reviews the most frequent renal tumors in children, including
their biologic properties, multidisciplinary therapies, and fu-
CHAPTER 30
Wilms’ Tumor
Peter F. Ehrlich and Robert C. Shamberger
Renal tumors account for 6.3% of cancer diagnoses for chil-
dren younger than 15 years of age, with a reported incidence
of 7.9 per million. Including adolescents younger than
20 years of age, this drops slightly to 4.4% of cancer diagno-
ses, with an incidence of 6.2 per million.1 Renal tumors
include Wilms’ tumor (WT) (also referred to as nephroblas-
toma or renal embryoma), renal cell carcinoma (RCC), clear
cell sarcoma of the kidney (CCSK), rhabdoid tumor of the
kidney (RTK), congenital mesoblastic nephroma, cystic renal
tumor, and angiomyolipoma.2,3 WT is by far the most com-
mon, accounting for approximately 91% of all renal tumors in
childhood. CCSK and RTK were originally considered sub-
types of WT, but are now recognized as separate tumors.
RCC comprises 5.9% of renal malignancies in children and
adolescents.1,4
The treatment strategy for children with renal tumors
evolved in conjunction with the definition of these pathologic
subtypes. Treatment is based on traditional risk factors, stage
and histology, and, more recently, on genetic markers. The
goal of “risk-based management” is to maintain excellent out-
comes but at the same time spare children with low-risk tu-
mors intensive chemotherapy and radiation, with their
long-term side-effects, and to intensify therapy for children
with high-risk tumors in an effort to increase their survival.
Despite these advances, children with rhabdoid, renal cell car-
cinoma, and anaplastic tumors still do poorly. This chapter
ture challenges.
Wilms’ Tumor
------------------------------------------------------------------------------------------------------------------------------------------------
WT is the most common primary malignant renal tumor
of childhood and comprises 6% of all pediatric tumors.5,6
Outcomes for children with WT improved dramatically over
the last 50 years, with long-term survival in both North
American and European trials approaching 85% (Fig. 30-1).
Survival rates for many of the low-stage tumors are 95% to
99%.7,8 Current treatment protocols for children with WT
were developed through a series of multidisciplinary cooper-
ative group trials in both North America and Europe by the
Children’s Oncology Group (COG), formerly the National
Wilms’ Tumor Study Group (NWTSG), and the Société Inter-
nationale d’Oncologie Pédiatrique (SIOP). Their series of
well-designed prospective randomized studies provide a large
body of evidence-based knowledge to establish the optimal
surgical, radiotherapy, and chemotherapy treatments for tu-
mors based on the early studies on stage and histology and,
more recently, also on cytogenetic and response-based factors.
There are differences between the approaches of these two
groups that affect staging and risk classification that are critical
to understand when considering outcomes that will be dis-
cussed later in the chapter (Table 30-1).
History
------------------------------------------------------------------------------------------------------------------------------------------------
WT is named after Carl Max Wilhelm Wilms, a German pa-
thologist and surgeon. He was one of the first to propose that
tumor cells originate during the development of the embryo.
He published his findings in 1897 and 1899 in an influential
monograph titled “Die Mischgeschwülste der Niere,” which
described seven children with nephroblastoma as part of a
monograph on “mixed tumors.”9,10 Although reports of suc-
cessful excision of renal tumors in children appeared in the
end of the 19th century, his name has been indelibly applied
to them. Dr. Thomas Jessop (1837 to 1903), probably per-
formed the first successful nephrectomy at the General Infir-
mary in Leeds, England, on June 7, 1877, on a 2-year-old child
with hematuria and a tumor of the kidney.11,12
At the beginning of the 20th century, survival for a child
with WT was 5%. Surgery was the first effective treatment
for nephroblastoma and continues to be a critical component
of successful multimodality therapy. Although surgery at that
time was the only option for cure, it carried a significant op-
erative mortality. In 1916, radiation therapy was added by
Friedlander.13 In the late 1930s, Ladd described removing
renal tumors in selected children. His technique included a
large transverse transabdominal approach with early ligation
of the renal vessels and removal of the surrounding Gerota
fat and fascia. This modification improved the outcome in
children with nonmetastatic nephroblastoma to a 32.2% sur-
vival at 3 years, with an operative mortality reduced from 23%
to 7%. The basic tenets of this operative procedure described
by Ladd are used today, with the exception of early ligation of
the renal vessels.12–15
423
424 PART III MAJOR TUMORS OF CHILDHOOD

5-YEAR WT SURVIVAL with congenital syndromes associated with WT, such as Beck-
100
with-Wiedemann, have a higher risk of developing BWT.
87 92 92 92
90 Congenital anomalies, either isolated or as part of a con-
80 73
70 60
genital syndrome, occur in about 10% of children with
WT.20 WAGR syndrome (WT, aniridia, genitourinary malfor-
Percent

60
50 47 WT
40 mation, mental retardation) is a rare genetic syndrome associ-
30
20
20 ated with a chromosomal defect in 11p13. Children with
10 5 WAGR syndrome are at a 30% higher risk of developing
0
1899 1938 1954 1960 1975 1981 1987 1995 2003
WT than a normal child. Because of the presence of aniridia,
Year most children with WAGR syndrome are diagnosed at birth.
FIGURE 30-1 This graph shows the improved survival of children with Children with WAGR account for about 0.75% of all children
Wilms’ tumor (WT) over time. with WT.21
Beckwith-Wiedemann syndrome (BWS) is a congenital dis-
order of growth regulation, affecting 1 in 14,000 children.
Epidemiology Children with BWS have visceromegaly, macroglossia,
------------------------------------------------------------------------------------------------------------------------------------------------
omphalocele, and hyperinsulinemic hypoglycemia at birth.
In the United States, there are 500 to 550 cases of WT per year. They also have an increased risk of tumor development.
It is the second most common malignant abdominal tumor in The risk is greatest in the first decade of life and thereafter ap-
childhood after neuroblastoma. The risk of developing WT in proaches that of the general population. Three large studies
the general population is 1:10,000.16 The incidence is slightly of children with BWS reported tumor frequencies of 7.1%
elevated for American and African blacks compared with (13/183), 7.5% (29/388), and 14% (22/159).22–25 The most
whites and is significantly lower in Asians. The mean age at frequently observed tumors in BWS are WT and hepatoblas-
diagnosis is 36 months, with most children presenting be- toma, which comprise 43% and 12% of reported cancers, re-
tween the ages of 12 and 48 months. Tumors tend to occur spectively.22,26 Denys-Drash syndrome (DDS) (nephropathy,
about 6 months later in girls than in boys. WT is rare at greater renal failure, male pseudohermaphroditism, and WT) is also
than 10 years and at less than 6 months of age. Tumors can be associated with an increased risk of WT. Some investigators
unilateral or bilateral (Figs. 30-2 and 30-3). Bilateral Wilms’ have recommended prophylactic nephrectomy in children
tumors (BWT) occur in 4% to 13% of patients.5,17–19 Children with this syndrome once they develop renal failure.27,28 Other

TABLE 30-1
Children’s Oncology Group (COG) and Société Internationale d’Oncologie Pédiatrique (SIOP) Staging Systems
COG Wilms’ Tumor Staging

Stage Criteria
I The tumor is limited to the kidney and has been completely resected.
The tumor was not ruptured or biopsied prior to removal.
There is no penetration of the renal capsule or involvement of renal sinus vessels.
II The tumor extends beyond the capsule of the kidney but was completely resected with no evidence of tumor at or beyond the margins
of resection.
There is penetration of the renal capsule or invasion of the renal sinus vessels.
III Gross or microscopic residual tumor remains postoperatively, including inoperable tumor, positive surgical margins, tumor spillage surfaces,
regional lymph node metastases, positive peritoneal cytology, or transected tumor thrombus.
The tumor was ruptured or biopsied prior to removal.
IV Hematogenous metastases or lymph node metastases outside the abdomen (e.g., lung, liver, bone, brain).
V Bilateral renal involvement is present at diagnosis, and each side may be considered to have a stage.
SIOP Staging
Stage Criteria
I The tumor 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 tumor, but it does not reach the outer surface, and it is completely resected. The tumor may be
protruding (bulging) into the pelvic system and dipping into the ureter, but it is not infiltrating the walls. The vessels of the renal sinus are not
involved. Intrarenal vessels may be involved.
II The tumor extends beyond the kidney or penetrates through the renal capsule and/or fibrous pseudocapsule into the perirenal fat, but it
is completely resected. The tumor infiltrates the renal sinus and/or invades blood and lymphatic vessels outside the renal parenchyma, but
it is completely resected. The tumor infiltrates adjacent organs or vena cava, but it is completely resected. The tumor has been surgically
biopsied (wedge biopsy) prior to preoperative chemotherapy or surgery.
III There is incomplete excision of the tumor, which extends beyond resection margins (gross or microscopic tumor remains postoperatively).
Any positive lymph nodes are involved. Tumor ruptures before or during surgery (irrespective of other criteria for staging). The tumor has
penetrated the peritoneal surface. Tumor implants are found on the peritoneal surface. The tumor thrombi present at resection, margins of
vessels or ureter are transected or removed piecemeal by surgeon.
IV Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases are outside the abdominopelvic region.
V Bilateral renal tumors present at diagnosis. Each side has to be substaged according to above classifications.
 CHAPTER 30 WILMS’ TUMOR 425

are several candidate genes that are been investigated and eval-
uated or are being evaluated in the clinical setting. These are
described later.

