients with favorable histology Wilms
tumor. Cancer Res 59:43014307
26. Dome JS, Bockhold CA, Li SMet al (2005) High telomerase RNA
expression level is an adverse prognostic factor for favorable-
histology Wilms tumor. J Clin Oncol 23:91389145
27. Grundy P, Green D, Coppes M (2002) Renal tumors. In: Pizzo PA,
Poplack DG (eds) Principles and practice of pediatric oncology.
Lippincott Williams & Wilkins, Philadelphia
28. Tournade MF, Com-Nougue C, de Kraker J et al (2001) Optimal
duration of preoperative therapy in unilateral and nonmetastatic
Wilms tumor in children older than 6 months: results of the
Ninth International Society of Pediatric Oncology Wilms Tumor
Trial and Study. J Clin Oncol 19:488500
29. Graf N, Tournade MF, de Kraker J (2000) The role of
preoperative chemotherapy in the management of Wilms tumor.
The SIOP studies. International Society of Pediatric Oncology.
Urol Clin North Am 27:443454
30. Lemerle J, Voute PA, Tournade MF et al (1976) Preoperative
versus postoperative radiotherapy, single versus multiple courses
of actinomycin D, in the treatment of Wilms tumor. Preliminary
results of a controlled clinical trial conducted by the International
Society of Paediatric Oncology (S.I.O.P.). Cancer 38:647654
31. Lemerle J, Voute PA, Tournade MF et al (1983) Effectiveness of
preoperative chemotherapy in Wilms tumor: results of an
International Society of Paediatric Oncology (SIOP) clinical
trial. J Clin Oncol 1:604609
32. Tournade MF, Com-Nougue C, Voute PA et al (1993) Results of
the Sixth International Society of Pediatric Oncology Wilms
Tumor Trial and Study: a risk-adapted therapeutic approach in
Wilms tumor. J Clin Oncol 11:10141023
33. de Kraker J, Graf N, van Tinteren H et al (2004) Reduction of
postoperative chemotherapy in children with stage I intermedi-
ate-risk and anaplastic Wilms tumour (SIOP 93-01 trial): a
randomised controlled trial. Lancet 364:12291235
34. DAngio GJ, Evans AE, Breslow N et al (1976) The treatment of
Wilms tumor: results of the national Wilms tumor study. Cancer
38:633646
35. DAngio GJ, Evans A, Breslow N et al (1981) The treatment of
Wilms tumor: results of the Second National Wilms Tumor
Study. Cancer 47:23022311
36. DAngio GJ, Breslow N, Beckwith JB et al (1989) Treatment of
Wilms tumor. Results of the Third National Wilms Tumor Study.
Cancer 64:349360
37. Green DM, Breslow NE, Beckwith JB et al (1998) Effect of
duration of treatment on treatment outcome and cost of treatment
for Wilms tumor: a report from the National Wilms Tumor Study
Group. J Clin Oncol 16:37443751
38. Grundy PE, Breslow NE, Li S et al (2005) Loss of heterozygosity
for chromosomes 1p and 16q is an adverse prognostic factor in
favorable-histology Wilms tumor: a report from the National
Wilms Tumor Study Group. J Clin Oncol 23:73127321
39. Dome J, Green D (2005) Treatment of anaplastic Wilms Tumor:
a report from the National Wilms Tumor Study Group (abstract
8508). Proceedings of the 41st ASCO Annual Meeting, 1317
May 2005, Orlando, FL
40. Horwitz JR, Ritchey ML, Moksness J et al (1996) Renal salvage
procedures in patients with synchronous bilateral Wilms tumors:
a report from the National Wilms Tumor Study Group. J Pediatr
Surg 31:10201025
41. Sugawara Y, Zasadny KR, Grossman HB et al (1999) Germ cell
tumor: differentiation of viable tumor, mature teratoma, and necrotic
tissue with FDGPETand kinetic modeling. Radiology 211:249256
42. Ritchey ML (2005) Renal sparing surgery for Wilms tumor. J
Urol 174:11721173
43. Ritchey M (2003) Editorial comment for partial nephrectomy for
unilateral Wilms tumor results of study SIOP93-01/GPOH. J Urol 170
44. Gross R (1953) The surgery of infancy and childhood. WB
Saunders, Philadelphia
45. Kung F, Wi N (1982) Cancer Medicine, 2nd edn. Lea & Febiger,
Philadelphia, pp 21812192
46. de Kraker J, Graf N, van Tinteren H et al (2004) Reduction of
postoperative chemotherapy in children with stage I intermediate-
risk and anaplastic Wilms tumour (SIOP 93-01 trial): a
randomised controlled trial. Lancet 364:12291235
47. Jereb B, Tournade MF, Lemerle J et al (1980) Lymph node
invasion and prognosis in nephroblastoma. Cancer 45:16321636
48. Godzinski J, deKraker J (2004) Is the number of lymph nodes
sampled at Wilms tumor nephrectomy predictive for detection of
the regional extension of the disease? International Society of
Paediatric Oncology, SIOP XXXVI Congress Meeting: Abstracts.