LOSS OF HETEROZYGOSITY
AND DNA PLOIDY
Loss of heterozygosity (LOH) refers to loss of genetic material
and allelic uniqueness. LOH was found initially in children
with WT on chromosomes 11p (33% of tumors), 16q
(20%), and 1p (11%). A major aim of the fifth National Wilms’
Tumor Study (NWTS-5) was to determine if tumor-specific
LOH for chromosomes 11p, 1p, or 16q was associated with
an adverse prognosis for children with favorable-histology
(FH) WT, a finding suggested in earlier retrospective stud-
ies.34 Chromosomes 11p, 16q, and 1p were prospectively
evaluated. Results demonstrated that outcomes for patients
with LOH at 1p and 16q were at least 10% worse than those
without LOH (Figs. 30-4 and 30-5). These findings are used
as determinants of therapy on the current renal tumor studies
of the COG.
A similar but smaller study was reported from the United
Kingdom (United Kingdom Children Cancer Study Group
FIGURE 30-2 A computed tomography (CT) scan of a unilateral Wilms’ Wilms Tumor trials 1 to 3) in which a comparable incidence
tumor. of LOH for 16q (14%) and 1p (10%) was found, but in this
study there was no association between poor outcomes and
LOH at 1p.42 The reasons for the different results are unclear;
possible explanations include a smaller sample size of the
syndromes associated with WT include hemihypertrophy British study or that the larger doses of doxorubicin used in
and Perlman syndrome. Urologic abnormalities, such as hypo- the U.K. studies served to eliminate part of the adverse impact
spadias, cryptorchidism, and nephromegaly, are also associ- on prognosis.
ated with WT. Analyses from patients with WT have also identified recur-
rent deletions and translocations involving the short arm of
chromosome 7.43,48,55 Studies suggest a locus of interest
Molecular Biology and Genetics between 7p13 and 7p21, perhaps the POU6F2 gene at
------------------------------------------------------------------------------------------------------------------------------------------------
7p14.57–59 Clinical correlates of 7p LOH have not been pub-
A number of important advances in WT development have oc- lished, and so the exact prognostic role of this possible Wilms’
curred since the early 1990s. A detailed description is beyond locus, if any, has yet to be determined.
the scope of this chapter. Table 30-2 summarizes some of the Another aim of NWTS-5 was to determine whether DNA
key genes and more detailed references are cited.29–56 There ploidy status is associated with worse outcome in children

FIGURE 30-3 Two computed tomography (CT) scans of bilateral Wilms’ tumor at presentation and after 6 weeks of chemotherapy.
426 PART III MAJOR TUMORS OF CHILDHOOD

TABLE 30-2
Summary of Current Genes Being Investigated in Wilms’ Tumor
Gene(s) Location Function Clinical Relevance
WT1 11.13 Tumor Supressor Functions in normal kidney development WAGR syndrome Deletions
Denys-Drash point mutation
WT2 11p15.5 Several gene loci IGF-2 BWS syndrome Genomic
Cell growth and encodes an embryonal growth factor that is imprinting
highly expressed in fetal kidney and WT
Genomic imprinting
Cadherin-associated 3p21 Cellular adhesion protein that also associates with members Highly correlated with WT1
protein b1 gene4 of the T-cell factor (TCF) family of transcription factors to genes
promote expression of growth-related genes such as c-MYC
and CYCLIN D1
WTX Xq11.1 WTX inhibits the Wnt signal transduction to promote Unknown
post-translational modification and degradation
Familial Wilms’ genes 17q and 19q13.3-q13.4 Unknown Unknown

BWS, Beckwith-Wiedemann syndrome; IGF, insulin growth factor; WAGR, Wilms’ tumor, aniridia, genitourinary malformation, mental retardation.

1.0 1.0
Proportion relapse free

0.9 Proportion relapse free 0.9

0.8 0.8

0.7 No LOH 0.7 No LOH

LOH 1p only LOH 1p only
LOH 16q only LOH 16q only
LOH both loci LOH both loci
0.6 0.6
0 1 2 3 4 0 1 2 3 4
Time since diagnosis (years) Time since diagnosis (years)
FIGURE 30-4 Relapse-free survival by joint loss of heterozygosity (LOH) FIGURE 30-5 Relapse-free survival by joint loss of heterozygosity (LOH)
at chromosomes 1p and 16q for stage I/II favorable-histology Wilms’ tumor at chromosomes 1p and 16q for stage III/IV favorable-histology Wilms’
patients. (From Grundy PE, Breslow N, Li S, et al: Loss of heterozygosity tumor patients. (From Grundy PE, Breslow N, Li S, et al: Loss of heterozy-
for chromosomes 1p and 16q is an adverse prognostic factor in favorable- gosity for chromosomes 1p and 16q is an adverse prognostic factor in
histology Wilms tumor: A report from the National Wilms Tumor Study favorable-histology Wilms tumor: A report from the National Wilms Tumor
Group. J Clin Oncol 2005;23:7312-7321.) Study Group. J Clin Oncol 2005;23:7312-7321.)

with favorable-histology DNA index as a prognostic marker:
DNA index greater than 1.5 was strongly associated with an-
aplastic histology and predictive of poor outcome. However,
DNA content was not predictive of outcome when stratified
by stage and histology.60
anaplastic WT have TP53 mutations. In the current COG
study, one of the aims of the high-risk protocol is to study
the incidence and association of TP53 mutations.
Clinical Presentation
------------------------------------------------------------------------------------------------------------------------------------------------

TP53 GENE
The TP53 gene is located on chromosome 17. The Tp53 pro-
tein is a negative regulator of cell proliferation and a positive
regulator of apoptosis in response to DNA damaging agents.
TP53 is the most common mutated gene associated with
human cancer. Li-Fraumeni syndrome is a multicancer predis-
position syndrome that has constitutional TP53 mutations.61
However, WT rarely develops in Li-Fraumeni syndrome,
and the majority of WT develop in the presence of wild-type
TP53.62 TP53 mutations in WT are almost exclusively found in
tumors with anaplastic histology. Seventy-five percent of
Most children with WT present with an asymptomatic abdom-
inal mass, often discovered by either a parent or pediatrician.
Nonpalpable tumors are typically discovered by ultrasonogra-
phy during evaluation for abdominal pain. Gross hematuria
has been reported in 18.2% of patients and microscopic
hematuria in 24.4%. Ten percent of children with WT have
coagulopathy, and 20% to 25% present with hypertension
because of activation of the renin-angiotensin system.63 Fever,
anorexia, and weight loss occur in 10%. Extension of tumor
thrombus into the renal vein can obstruct the spermatic vein
and result in a left varicocele and, in rare cases, tumor
 CHAPTER 30 WILMS’ TUMOR 427

extension into the atrium may produce cardiac malfunction. modality to screen for WT. It is widely available, noninvasive,
Tumor rupture and hemorrhage are also infrequent events that does not involve radiation exposure, and generally does not
can present as an acute abdomen. require use of sedation. It is recommended that children be
The differential diagnosis for an abdominal mass includes scanned every 3 to 4 months. Debaun and colleagues assessed
neuroblastoma, hepatoblastoma, rhabdomyosarcoma, and the cost effectiveness of screening for WT and hepatoblastoma
lymphoma. Neuroblastoma is the most common solid abdom- in children with Beckwith-Wiedemann syndrome (BWS).70 In
inal tumor in children. One clinical observation to help distin- this analysis, screening a child with BWS from birth until
guish between WT and neuroblastoma is that children with 4 years of age resulted in a cost per life-year saved of
neuroblastoma are often ill because of extensive metastatic $9,642, while continuing until 7 years of age resulted in a cost
disease at presentation. In contrast, children with WT are per life-year saved of $14,740, although it is not truly estab-
generally healthy toddlers with a palpable abdominal mass. lished that the rate of cure or event-free survival (EFS) is
higher based on this early monitoring protocol. Three retro-
spective studies have evaluated screening in children at risk
Diagnosis for WT. One study from the United Kingdom of 41 children
------------------------------------------------------------------------------------------------------------------------------------------------
with WT and aniridia, BWS, or IHH showed no difference
After an abdominal mass is identified, radiographic imaging is in outcome or stage distribution between screened and
performed to determine the anatomic location and extent of unscreened populations.71 In a second study of BWS/IHH,
the mass. Ultrasonography (US) is a good screening examina- Choyke and colleagues demonstrated that evaluation by US
tion of a mass to determine its site of origin and to assess for every 3 months until age 8 years in 12 children with BWS
possible intravascular or ureteral extension. About 4% of WT lowered the proportion of patients with late-stage tumors to
present with inferior vena cava (IVC) or atrial involvement and 0%, which was significantly reduced compared with the
11% with renal vein involvement.5,6 Embolization of a caval 42% incidence of late-stage tumors in 59 unscreened patients
thrombus to the pulmonary artery can be lethal, and the pres- with BWS/IHH.72 A third study analyzed the impact of sur-
ence of a thrombus must be identified preoperatively to pre- veillance in children with aniridia, BWS, and IHH who had
vent this occurrence. US is a sensitive technique to identify developed WT.73 There was a higher proportion of stage I
vascular extension.64,65 A computed tomography (CT) scan tumors identified in children who underwent routine screening
of the abdomen will confirm the renal origin of the mass than in those who did not. Although ultrasonography is easy,
and determine whether there are bilateral tumors. Early gen- false-positive results have been reported and have led to unnec-
erations of CT scans missed 7% to 10% of bilateral lesions. essary investigations and surgery in patients who had benign
Hence, contralateral exploration of the kidney was recom- lesions, such as cysts, nephrogenic rests, or foci of renal dyspla-
mended in NWTSG protocols to assess for bilateral lesions.66 sia, supporting the use of either MRI or CT to further define
A recent review of children with bilateral WT, however, dem- the lesions before surgical intervention.72–74 The U.K. Wilms’
onstrated that only 0.25% of bilateral tumors were missed Tumor Surveillance Working Group suggests that surveillance
with modern helical CT scans, all of which were small.67 Based should be offered to children who are at a greater than 5%
on these results, bilateral exploration is not recommended in risk of WT.75
current protocols from the COG. Although magnetic reso- Children with Perlman syndrome are at a significantly
nance imaging (MRI) avoids radiation exposure, it has not increased risk of WT; therefore surveillance specifically for
been shown to be superior to CT scanning in standard assess- WT is warranted. Based on a review by Tan and colleagues,
ments. MRI is currently being evaluated as a method to help there is currently insufficient evidence to justify tumor sur-
distinguish nephrogenic rests from WT and may be the pre- veillance in Sotos, Weaver, Proteus, and Bannayan-Riley
ferred method to follow children with bilateral WT after Ruvalcaba syndromes or the syndrome of macrocephaly-cutis
resection. marmorata telangiectatica congenita. Of interest, children
The common sites of metastatic spread are the lungs and with Klippel-Trenaunay syndrome (KTS) had been considered
the liver. Therefore, in addition to abdominal imaging, pulmo- to be at increased risk for developing WT. In a 2004 study
nary imaging must be performed. In NWTS-4 and NWTS-5, by Fishman and colleagues, the risk of developing WT in
13% of patients (575 of 4,006) with unilateral favorable- children was assessed using the NWTSG database.76 The risk
histology tumors presented with pulmonary disease. Initially of WT in children with KTS was no different than in the
this was routinely evaluated based upon a chest radiograph. general population, and thus routine ultrasonography surveil-
In current protocols, it is based upon CT scans. lance is not recommended.
18
F-fluorodeoxyglucose positron emission tomography
(FDG PET) has not been fully delineated in pediatric can-
cers.65 It is recognized that FDG PET has an established
role in Hodgkin lymphoma and increasingly in sarcomas in Pathology
children, but its role in WT is unclear.68,69 ------------------------------------------------------------------------------------------------------------------------------------------------

Tumor histology is a major determinant of therapeutic strati-

fication for children with WT. The diagnostic classification of
Screening pediatric renal tumors has benefited from central review of tu-
------------------------------------------------------------------------------------------------------------------------------------------------
mors from patients treated in the cooperative group trials.77
Screening is reserved for children at risk for developing WT. This success has enabled the introduction of disease-specific
This includes children with genetic syndromes such as BWS, and risk-based therapy. For example, clear cell sarcoma of
idiopathic hemihypertrophy (IHH), WAGR, DDS, and Perl- the kidney (CCSK) and malignant rhabdoid tumor (MRT)
man syndrome. Renal ultrasound examination is the preferred were initially considered to be variants of WT and were
428 PART III MAJOR TUMORS OF CHILDHOOD
managed with chemotherapeutic agents for WT, but they are
now considered distinct entities with separate therapies.
WT are embryonal tumors containing components seen in
normal developing kidneys. The classic WT consists of three
elements: blastemal, stromal, and epithelial tubules. Tumors
contain various proportions of each of these elements. Tripha-
sic patterns containing blastemal, stromal, and epithelial cell
types are the most characteristic, but biphasic and monopha-
sic lesions occur.78 Less frequently, abnormal mucinous or
squamous epithelium, skeletal muscle, cartilage, osteoid, or
fat are found in WT.79
When the tumors are monophasic, they can be very inva-
sive and difficult to distinguish from other childhood tumors,
such as primitive neuroectodermal tumor, neuroblastoma,
and lymphoma. Monophasic undifferentiated stromal WT
look like sarcomas, such as clear cell sarcoma of the kidney,
congenital mesoblastic nephroma, or synovial sarcoma. Other
WT may have differing amounts of skeletal-muscle differenti-
ation, from well-differentiated (rhabdomyomatous) to poorly
differentiated (rhabdomyoblastic) skeletal muscle. A WT that
is entirely tubular and papillary can be difficult to distinguish
from papillary renal cell carcinoma.79
WT are divided into two groups: those with “favorable”
histology and those with “unfavorable” histology. Favorable-
histology tumors comprise 90% of the unilateral and bilateral
tumors.
Anaplastic histology is considered unfavorable histology
along with the CCSK and rhabdoid tumors. Unfavorable his-
tology is found in about 10% of childhood renal tumors. It is
rare in the first 2 years of life (2%), then increases in patients
older than 5 years to 13%. It is also more frequent in nonwhite
(African-American and Latino populations) than in white
patients.80 In a report by Bonadio and colleagues, 30.1% of
anaplastic tumors occurred in the nonwhite population. In
a multivariate analysis, older age, being nonwhite, and lymph
node positivity were the significant predictors of anaplastic
WT histology. Finally, anaplasia has been strongly associated
with the presence of TP53 mutations.81
Different treatment protocols for children with anaplastic
versus favorable-histology tumors were first used in NWTS-3.
Anaplasia is defined by multipolar polyploid mitotic figures,
marked nuclear enlargement (giant nuclei with diameters at
least 3 times those of adjacent cells), and hyperchromasia.82
Focal anaplasia is defined as the presence of one or a few
sharply localized regions of anaplasia within a primary
tumor, the majority of which contain no nuclear atypia. The
cells must not be present in any sites outside of the kidney. Tu-
mors with diffuse anaplasia must have at least one of the follow-
ing four criteria. Anaplastic cells outside of the kidney, presence
of anaplasia in a random kidney biopsy, anaplasia in more
than one region of the kidney, and anaplasia in one region,
with extreme nuclear pleomorphism in another site. The
difference between focal and diffuse anaplasia has been
demonstrated to have prognostic significance.83 Anaplasia is
a marker of resistance to therapy, not of tumor aggressive-
ness.78,82,84 Although associations between histologic features
and prognosis or responsiveness to therapy have been sug-
gested, with the exception of anaplasia (unfavorable histology),
none of these features have reached statistical significance
and therefore have not been used to determine therapy.78,84
The classic WT is triphasic, but some tumors can have
dominant blastemal, stromal, and epithelial elements. Stromal
dominant tumors are associated with intralobar nephrogenic
rests, and epithelial dominant tumors have been associated
with perilobar nephrogenic rests.
PRETREATED TUMORS AND PATHOLOGY
Tumors that have been treated with chemotherapy before re-
section differ in their histopathologic findings from tumors
resected primarily. In the SIOP-9 study, the most common
subtype of tumors resected without neoadjuvant chemother-
apy was triphasic mixed histology (45.1%), followed by blas-
temal (39.4%) and epithelial dominant (15.5%), whereas in
tumors that received preoperative chemotherapy, the most
common histology was regressive (37.6%), followed by mixed
(29.4%), stromal (14%), blastemal (9.3%), and epithelial
predominant (3.1%); 6.6% of tumors were completely ne-
crotic.85,86 The SIOP risk classification uses these histologic
findings as prognostic indicators to determine further thera-
pies (Table 30-3). In addition, chemotherapy may produce
tumor differentiation.82,86,87 Anderson evaluated the histo-
logic changes in tumors from 15 BWT patients that did not
decrease in size radiographically following chemotherapy.88
One had complete necrosis, 4 had rhabdomyomatous dif-
ferentiation, and 10 had mature stromal differentiation.
Despite their absence of regression in size, these patients
had favorable outcomes, especially if there was rhabdomyo-
matous differentiation.
In SIOP-9, 10% of patients had postchemotherapy tumors
that were completely necrotic. These patients had excellent out-
comes. The SIOP-9 study also demonstrated that preoperative
chemotherapy extensively ablates the blastemal component of
WT.87,89,90 The frequency of tumors with dominant blastemal
components was markedly reduced (to 7.7%) by preoperative
treatment compared with the no-treatment group (36%). Fur-
thermore, this response is clearly an important prognostic
factor. If predominant blastemal elements persist after initial
therapy, the tumors were found to be highly aggressive. In
SIOP-9, 5 of 16 (31%) of the postchemotherapy blastemal pre-
dominant tumors recurred, compared with none of the tumors
that were predominantly epithelial or stromal after chemother-
apy. Prior SIOP studies have also shown the prognosis for the
purely blastemal group (after preoperative chemotherapy) to
be inferior to that for the epithelial and stromal dominant
tumors.
TABLE 30-3
Revised International Société Internationale d’Oncologie
Pédiatrique Working Classification of Renal Tumors
of Childhood (2001)
Stage Risk Histology
I Low Mesoblastic nephroma
Cystic partially differentiated
nephroblastoma
II Intermediate Nephroblastoma epithelial type
Nephroblastoma stromal type
Nephroblastoma mixed type
Nephroblastoma regressive type
Nephroblastoma focal anaplasia type
III High Nephroblastoma blastemal type
Nephroblastoma diffuse anaplasia type
Clear cell sarcoma of the kidney
Rhabdoid tumor of the kidney