Pediatr Blood Cancer 43(4):329
49. Godzinski J, Heij H (2005) Does the pretreatment tumor rupture
influence the outcome in patients with nephroblastoma? Interna-
tional Society of Paediatric Oncology, SIOP XXXVII Annual
Congress Meeting: Abstracts. Pediatr Blood Cancer 45(4):387
50. Brisse H, Schleiermacher G, Neuenschwander S (2006) Evalua-
tion of 61 nephroblastoma patients with clinical and/or radiolog-
ical signs of tumor rupture: a single institution study. International
Society of Paediatric Oncology, SIOP XXXVIII Congress
Meeting: Contents and Abstracts. Pediatr Blood Cancer 47(4):364
51. Ritchey ML, Green DM, Breslow NB et al (1995) Accuracy of
current imaging modalities in the diagnosis of synchronous
bilateral Wilms tumor. A report from the National Wilms Tumor
Study Group. Cancer 75:600604
52. Ritchey ML, Shamberger RC, Hamilton T et al (2005) Fate of
bilateral renal lesions missed on preoperative imaging: a report
from the National Wilms Tumor Study Group. J Urol 174:1519
1521; discussion 1521
Pediatr Radiol (2008) 38:217 15
53. Ribeiro RC, Schettini ST, Abib Sde C et al (2006) Cavectomy
for the treatment of Wilms tumor with vascular extension. J Urol
176:279283; discussion 283274
54. Shamberger RC, Ritchey ML, Haase GM et al (2001) Intravas-
cular extension of Wilms tumor. Ann Surg 234:116121
55. Godzinski J, Tournade MF, De Kraker J et al (1999) The role of
preoperative chemotherapy in the treatment of nephroblastoma: the
SIOP experience. Societe Internationale dOncologie Pediatrique.
Semin Urol Oncol 17:2832
56. Thompson WR, Newman K, Seibel N et al (1992) A strategy for
resection of Wilms tumor with vena cava or atrial extension. J
Pediatr Surg 27:912915
57. Daum R, Roth H, Zachariou Z (1994) Tumor infiltration of the
vena cava in nephroblastoma. Eur J Pediatr Surg 4:1620
58. Inserra A (2006) Relationship between the Wilms tumour and
the neoplastic thrombosis: does it influence the outcome?