In the SIOP studies, postchemotherapy risk stratification
and stage are used to determine additional therapy after resec-
tion. This categorization is different than the risk stratification
used for tumors resected primarily in North America. Low-risk
tumors are those that are completely necrotic following preop-
erative chemotherapy. Intermediate-risk tumors include all his-
tologies other than completely necrotic, rhabdoid, anaplastic,
or blastemal (less than 66%) dominant. High-risk tumors are
those with diffuse anaplasia, rhabdoid, and blastemal domi-
nance (greater than 66%) after chemotherapy (see Table 30-3).
NEPHROGENIC RESTS AND
NEPHROBLASTOMATOSIS
Nephrogenesis in the normal kidney is usually complete by 34
to 36 weeks’ gestation. Nephrogenic rests (NR) are “areas of
metanephric (embryonal tissue) persisting after the 36th week
of life.” The presence of multiple or diffuse nephrogenic rests
is termed nephroblastomatosis.91 Diffuse hyperplastic perilo-
bar nephrogenic rests (DHPLNR) represent a unique category
of nephroblastomatosis in which the rests form a thick rind
around the kidney. The rests that cause the greatest diagnostic
challenge are those that are actively proliferating or hyperplas-
tic, and can be mistaken for WT. Hyperplastic NR can produce
masses as large as conventional WT. Complicating things fur-
ther is the fact that neoplastic induction of NR can occur. The
diagnosis of DHPLNR is often made based on radiographs
(Fig. 30-6). Histologically, a rest consists of predominantly
small clusters of blastemal cells, but tubules and stromal com-
ponents can be present. NRs are classified by their growth
phase and location: perilobar or intralobar. Perilobar nephro-
genic rests are limited to the periphery (subcapsular) of the
lobes, while intralobar rests occur within the renal lobes
and have an irregular margin. The growth phase of a rest is
divided into (1) incipient or dormant nephrogenic rests that
show few well-formed tubular structures but no evidence of
proliferation and no mitoses, (2) hyperplastic nephrogenic
rests that are composed of epithelial elements with nodular ex-
pansive growth, and (3) sclerosing rests that consist of stromal
and epithelial elements with few blastemal nephrogenic ele-
ments (Fig. 30-7).
FIGURE 30-6 Computed tomography (CT) scans showing diffuse hyper-
plastic perilobar nephrogenic rests.
CHAPTER 30 WILMS’ TUMOR 429
NRs are considered precursor lesions to WT; however, only
a small number develop clonal transformation into a WT. A
child with a WT and NRs in the resected specimen is at in-
creased risk of developing a metachronous tumor in the other
kidney.92 For a child less than 1 year of age, this risk is very sig-
nificant, and these children need to be followed very carefully
with sequential US examinations. A patient who has a unilateral
tumor and a presumed nephrogenic rest is thought to be at in-
creased risk of developing a metachronous tumor, but data to
support that assumption does not exist. The prevalence of NRs
in unilateral WT has been reported to be 28% to 41% in
unilateral WT and close to 100% in bilateral WT.93 Pathologic
distinction between NR and WT can be very difficult. To make
the diagnosis, it is critical to examine the juncture between the
lesion and the surrounding renal parenchyma to distinguish
between the two entities. Most hyperplastic NRs lack a pseudo-
capsule at the periphery, while most WTwill have this feature.
An incisional biopsy is of limited value, because it is uncom-
mon for it to contain the interface between the lesion and the
adjacent kidney. This is particularly true for patients with
DHPLNR. In a study by Perlman and colleagues, pathology
alone was insufficient to establish the diagnosis of DHPLNR
in 21 of 33 cases that underwent biopsy at the time of initial
diagnosis.94 In addition, because rests are found within and
adjacent to WT, a biopsy may result in the inadvertent patho-
logic diagnosis of WT. Alternatively, a small WT may be present
within a large field of nephroblastomatosis, obscuring it for bi-
opsy. Taken together, in these situations where a renal mass
could be a tumor or a rest where a biopsy is performed, Perlman
and colleagues suggest using the term “nephrogenic process,
consistent with a WT or a nephrogenic rest.”
Staging
------------------------------------------------------------------------------------------------------------------------------------------------
The COG/NWTS and SIOP staging systems are fundamentally
different. In COG/NWTS protocols, initial surgical resection is
recommended in most cases. Thus for unilateral tumors, the
pathology of the tumor is established prior to administration
of chemotherapy or radiotherapy. In contrast, SIOP protocols
generally recommend chemotherapy followed by nephrec-
tomy, and surgicopathologic staging is assessed at that time.
The COG/NWTS staging system has evolved as features as-
sociated with prognosis have been defined. A very important
concept for this staging system is that there is a local stage and
a disease stage. Local staging refers to the abdominal disease
Hyperplastic
Wilms’
tumor
Incipient
or dormant
Regressing
Obsolete
FIGURE 30-7 Cartoon of growth phases and classification of nephrogenic
rests.
430 PART III MAJOR TUMORS OF CHILDHOOD

only, whereas disease stage considers both the local and dis- and fascia to remove potential sites of lymphatic spread and
tant hematogenous metastatic disease. Both factors determine early control of the renal vessels.12,100 Lymph node sampling
therapy; the use of local radiation therapy to the tumor bed is is now established as crucial for accurate staging.101 Under-
based on the local stage, and the use of additional chemother- staging the extent of the tumor can increase a child’s risk of
apy is based on both stage III local disease or distant metasta- relapse, and overstaging will result in increasing the intensity
sis.95 The current COG and SIOP staging systems are shown in of chemotherapy or radiation. A transverse transabdominal or
Table 30-1. thoracoabdominal incision provide the best exposure
and are associated with fewer complications than a flank
incision.98,102–104 The thoracoabdominal incision is best for
Treatment
------------------------------------------------------------------------------------------------------------------------------------------------
large tumors, to optimize visualization of the plane between
the tumor and the diaphragm to avoid rupture from excessive
The successful treatment for children with WT has been the traction on the tumor. Intraoperative events that negatively
direct result of prior multidisciplinary studies from coopera- affect patient survival include tumor spill and inadequate
tive group trials, including the NWTSG, SIOP, and the United staging.97–99
Kingdom Children’s Cancer Study Group (UKCCSG), that Early examination for involvement of the liver, renal vein,
have defined the key components to therapy. These trials have or IVC or peritoneal surfaces is important, as is identification
identified several prognostic factors used for risk stratification of preoperative rupture of the tumor. Routine exploration of
in current protocols, including biologic markers. This section the contralateral kidney for bilateral disease was mandated
will review these prognostic factors, operative therapy, chemo- in NWTS-1 to NWTS-5. In 1995, Ritchey and colleagues
therapy, and radiotherapy (with a focus on COG studies). reviewed the accuracy of imaging in assessing bilateral disease
from NWTS-4 (1986 to 1994). He found that bilateral tumors
PROGNOSTIC FACTORS were missed in 7% of children by using the preoperative im-
aging studies. Thus, for NWTS-5, routine contralateral explo-
The current prognostic factors used in COG trials are histol- ration was mandated. In 2005, Ritchey and colleagues did a
ogy, stage, age, tumor weight, response to therapy, and loss of follow-up study to look at what happened in those patients
heterozygosity at 1p and 16q. The two most important con- whose lesions were missed by imaging on NWTS-4. The size
tinue to be the histology and the stage of the tumor.7,8,96 of the missed lesions was less than 1 cm in six patients and 1 to
Histology: The details and prognostic significance of tumor 2 cm in three patients. Management of missed lesions in-
pathology have been previously discussed in the Pathol- cluded enucleation in two cases, biopsy in six, and no surgery
ogy section. in one. No patient underwent irradiation. The postoperative
Stage: The tumor stage is determined by the results of the chemotherapy regimen consisted of doxorubicin, dactinomy-
imaging studies and both the surgical and pathologic cin, and vincristine in six children, and dactinomycin and vin-
findings at nephrectomy (see Table 30-1). cristine in three. Median follow-up was 9 years. There were no
Rapid response: This is a prognostic category being evalu- recurrences in any kidney with a missed lesion. All nine pa-
ated in patients who have stage IV disease that is based tients were alive and disease free at last follow-up. The results
on lung metastasis alone. The goal in these patients is to of this study in conjunction with the advances in imaging
avoid lung radiation. Response to therapy is also being quality means that routine contralateral exploration in the
assessed in bilateral disease. presence of a negative CT is not mandated.66,67 If a clear con-
Loss of heterozygosity: LOH (described previously) at both tralateral lesion is present, then the child should be treated on
1p and 16q are now used as determinants of therapy the bilateral protocol. If studies suggest a possible contralat-
on the current COG renal tumor studies.96 eral lesion on the kidney, the contralateral kidney should be
formally explored prior to nephrectomy.
OPERATIVE THERAPY Ladd and Gross stressed the need for early vascular ligation
prior to the development of chemotherapy. This is no longer
Surgical therapy is a primary component in the multidisciplin- practiced because of the risk of injury to the vessels, particu-
ary treatment of WTor other neoplastic renal lesions. Irrespec- larly to the superior mesenteric artery in large left-sided tu-
tive of whether surgery is performed as a primary therapy or in mors. The tumor should be mobilized by opening the
a delayed fashion after chemotherapy, there are a number of lateral peritoneal reflection and reflecting the colon and its
fundamental tasks that are required of the surgeon. These are mesentery off the anterior surface of the kidney. For right-
(1) safe resection of the tumor, (2) accurate staging of the tumor, sided tumors, a Kocher procedure is also helpful. When ligat-
(3) avoidance of complications that will “upstage the tumor” ing the renal pedicle, it is best to ligate the renal artery first if
(rupture or unnecessary biopsy), and (4) accurate documenta- it can be safely identified, to avoid increasing the venous
tion of operative findings and details of the procedure in the pressure within the tumor, which can result in rupture of
operative note. Intraoperative events that negatively affect the capsule. Vascular control in most cases is best completed
patient survival include tumor spill, failure to biopsy lymph after the tumor is fully mobilized.99,105,106 The renal vein
nodes, incomplete tumor removal, failure to assess for extrare- should be palpated prior to ligation to be certain there is
nal tumor extension and surgical complications.97–99 no venous extension of the tumor. The adrenal gland may
be left in place if it is not abutting the tumor; but, if the
Technical Concerns: Unilateral Tumors mass arises in the upper pole of the kidney, the adrenal
Ladd and Gross established the basic principles for resection gland should be removed with the neoplasm. The ureter is
of a presumed malignant tumor of the kidney, including wide ligated and divided as low as possible.107 The tumor and
abdominal exposure, resection of the surrounding Gerota fat kidney should be handled gently throughout the operation