International Society of Paediatric Oncology, SIOP XXXVIII
Congress Meeting: Contents and Abstracts. Pediatr Blood
Cancer 47(4):359
59. Gentil Martins A (1989) Partial nephrectomy for nephroblastoma
a plea for less radical surgery. Med Pediatr Oncol 17:320
60. Hoellwarth M (1999) Partial nephrectomy in patients with
unilateral Wilms tumor. 3rd International Congress of Paediatric
Surgery, 68 May, Brussels
61. Moorman C(1994) Partial nephrectomy in unilateral Wilms tumor
is feasible without local recurrence. Med Pediatr Oncol 23:218
62. Moorman C (1998) Is partial nephrectomy appropriate treatment
for unilateral Wilms tumour? J Pediatr Surg 33:165170
63. de Kraker J (1997) Wilms tumour stage IV: a report from the
SIOP-9 study. Med Pediatr Oncol 29:370
64. Godzinski J (1991) Stage IV nephroblastoma with extrapulmo-
nary metastatic involvement in the SIOP 6 and 9 study. Med
Pediatr Oncol 19:371
65. Cozzi DA, Zani A (2006) Nephron-sparing surgery in children
with primary renal tumor: indications and results. Semin Pediatr
Surg 15:39
66. Godzinski J (2001) Local treatment for extrapulmonary metas-
tases in the SIOP-9 initial stage IV Wilms tumour patients. Med
Pediatr Oncol 37:338
67. Ritchey ML, Kelalis PP, Breslow N et al (1992) Surgical
complications after nephrectomy for Wilms tumor. Surg Gynecol
Obstet 175:507514
68. Godzinski J, Tournade MF, deKraker J et al (1998) Rarity of
surgical complications after postchemotherapy nephrectomy for
nephroblastoma. Experience of the International Society of
Paediatric Oncology-Trial and Study SIOP-9. International
Society of Paediatric Oncology Nephroblastoma Trial and Study
Committee. Eur J Pediatr Surg 8:8386
69. Ritchey M (2003) Surgical complications following nephrecto-
my for Wilms tumor. Med Pediatr Oncol 41:251
70. Mankowski P (2004) Minimal invasive pulmonary metastasec-
tomy in stage IV malignancies in children. International Society
of Paediatric Oncology, SIOP XXXVI Congress Meeting:
Abstracts. Pediatr Blood Cancer 43(4):334
71. Duarte R, Denes F (2005) Further experience with laparoscopic
nephrectomy for Wilms tumour after chemotheraphy. BJU Int
98:155159
72. Shamberger RC, Haase GM, Argani P et al (2006) Bilateral
Wilms tumors with progressive or nonresponsive disease. J
Pediatr Surg 41:652657; discussion 652657
73. Haecker FM, von Schweinitz D, Harms D et al (2003) Partial
nephrectomy for unilateral Wilms tumor: results of study SIOP
93-01/GPOH. J Urol 170:939942; discussion 934943
74. Ritchey ML (1996) Primary nephrectomy for Wilms tumor:
approach of the National Wilms Tumor Study Group. Urology
47:787791
75. Breslow NE, Takashima JR, Ritchey ML et al (2000) Renal
failure in the Denys-Drash and Wilms tumor-aniridia syn-
dromes. Cancer Res 60:40304032
76. Ritchey M (2004) Editorial comment to conservative manage-
ment of hyperplastic and multicentric nephroblastomatosis by
Cozzi F. J Urol 172:10691070
77. Wu HY, Snyder HM 3rd, DAngio GJ (2005) Wilms tumor
management. Curr Opin Urol 15:273276
78. Dome JS, Liu T, Krasin M et al (2002) Improved survival for
patients with recurrent Wilms tumor: the experience at St. Jude
Childrens Research Hospital. J Pediatr Hematol Oncol 24:192198
79. Abu-Ghosh AM, Krailo MD, Goldman SC et al (2002)
Ifosfamide, carboplatin and etoposide in children with poor-risk
relapsed Wilms tumor: a Childrens Cancer Group report. Ann
Oncol 13:460469
80. Pein F, Pinkerton R, Tournade MF et al (1993) Etoposide in
relapsed or refractory Wilms tumor: a phase II study by the
French Society of Pediatric Oncology and the United Kingdom
Childrens Cancer Study Group. J Clin Oncol 11:14781481
81. Campbell AD, Cohn SL, Reynolds M et al (2004) Treatment of
relapsed Wilms tumor with high-dose therapy and autologous