to avoid rupture, which will increase the intensity of
therapy and risk for local recurrence.99,105,106
Pathologic assessment of hilar and regional lymph nodes is
critical to accurately stage a child with a renal tumor.97,99 Rou-
tine lymph node sampling from the renal hilum, the pericaval, or
para-aortic areas must be performed. Simply looking at the
lymph nodes to determine whether they are positive is highly
inaccurate.108 Unfortunately, failure to sample lymph nodes
(whether dealing with a unilateral or bilateral tumor) is the
major technical error noted in WT surgery.97 Furthermore,
studies have demonstrated a higher risk of recurrence in chil-
dren who did not have their lymph node status documented
at the time of nephrectomy.12,99,109
WTs tend to displace rather than invade the surrounding
vessels. This feature of WT has two implications. First, the sur-
geon must be certain of the identity of the vessels to ligate.102
Second, most organs can be dissected away from the tumor,
because actual invasion is rare. When actual invasion is iden-
tified, radical en bloc resection (e.g., partial hepatectomy
or colectomy) is not warranted as primary therapy.98,99 WTs
are very chemosensitive, and, in these situations, prior
adjuvant therapy will result in a lower rate of complications
than a multiorgan resection.98 A small section of diaphragm,
psoas muscle, or tip of the pancreas, however, is acceptable.
Recent reports have suggested that hepatic metastasis
should be resected at presentation.110,111 To address this
question, the COG renal tumor study group reviewed out-
comes for patients with different sites of metastasis and found
no significant difference in outcome for patients with liver
versus lung metastasis. Primary resection of liver metastases
prior to adjuvant therapy is not currently recommended.112
Spill
“Spill” refers to a break in the tumor capsule during operative
removal, whether accidental, unavoidable, or by design. Stud-
ies have shown a higher risk of recurrence in patients who
had tumor spill or rupture, irrespective of the cause or extent
of the soiling.97–99 Spill is also considered to have occurred
if the renal vein or ureter are transected where they contain
tumor. In COG protocols, spill is also considered to have oc-
curred if a preoperative or intraoperative needle/open biopsy
was performed. This is not the case for those patients treated
following Société Internationale d’Oncologie Pédiatrique pro-
tocols: Fine-needle or Tru-Cut needle biopsy is allowed in
this study; however, incisional biopsies are considered as
ruptures, automatically stage III, and are contraindicated.
“Rupture” refers to either the spontaneous or post-traumatic
rupture of the tumor preoperatively, with the result that tumor
cells are disseminated throughout the peritoneal or retroper-
itoneal space.101 Bloody peritoneal fluid may be a sign of
rupture, and a thorough examination of the tumor surface
is mandated. Rupture is also considered to have occurred if
the tumor penetrates the kidney capsule, with open neoplastic
tissue surface being in free communication with the peritoneal
cavity. If found, all of these situations make the child stage III
and must be carefully documented in the operative note.
Unresectable Tumors
There are clinical situations where it is agreed that primary ne-
phrectomy is contraindicated. These are when (1) there is ex-
tension of tumor thrombus above the level of the hepatic
veins; (2) the tumor involves contiguous structures, whereby
CHAPTER 30 WILMS’ TUMOR 431
the only means of removing the kidney tumor requires re-
moval of the other structures (e.g., spleen, pancreas, and colon
but excluding the adrenal gland); (3) there are bilateral
tumors; (4) the tumor is in a solitary kidney; or (5) there is
pulmonary compromise resulting from extensive pulmonary
metastases. Studies conducted by the cooperative groups have
shown that pretreatment with chemotherapy almost always
reduces the bulk of the tumor.113–116 This makes tumor
removal easier and may reduce the incidence of surgical com-
plications.117 Preoperative chemotherapy does not result in
improved survival rates, and it may result in the loss of staging
information and changes the histology of the tumor as noted
previously.118,119
SPECIAL CONSIDERATIONS
Management of Tumor Extension in the Renal
Vein, Inferior Vena Cava, and Atrium
WT patients may present with tumor extension through the
renal vein to the IVC and even up to the right atrium. This
is found in 4% to 11% of children. Surgical treatment is de-
pendent on the extent of vascular invasion. Extension is usu-
ally asymptomatic, and many are detected preoperatively by
US, CT, and/or MRI scans. However, those that extend just
into the renal vein may only be detected at operation because
of compression and distortion of the veins by the tumor, rein-
forcing the need to palpate the renal vein and IVC at the start
of nephrectomy before any mobilization of the kidney that
might dislodge the thrombus.106,120,121 As noted previously,
a primary resection when tumor thrombus extends into the
inferior vena cava at the level of the liver or higher is discour-
aged. COG protocols recommend that these patients be man-
aged initially with preoperative chemotherapy. This approach
will often achieve significant shrinkage and regression of the
intravascular thrombus, facilitating subsequent surgical re-
moval.106,122 The severity and number of operative complica-
tions are reduced with preoperative chemotherapy for those
with vascular extension above the hepatic veins. Alternatively,
if the tumor extends only into the renal vein or renal vein and
IVC below the level of the liver, the tumor and thrombus can,
in most cases, be removed en bloc with the kidney.
Control of renal veins and cava above and below the tumor
with vessel loops is necessary, using standard vascular surgery
techniques. The tumor should not be transected, if possible,
because this will result in spill and upstaging of the patient.
In some cases, the tumor may be adherent to the vessel wall.
A similar technique used for removing plaque for a carotid
endarterectomy is helpful to lift the tumor off the vein wall.
It must be stated in the operative report if the intravascular tu-
mor extension was removed en bloc or if tumor was trans-
ected, as well as if the tumor thrombus is removed
completely and if there is evidence of either adherence to or
invasion of the vein wall. If, after preoperative chemotherapy,
the tumor still extends above the hepatic veins, cardiopulmo-
nary bypass is generally needed to remove the vascular exten-
sion of the tumor.
Management of Tumor Extension in the Ureter
Extension of WT into the ureter is a rare event.107 In NWTS-5,
the incidence of ureteral extension was 2%. Preoperative im-
aging detected ureteral extension in only 30% of these
432 PART III MAJOR TUMORS OF CHILDHOOD
patients; the rest were discovered at operation. Clinical pre-
sentations included gross hematuria, passage of tissue per ure-
thra, hydronephrosis, and a urethral mass. The diagnosis
should be suspected in these patients, and cystoscopy with
retrograde ureterogram may aid in preoperative diagnosis. If
extension of tumor into the ureter is detected or suspected,
the ureter should be resected with clear margins.
Horseshoe Kidney, Single Kidney,
and Nonfunctioning Kidney
A WT in a horseshoe kidney presents unique challenges.
Children with a tumor in a horseshoe kidney are treated as
unilateral tumors, NOT as bilateral tumors. Children with
horseshoe kidneys and WT must be carefully imaged prior to
any surgery.123 The blood supply to horseshoe kidneys is
quite variable and must be carefully imaged prior to surgery.123
At the time of operation, the blood supply to the kidney as well
as the location of the ureters must be identified and isolated. Ex-
posure and mobilization of the kidney on the side of the tumor
is carried out as in unilateral resection. The side of the kidney
containing the tumor, the isthmus, and the ipsilateral ureter
are resected. As with other unilateral procedures, the lymph
nodes are sampled for staging purposes. Children with a single
kidney, or a situation where a tumor occurs in one kidney but
the second kidney is nonfunctioning, should be managed using
a renal-sparing approach, with preoperative chemotherapy to
facilitate surgery and preserve more renal tissue.
Patients with Wilms’ Tumor Treated Only
with Surgery
NWTS-5 evaluated a subset of very-low-risk patients with
favorable-histology tumors who might be treated without
chemotherapy. The criteria for this arm of the study was stage
I FH in patients who had lymph nodes biopsied, had a spec-
imen weight of less than 550 g, and who were less than 2 years
of age. Seventy-five patients were enrolled before closure of
the study, and 8 developed recurrent disease (lung involve-
ment in 5 and the operative bed in 3). Three other patients
developed metachronous contralateral WT. Stringent stop-
ping rules for the study were designed to ensure closure of this
arm of the study if the 2-year EFS was 90% or less based on the
expectation that approximately 50% of the surgery-only chil-
dren would be salvaged after recurrence, thus attaining the
95% predicted survival of these children treated with vincris-
tine and dactinomycin (EE-4A). This limit was exceeded on
June 14th, 1998, and this arm of the study was closed when
the 2-year disease-free survival estimate reached 86.5%.124
Subsequent patients were treated with EE-4A. A recent
long-term follow-up study of the surgery-only cohort and
the EE-4A group, with a median follow-up of 8.2 years,
reported the estimated 5-year EFS for surgery only was 84%
(95% confidence interval [CI]: 73% to 91%); for the EE-4A
patients it was 97% (95% CI: 92% to 99%, P ¼ 0.002).
One death was observed in each treatment group. The esti-
mated 5-year overall survival (OS) was 98% (95% CI: 87%
to 99%) for surgery only and 99% (95% CI: 94% to 99%)
for EE-4A (P ¼ 0.70).125 The surgery-only EFS was less than
for EE-4A, consistent with the earlier report. The salvage rate
for the surgery-only cohort, however, exceeded that seen with
children who had received two-drug chemotherapy, which
had been predicted to be 50%. Thus 85% of the infants
avoided any chemotherapy, while those who did receive it
for relapse were treated with three agents (DD-4A). A current
study in the COG is assessing this cohort again and is evalu-
ating biologic markers for this very-low-risk group.126
Neonatal Tumors
Neoplastic renal lesions in the neonate are rare and include
benign and malignant tumors.127,128 Acute and long-term tox-
icity from therapy is a considerable concern in infants. The
distribution of tumors is age dependent. In the perinatal pe-
riod, congenital mesoblastic nephroma (CMN) is the leader,
accounting for greater than 50% of the renal tumors, followed
in rank by WT, RTK, and CCSK.127–131 WT, CMN, and rhab-
doid tumor of the kidney (RTK) are the principal neoplasms of
the kidney occurring after 3 months, when CMN accounts for
less than 10%. An international retrospective study of 750
neonatal renal tumors in children less than 7 months of age
found that 63.4% were WT.127 Eighty-two percent of these
were stage I/II. In contrast, RTK presented with advanced dis-
ease (53% stage III/IV). RTK accounted for nine of eleven tu-
mors presenting with metastases. Outcomes paralleled older
children, with excellent results for neonates with WT (5-year
OS of 93.4%) and poor for RTK (5-year OS of 16.4%).127
Acquired von Willebrand Disease in Children
with Wilms’ Tumor
von Willebrand disease (vWD) is an inherited coagulation
disorder characterized by mucocutaneous bleeding, a pro-
longed bleeding time (BT), and a reduced level of functional
von Willebrand factor (vWF). Secondary laboratory abnormal-
ities include a decreased level of procoagulant factor VIII (FVIII)
and activity of ristocetin cofactor (FVIII:RCoF) activity.132
Acquired vWD has been reported in patients with WTand other
malignancies and has important implications for the sur-
geon.133,134 A single prospective study of 50 WT patients found
the incidence of acquired vWD was 8%.134 However, the true
incidence and prevalence in WT is unknown, because a full
bleeding history and factor levels are rarely obtained. Until
recently, the literature has suggested that, when identified, the
bleeding has been clinically insignificant, characterized by
epistaxis, hematuria, gingival bleeding, and easy bruising.135
Recent reports of profuse intraoperative bleeding that only
stopped after ligation of the renal vessels have contradicted
this assumption.136,137 Despite normalization of FVIII and
vWF activity and antigen levels prior to surgery, during surgery
profuse intraoperative bleeding occurred, requiring multiple
transfusions with FVIII, FFP, cryoprecipitate, platelets, and
packed red blood cells.136 Immediately after ligation of the renal
vessels, all abnormal bleeding stopped, with normalization of
FVIII and vWF antigen activity.
The mechanism of acquired vWD in WT is unknown.
Tumor adsorption of vWF has been reported in other malig-
nancies; however, this was not seen in the WT cases where
intraoperative bleeding was significant. vWF inhibitors, rapid
abnormal clearance of vWF, and coagulopathy related to ele-
vated levels of hyaluronic acid and consequent blood hyper-
viscosity have also been proposed.138,139 Why some cases
had intraoperative bleeding and others do not is also not
known. Baxter136 suggests that these tumors may be more
hypervascular, but this is not proven. The risk of intraoperative
bleeding highlights the importance of recognizing acquired
vWD in children with WT. In all cases, the initial sign was a
prolonged prothrombin time (PT) and partial thromboplastin