hematopoietic stem-cell rescue: the experience at Childrens
Memorial Hospital. J Clin Oncol 22:28852890
82. Mertens AC, Yasui Y, Neglia JP et al (2001) Late mortality
experience in five-year survivors of childhood and adolescent
cancer: the Childhood Cancer Survivor Study. J Clin Oncol
19:31633172
83. Curry HL, Parkes SE, Powell JE et al (2006) Caring for
survivors of childhood cancers: the size of the problem. Eur J
Cancer 42:501508
84. Pritchard-Jones K, Pritchard J (2004) Success of clinical trials in
childhood Wilms tumour around the world. Lancet 364:1468
1470
85. Bailey S, Roberts A, Brock C et al (2002) Nephrotoxicity in
survivors of Wilms tumours in the North of England. Br J
Cancer 87:10921098
86. Kremer LC, van der Pal HJ, Offringa M et al (2002) Frequency
and risk factors of subclinical cardiotoxicity after anthracycline
therapy in children: a systematic review. Ann Oncol 13:819829
87. Sorensen K, Levitt G, Sebag-Montefiore D et al (1995) Cardiac
function in Wilms tumor survivors. J Clin Oncol 13:15461556
88. Marx M (2002) A multicentre analysis of anthracycline-induced
cardiotoxicity in children following treatment according to the
nephroblastoma studies SIOP 9/GPOH and SIOP 93-01/GPOH.
Med Pediatr Oncol 39:1824
89. Levitt G, Bunch K, Rogers CA et al (1996) Cardiac transplan-
tation in childhood cancer survivors in Great Britain. Eur J
Cancer 32A:826830
90. Sorensen K, Levitt GA, Bull C et al (2003) Late anthracycline
cardiotoxicity after childhood cancer: a prospective longitudinal
study. Cancer 97:19911998
91. Pein F, Sakiroglu O, Dahan M et al (2004) Cardiac abnormalities
15 years and more after adriamycin therapy in 229 childhood
survivors of a solid tumour at the Institut Gustave Roussy. Br J
Cancer 91:3744
92. Shalet SM, Gibson B, Swindell R et al (1987) Effect of spinal
irradiation on growth. Arch Dis Child 62:461464
93. Makiprnaa A (1993) Spinal deformity induced by radiotherapy
for solid tumours in childhood: a long-term study. Eur J Pediatr
Surg 152:197200
94. Wallace WH, Shalet SM, Morris-Jones PH et al (1990) Effect of
abdominal irradiation on growth in boys treated for a Wilms
tumor. Med Pediatr Oncol 18:441446
95. Counsell R, Bain G, Williams MV et al (1996) Artificial
radiation menopause: where are the ovaries? Clin Oncol (R Coll
Radiol) 8:250253
16 Pediatr Radiol (2008) 38:217
96. Wallace WH, Shalet SM, Crowne EC et al (1989) Ovarian failure
following abdominal irradiation in childhood: natural history and
prognosis. Clin Oncol (R Coll Radiol) 1:7579
97. Hawkins MM, Smith RA (1989) Pregnancy outcomes in
childhood cancer survivors: probable effects of abdominal
irradiation. Int J Cancer 43:399402
98. Green DM, Whitton JA, Stovall M et al (2002) Pregnancy
outcome of female survivors of childhood cancer: a report from
the Childhood Cancer Survivor Study. Am J Obstet Gynecol
187:10701080
99. Nussbaum Blask AR, Nicholson HS, Markle BM et al (1999)
Sonographic detection of uterine and ovarian abnormalities in
female survivors of Wilms tumor treated with radiotherapy. Am
J Roentgenol 172:759763
100. Nicholson HS, Blask AN, Markle BM et al (1996) Uterine
anomalies in Wilms tumor survivors. Cancer 78:887891
101. Byrne J, Nicholson HS (2002) Excess risk for Mullerian duct
anomalies in girls with Wilms tumor. Med Pediatr Oncol
38:258259
102. Breslow NE, Collins AJ, Ritchey ML et al (2005) End stage
renal disease in patients with Wilms tumor: results from the
National Wilms Tumor Study Group and the United States Renal
Data System. J Urol 174:19721975
103. Libshitz H, Cohen MA (1982) Radiation-induced osteochondro-
mas. Radiology 142:643647
104. Walker DA, Dillon M, Levitt G et al (1992) Multiple exostosis
(osteochondroma) and Wilms tumour a possible association.