time (PTT). When found, this should mandate acquiring a
further history for bleeding and factor analysis. Although cor-
rection of factor levels prior to surgery appears to help in most
cases, it does not guarantee that significant intraoperative
bleeding will not occur. In the case reports of profound
intraoperative bleeding, it was observed that, once the renal
vessels were ligated, the bleeding ceased. Thus preoperative
embolization should be considered as a management strategy.
Alternatively, preoperative chemotherapy may also be a safe
option.
BILATERAL WILMS’ TUMOR
Bilateral Wilms’ tumors BWT occur in 4% to 13% of patients
(see Fig. 30-3).5,17–19 Unfortunately, outcomes for children
with bilateral tumors have not been as good as those of chil-
dren with unilateral tumors. In NWTS-5, the 4-year OS was
80.8% for a child with favorable histology and 43.8% for a
child with anaplastic histology.84 In 1998, the United
Kingdom Children’s Cancer Study Group published their
experience with BWT patients treated between 1980 and
1995.140 In 57 patients, conservative surgical treatment with
initial biopsy was followed by chemotherapy and delayed
tumor resection, while 13 underwent initial surgical resection
followed by chemotherapy. Overall survival was 69%, with
similar survival in the patients with initial surgery versus
neoadjuvant chemotherapy. BWT with an unfavorable histol-
ogy was associated with a poor prognosis, with only one of
seven patients surviving. Renal failure was seen in 6% of
the survivors who were conservatively treated and in 20%
of the survivors who underwent initial resection. In 2004,
Weirich reported BWT outcomes from SIOP-9. Twenty-eight
patients were evaluated. Although therapy was individualized,
all 28 patients with BWT were treated with preoperative
therapy. Overall survival at 5 years was 85.1% (95% CI:
71.6% to 98.6%; four deaths), and relapse-free survival was
80.5% (95% CI: 65.2% to 95.8%; five relapses).141
Renal failure is another concern of children with BWT
(Figs. 30-8 and 30-9). The etiology of renal failure in WT pa-
tients is multifactorial.142–144 Factors that contribute to renal
failure include intrinsic progressive renal disease related to
a genetic predisposition, inadequate renal parenchyma after
one or more tumor resections, the nephrotoxic effects of
80
DDS (12/17)
Cumulative incidence of
60 WAGR (11/37)
ESRD (%)
40
20
GU (5/125)
Other (28/5, 347)
0
0 5 10 15 20 25
Time since diagnosis of
unilateral Wilms’ tumor (years)
FIGURE 30-8 Kaplan-Meier plot of renal failure rates at 20 years of age in
children with a unilateral Wilms’ tumor (WT). DDS, Denys-Drash syndrome;
ESRD, end-stage renal disease; GU, genitourinary; WAGR (syndrome),
Wilms’ tumor, aniridia, genitourinary malformation, mental retardation.
CHAPTER 30 WILMS’ TUMOR 433
chemotherapy and radiation, and the potential for hyperfiltra-
tion injury to the remaining renal parenchyma. Ritchey
defined the incidence and etiology of renal failure in patients
treated on NWTS-1 to NWTS-4. BWT was the greatest risk
factor for renal failure (16.4% for NWTS-1 and NWTS-2,
9.9% for NWTS-3, and 3.8% for NWTS-4). Other risk factors
identified were Denys-Drash syndrome, metachronous tu-
mor, progressive disease in patients with bilateral tumors re-
quiring bilateral nephrectomies and radiation nephritis.144
Breslow reported the 20-year end-stage renal disease (ESRD)
outcomes in children treated for WT (see Figs. 30-7 and
30-8).142 The major risk factors he identified for renal failure
were BWT and congenital syndromes—Denys-Drash, WAGR,
and genital urinary anomalies (hypospadias or cryptorchi-
dism). Thus preservation of renal tissue without sacrificing
long-term survival is of particular importance for those
with BWT.
Despite 40 years of clinical trials for WT, it was not until
2009 that a formal BWT trial was opened by COG. Several
prior reports contributed to the development of this protocol.
Shamberger and colleagues examined 38 of 188 patients with
BWT with progressive or nonresponsive disease (PNRD).145
The mean duration of chemotherapy was 7 months; 36 pa-
tients were treated with two regimens of chemotherapy, and
21 patients received three. Patients with PNRD fell into two
categories: first, patients with anaplasia whose tumors were
not sensitive to the therapy administered (4 patients); second,
patients who had tumors with very mature rhabdomyomatous
or differentiated stromal elements (14 patients) and 1 with
complete necrosis. A second study from Anderson looked
at the histologic changes in BWT patients who did not re-
spond to chemotherapy and the relationship between these
changes and prognosis.146 Their results mirrored those of
the NWTS study. Fifteen patients whose tumors did not re-
spond were evaluated. One had complete necrosis, 4 had
rhabdomyomatous differentiation, and 10 had mature stromal
differentiation. Despite not radiographically responding
to chemotherapy, these patients had favorable outcomes.
Patients in these studies fell into two categories. First, there
were patients with anaplasia whose tumors were not sensitive
to the therapy administered. Anaplastic tumors respond poorly
to chemotherapy and, once the diagnosis of anaplasia is
made, a complete resection is needed.84,140,147,148 Second,
100
WAGR (5/10)
Cumulative incidence of
80 GU (8/25)
ESRD (%)
60
DDS (3/6)
40
20 Other (44/409)
0
0 5 10 15 20 25
Time since diagnosis of bilateral Wilms’ tumor (years)
FIGURE 30-9 Kaplan-Meier plot of renal failure rates at 20 years of age in
children with bilateral Wilms’ tumor (BWT). DDS, Denys-Drash syndrome;
ESRD, end-stage renal disease; GU, genitourinary; WAGR (syndrome),
Wilms’ tumor, aniridia, genitourinary malformation, mental retardation.
434 PART III MAJOR TUMORS OF CHILDHOOD
there were patients who had tumors with very mature rhabdo-
myomatous or differentiated stromal elements and complete
necrosis, all of whom had an excellent outcome. Again these
patients are best served with resection.146 Therefore if the bilat-
eral lesions do not respond radiographically to therapy, it is crit-
ical to establish whether this is due to anaplasia or mature
histology.
Hamilton and colleagues have demonstrated the difficulty
in identifying anaplasia in patients with BWT.148 Twenty-
seven patients with anaplasia were reviewed from NWTS-4.
Discordant pathology between the kidneys was seen in 20 pa-
tients, highlighting the importance of obtaining tissue from
both kidneys. Seven children who were eventually found to
have diffuse anaplasia had core needle biopsies, which failed
to establish the diagnosis in all of these cases. Anaplasia was
identified in only three of nine patients who had an open
wedge biopsy and in seven of nine patients by partial or com-
plete nephrectomy. Thus percutaneous biopsies rarely
establish the diagnosis, and open biopsies were successful
in only a third of the cases.
An important question is to determine how long to treat a
child who has BWT with chemotherapy before intervening
surgically. In SIOP-9, patients with unilateral tumors were
randomized to receive either 4 or 8 weeks of dactinomycin
and vincristine preoperatively. There was an average 48% re-
duction in tumor volume after 4 weeks that increased to 62%
after 8 weeks of chemotherapy.116,149 A review by the German
Pediatric Hematology Group (GPOH) of their patients with
BWT reported that maximum tumor shrinkage occurred in
the first 12 weeks of chemotherapy.150
The two principal aims of the COG BWT study are to
improve 4-year event-free survival and to prevent complete
removal of at least one kidney in 50% of patients with BWT
by using preoperative chemotherapy. This is a response-based
protocol starting with chemotherapy, followed by evaluation
at 6 and 12 weeks with definitive surgical therapy in all pa-
tients by 12 weeks (see Fig. 30-3). This protocol does not
mandate an initial tissue diagnosis because bilateral renal tu-
mors in children are invariably WT; biopsy does not change
the therapy in most cases; anaplasia is hard to diagnose,
and the biopsy will effectively increase the stage of the tumor
and its risk for local recurrence.148 In the current COG pro-
tocol, local spill of the tumor is designated as stage III. This clas-
sification was changed because of the finding of an increased
incidence of abdominal recurrences in NWTS-4 patients with
tumor spill.99 First, for patients with BWT, the initial regimen
will consist of regimen vincristine, actinomycin D, doxorubicin
(VAD) (vincristine [VCR], dactinomycin [DACT], doxorubicin
[DOX]), a more intensive combination of drugs based on reg-
imens used with good results and minimal toxicities by both
SIOP and the UKCCSG WT groups, which enables patients
to receive two doses of DOX, in addition to six of VCR and
two of DACT, during the first 6 weeks of therapy.151 It differs
from the standard three-drug regimen, DD-4A, in which
the DOX and DACT are administered in separate cycles.152
The three-drug chemotherapy regimen of VAD was chosen to
give an enhanced therapy for possible stage III disease, because
patients rarely have a lymph node biopsy before initiation of
therapy. Second, it was elected to enhance the chemotherapy
rather than administer radiotherapy, which might increase
the occurrence of radiation nephritis in the remaining kidney.
Third, a more intensive therapy was selected for treatment
to avoid the use of a sequential regimen of increasing intensity,
which was seen in the review of the prior cohort of NWTS-4
BWT patients.
CHEMOTHERAPY
In 1963, Farber first reported that dactinomycin had activity
against WT.153 Today, dactinomycin continues to be part of
the backbone of therapy for children with WT. Other active
chemotherapeutic agents have been identified subsequently,
including vincristine, doxorubicin, and cyclophosphamide.
Clinical trials conducted by NWTSG and SIOP have evalu-
ated, stage by stage, different chemotherapeutic protocols to
assess the efficacy of various combinations and duration of
therapy.105,154–159 In NWTS-4, 4-year event-free survival
and overall survival averaged 90% for patients with favorable
histology.154,159 Therefore NWTS-5 focused on evaluating
biologic markers of prognosis, such as LOH, developing more
effective therapy for recurrent disease, and reducing therapy
in children with low-risk tumors.
Treatment on the current COG protocols for favorable-
histology WT is determined by stage, histology, and LOH.
For children with favorable-histology stage I and II tumors
without LOH, 18 weeks of vincristine and dactinomycin (reg-
imen EE-4A) is recommended. Results from NWTS-5 showed
these children had an overall survival of 98.4% and 98.7%,
respectively. For children with FH stage III and IV tumors
without LOH, 24 weeks of vincristine, dactinomycin, and
doxorubicin is recommended (regimen DD-4A). For those
patients who have positive LOH at both loci (1p and 17q),
treatment will be intensified. If they are stage I or II and
LOH positive, they will receive DD-4A, and if they are stage
III and IV LOH positive, they will receive vincristine, dactino-
mycin, and doxorubicin with alternating cycles of cyclophos-
phamide versus etoposide (regimen M). Dosing modifications
are made for children less than 12 months of age.
Anaplastic tumors have been less successfully treated.
NWTS-3 and NWTS-4 were the first studies to prospectively
evaluate the benefit of additional/different chemotherapy
therapy for these tumors. One randomized arm compared
15 months of vincristine, dactinomycin, and doxorubicin,
with or without cyclophosphamide. For patients with stage
II to IV diffuse anaplastic histology, the addition of cyclophos-
phamide resulted in a 4-year relapse-free survival estimate of
54.8% when treated with cyclophosphamide compared with
27.2% when treated without it (P ¼ 0.02).160 In NWTS-5,
patients with focal anaplasia or diffuse stage I were treated
with EE-4A. This was based on prior historical data, with a
goal of reducing therapy. Unfortunately, the 4-year event-free
and overall survival estimates for stage I (focal or diffuse)
anaplastic WT were lower than previous studies (EFS 69.5%
and OS 82.6%). Thus therapy with EE-4A is inadequate.
Patients with focal anaplasia stage II to IV were treated with
DD-4A. Children with stage II to IV diffuse anaplastic WTwere
treated with vincristine, doxorubicin, and cyclophosphamide
(VDC) alternating with cyclophosphamide and etoposide
(CyE) (regimen I). The 4-year event-free survival estimates
for stage II to IV diffuse anaplastic WT on NWTS-5 were
82.6%, 64.7%, and 33.3%, respectively, with similar overall
survival.84 The current protocols and chemotherapy agents
for unilateral tumors are shown in Table 30-4.