Med Pediatr Oncol 20:360361
105. Breslow NE, Takashima JR, Whitton JA et al (1995) Second
malignant neoplasms following treatment for Wilms tumor: a
report from the National Wilms Tumor Study Group. J Clin
Oncol 13:18511859
106. Carli M, Frascella E, Tournade MF et al (1997) Second
malignant neoplasms in patients treated on SIOP Wilms tumour
studies and trials 1, 2, 5, and 6. Med Pediatr Oncol 29:239244
107. Hawkins MM, Wilson LM, Burton HS et al (1996) Radiother-
apy, alkylating agents, and risk of bone cancer after childhood
cancer. J Natl Cancer Inst 88:270278
108. Garwicz S, Anderson H, Olsen JH et al (2000) Second malignant
neoplasms after cancer in childhood and adolescence: a
population-based case-control study in the 5 Nordic countries.
The Nordic Society for Pediatric Hematology and Oncology. The
Association of the Nordic Cancer Registries. Int J Cancer
88:672678
109. Neglia JP, Friedman DL, Yasui Y et al (2001) Second malignant
neoplasms in five-year survivors of childhood cancer: childhood
cancer survivor study. J Natl Cancer Inst 93:618629
110. Hawkins MM, Draper GJ, Kingston JE (1987) Incidence of
second primary tumours among childhood cancer survivors. Br J
Cancer 56:339347
111. Tucker MA, DAngio GJ, Boice JD Jr. et al (1987) Bone
sarcomas linked to radiotherapy and chemotherapy in children. N
Engl J Med 317:588593
112. Oeffinger KC, Mertens AC, Sklar CA et al (2006) Chronic health
conditions in adult survivors of childhood cancer. N Engl J Med
355:15721582
113. Landier W, Bhatia S, Eshelman DA et al (2004) Development of
risk-based guidelines for pediatric cancer survivors: the Child-
rens Oncology Group Long-Term Follow-Up Guidelines from
the Childrens Oncology Group Late Effects Committee and
Nursing Discipline. J Clin Oncol 22:49794990
114. Landier W, Wallace WH, Hudson MM (2006) Long-term follow-
up of pediatric cancer survivors: education, surveillance, and
screening. Pediatr Blood Cancer 46:149158
115. Ehrlich PF (2001) Wilms tumor: progress to date and future
considerations. Expert Rev Anticancer Ther 1:555564
116. Wilimas JA, Kaste SC, Kauffman WM et al (1997) Use of chest
computed tomography in the staging of pediatric Wilms tumor:
interobserver variability and prognostic significance. J Clin
Oncol 15:26312635
117. Taylor RE (1997) Morbidity from abdominal radiotherapy in the
First United Kingdom Childrens Cancer Study Group Wilms
Tumour Study. United Kingdom Childrens Cancer Study Group.
Clin Oncol (R Coll Radiol) 9:381384
118. Reinhard H, Semler O, Burger D et al (2004) Results of the SIOP
93-01/GPOH trial and study for the treatment of patients with
unilateral nonmetastatic Wilms Tumor. Klin Paediatr 216:132140
119. Green DM, Donckerwolcke R, Evans AE et al (1995) Late
effects of treatment for Wilms tumor. Hematol Oncol Clin North
Am 9:13171327
Pediatr Radiol (2008) 38:217 17