TABLE 30-4
Current Children’s Oncology Group Chemotherapy Regimens
for Unilateral Wilms’ Tumor
Regimen Agents
EE-4A Vincristine and dactinomycin
DD-4A Vincristine, dactinomycin, doxorubicin,
and radiation therapy (XRT)
Regimen I Vincristine, dactinomycin, doxorubicin,
cyclophosphamide (CPM1), and etoposide
(ETOP), as well as radiation therapy (XRT)
Regimen M Vincristine, dactinomycin, doxorubicin,
cyclophosphamide, and etoposide;
radiation therapy also to be administered as
part of this regimen
Revised UH-1 Vincristine, dactinomycin, doxorubicin,
cyclophosphamide, carboplatin, etoposide,
and radiation
Revised UH-2 Vincristine, dactinomycin, doxorubicin,
cyclophosphamide, carboplatin, etoposide,
irinotecan, and radiation therapy (XRT)
Vincristine/irinotecan Vincristine and irinotecan in conjunction
window therapy with revised UH-1 or revised UH-2,
depending on response
Recurrent Tumor
Treatment of recurrent disease in children with WT is chal-
lenging. Recurrence occurs in 15% of patients with favorable
histology tumors and in 50% with anaplastic histology. Recur-
rence is most frequent within 2 years of the initial diagnosis and
most common in the lungs, tumor bed, and liver.161 Less com-
mon sites are bone, brain, and distant lymph nodes.
Recurrent disease is treated by chemotherapy, surgery, and
radiotherapy. NWTS-5 evaluated two protocols for recurrent
disease, avoiding use of agents included in the primary proto-
cols. Stratum B was for patients with stage I and II disease ini-
tially treated with EE-4A. The chemotherapy for this relapse
protocol was regimen I (alternating courses of vincristine/
doxorubicin with cyclophosphamide), in addition to surgical
resection and radiation therapy. Event-free survival at 4 years
was 71.1%, and 4-year overall survival was 81.8% for all pa-
tients and was 67.8% and 81.0%, respectively, for those who
relapsed only to their lungs.162 Stratum C was for patients ini-
tially treated with DD-4A.163 The chemotherapy protocol for
this group was alternating cycles of cyclophosphamide versus
etoposide and carboplatin versus etoposide. Four-year event-
free survival and overall survival were 42.3% and 48.0%,
respectively, for all patients and were 48.9% and 52.8% for
those who relapsed in the lungs only. Bone marrow transplan-
tations have been performed for patients with recurrent disease,
with reported event-free or disease-free survival rates of 36% to
60% in these small series.164–166 At present, there is no open
relapsed study in SIOP or COG, because the groups are await-
ing new and more effective agents for treatment of this disease.
RADIOTHERAPY
Analogous to surgery and chemotherapy, the cooperative
group trials have refined the indications for radiotherapy. In
addition, technologic advances have helped to deliver irradi-
ation with increased efficacy and less toxicity to surrounding
tissues. The three principle fields for radiotherapy for renal tu-
mors are whole abdominal, flank, and lung (metastatic lung
CHAPTER 30 WILMS’ TUMOR 435
disease). All five NWTSG studies and the current COG studies
use radiotherapy as part of the multimodality treatment for
advanced-stage tumors.
In 1950, Gross and colleagues demonstrated the efficacy
of radiotherapy as an adjuvant therapy prior to the advent
of chemotherapy. In this series, nephrectomy with postopera-
tive radiation improved survival to 47%.167 Favorable histol-
ogy tumors are generally very radiosensitive. NWTS-1 to
NWTS-3 helped define the indications, timing, and dose of
radiotherapy. NWTS-1 established that irradiation provided
no advantage in children younger than 24 months with stage
I FH tumors who also received 15 months of dactinomycin.168
That study also demonstrated that in stage III tumors with lo-
cal tumor spill or previous biopsy, there was no need for irra-
diation of the whole abdomen, thus sparing patients the
associated toxicity.169 NWTS-2 showed that radiotherapy
could be avoided in all children with stage I WT if they re-
ceived vincristine and dactinomycin.170 NWTS-3 established
that radiotherapy could be avoided in children with stage II
tumors given vincristine and dactinomycin and also demon-
strated that children with stage III favorable-histology tumors
who received 10.8 Gy radiotherapy and vincristine, dactino-
mycin, and doxorubicin had similar tumor control to those
who received 20 Gy with vincristine and dactinomycin. This
was an important finding, because it eliminated the need for
an age-adjusted dose schedule and significantly reduced the
recommended dose of radiation.157
Timing of radiation following nephrectomy was assessed
on NWTS-2, where a delay of 10 days or more before initia-
tion of radiotherapy was associated with a higher rate of
abdominal relapse, particularly among patients with unfavor-
able-histology tumors and a small radiation field.157,168,169 A
recent review of this issue from NWTS-3 and NWTS-4 data
confirmed this observation.171 Thus, in the COG protocols, it
is recommended that abdominal irradiation be delivered as
soon as practical after nephrectomy and not later than 14
days after surgery. The current recommendation for radiation
therapy for COG protocols is shown in Table 30-5.
In contrast to FH tumors, the ideal dose for patients with
anaplastic tumors is unknown. Anaplastic tumors are more
resistant to chemotherapy and seem to be more resistant to
radiotherapy as well. Anaplastic tumors have not demon-
strated a radiation dose response between 10 Gy and 40 Gy.160
The radiotherapy strategy for patients with anaplastic his-
tology (AH) on NWTS-5 included no irradiation for stage I AH
tumors and 10-Gy radiotherapy for AH stage II and III in con-
junction with nephrectomy and regimen I. The outcomes for
both of these treatment strategies were suboptimal. Stage 1 pa-
tients had a 4-year EFS and overall survival of only 69.5% and
82.6%, respectively. Stage II, III, and IV patients had a 4-year
OS after immediate nephrectomy, irradiation, and regimen I
chemotherapy of 82.6%, 64.7%, and 33.3%, respectively.84
EFS was similar to OS in all groups. Fifty percent of stage
III recurrences were local, suggesting that the dose of 10 Gy
was not adequate. These results form the basis for the current
COG study that recommends the addition of irradiation for
patients with stage I anaplasia and augmentation of irradiation
for patients with stage III anaplasia.
For liver metastases, only those that are unresectable at diag-
nosis are irradiated. The treatment portal includes that portion of
the liver known to be involved as identified by CTor MRI studies.
The whole liver is treated in children with diffuse metastases.
436 PART III MAJOR TUMORS OF CHILDHOOD

TABLE 30-5 (WLI), and the 4-year survival rate improved to 75%.181 A
Radiotherapy for Favorable-Histology Wilms’ Tumor COG study of patients with pulmonary lesions detected by
Treatment Site Clinical Presentation and Dose (Gy)
CT only (as opposed to CT and chest radiograph) and treated
with only two chemotherapeutic agents showed an inferior
Flank irradiation Stage III favorable histology 10.8 outcome compared with those treated with three drugs irre-
All instances of soilage Recurrent Wilms’ tumor 10.8
will be classified as Stage
spective of whether or not they received pulmonary radia-
III and require abdominal tion.172 A fourth study examined the value of biopsy prior
radiation. Flank radiation to treating patients with lesions detected only by CT.175
is given to all Stage III Two thirds of the children had tumor on biopsy, suggesting
patients with three that histologic evaluation may be valuable in directing therapy.
exceptions (the patients
meeting any of these The current COG study is evaluating the use of radiographic
exceptions requiring response to chemotherapy to predict the need for whole lung
whole abdominal irradiation. Those patients with stage IV favorable-histology
radiation). WT with pulmonary metastases who have complete CT reso-
Whole abdomen irradiation Abdominal stage III 10.5 lution of the pulmonary lesions after 6 weeks of vincristine/dac-
(WAI) Preoperative tumor rupture
Peritoneal metastases are
tinomycin/doxorubicin chemotherapy will continue the same
found at initial surgery chemotherapy without whole lung irradiation. Those who do
A large intraoperative tumor not have resolution of pulmonary metastases by week 6 will
spill affecting areas outside have the addition of cyclophosphamide and etoposide to the
the tumor bed as other three drugs and will receive whole lung irradiation.
determined by the surgeon/
treating institution.
Abdominal Stage III 21 LATE EFFECTS
Diffuse unresectable
peritoneal implants The increasing numbers of survivors of WT have led to a
Liver irradiation Focal metastases 19.8 better understanding of adverse medical conditions related
Patients with residual Diffuse metastases 19.8 to treatment of their disease that can develop over time.182
tumor will receive
supplemental irradiation
Treatment for WT impacts renal function (discussed earlier),
with 5.4 to 10.8 Gy. pregnancy, cardiac and pulmonary function, and second
malignancies may develop.178,183–187
Lung Radiotherapy Pregnancy
Historically, pulmonary metastases were diagnosed based on Treatment for WT impacts reproductive capacity and increases
lesions found on routine chest radiographs and were treated the risk of complications during pregnancy. The National
with whole lung radiation. For COG studies, it is delivered Wilms’ Tumor Long-Term Follow-Up Study evaluated 700
in eight treatments of 12 Gy. From NWTS-5, the 5-year EFS maternal/offspring pairs.188 If a woman had received flank
(95% CI) for stage IV category was lung only 76% (72% to radiation for unilateral WT, the dose of radiation correlated
80%) (513 patients) and liver and lung 70% (57% to 80%) with increased risk of hypertension, fetal malposition, and
(62 patients).172 Advances in imaging have changed the as- premature labor. The children were also more at risk
sessment of lung disease from plain radiograph to widespread for low birth weight and prematurity (birth before 37 weeks).
use of chest computed tomography. Lesions are detected on Premature labor was seen in 10.2% of women who did not
CT scan that are not found on standard radiographs.173–175 receive flank radiation and 22% of those who received
Thus more lesions are being identified. Complicating the 35Gy (P ¼ 0.001). Radiation therapy to the abdomen has
use of radiation therapy is the fact that it is a major cause of resulted in absent/abnormal function of the ovaries, a small
long-term morbidity, particularly to the lung and heart, pro- uterus, and premature menopause.189–193 Male infertility is
ducing congestive heart failure, pulmonary fibrosis, and sec- not at risk unless alkylating agents were used.
ond malignancy.176–178 Recent studies suggest that the
Secondary Malignancies
management for pulmonary nodules should be reexamined.
In SIOP-9, by 70 days of therapy, resolution of pulmonary Patients who have been treated for pediatric cancer are known
nodules on CT scan in children with FH tumors was a favor- to have an increased risk of second malignancies. This is in
able prognostic indicator.179 In SIOP-9, many of these patients part due to treatment with known carcinogens, such as alky-
were spared whole lung irradiation, if complete resolution of lating agents and radiotherapy.183,194,195 An international co-
pulmonary metastases occurred after 6 weeks of prenephrect- hort of 13,351 children with WT diagnosed before 15 years of
omy chemotherapy with vincristine, dactinomycin, and doxo- age, from 1960 to 2004, was established to determine the risk
rubicin with or without surgical excision of residual of second malignant neoplasms (SMN).178 One hundred and
metastases. The 5-year relapse-free survival (RFS) for stage seventy-four solid tumors and 28 leukemias were found in
IV patients receiving preoperative chemotherapy was 195 people. Median survival after a secondary malignancy
62.5%.179 The results of this study have been controversial. was diagnosed 5 years or more from WT was 11 years; it
The United Kingdom Children’s Cancer Study Group was 10 months for leukemia. Age-specific incidence of sec-
(UKCCSG) Wilms Tumor Study 1 followed a similar protocol; ondary solid tumors increased from approximately 1 case
yet, their 6-year EFS was only 50%.180 In their second study, per 1,000 person-years at age 15 years to 5 cases per 1,000
UKCCSG-Wilms Tumor Study (UKWT2), the majority of chil- person-years at age 40 years. The cumulative incidence of
dren with lung metastases received whole lung irradiation solid tumors at age 40 years was 6.7%. In those patients whose
 CHAPTER 30 WILMS’ TUMOR 437

WT was diagnosed after 1980, there was a lower age-specific used to exclude other renal tumors. CCSK is nonspecifically
incidence rate for second tumors compared with those treated vimentin and Bcl-2 positive. Gene-expression profiling studies
before 1980. Paradoxically, the incidence of leukemia was demonstrate the expression of neural markers (e.g., nerve
higher in those diagnosed after 1990. This may be due to de- growth factor receptor), expression of member genes of the
creasing use of radiation therapy and increasing intensity of Sonic Hedgehog pathway and the phosphoinositide-3-kinase/
chemotherapy in modern protocols for treatment of WT. Akt cell proliferation pathway.201,202 Recently, a translocation
t(10;17) and deletion 14q have also been described in CCSK,
Congestive Heart Failure suggesting that they may play a role in its pathogenesis.203
Congestive heart failure has been identified as a significant mor- CCSK is characterized by bone and brain metastases and the
bidity in children treated with doxorubicin, and this is exacer- increased tendency for late recurrences. Long-term follow-
bated in patients who receive thoracic radiation. The cumulative up of CCSK patients is needed because 30% of relapses oc-
frequency of congestive heart failure in patients treated on curred more than 3 years after diagnosis, and some occurred as
NWTS-1 to NWTS-4 was 4.4% at 20 years for patients treated late as 10 years after diagnosis.204 The tumor is generally uni-
initially with doxorubicin, but that percentage is expected to be lateral and unicentric, with solid and, occasionally, cystic areas.
lower with current cumulative doses.184,185,196 The relative risk On NWTS-1 to NWTS-3, treatment for CCSK was the same as
of congestive heart failure was found to be increased in females for WT, and the outcomes were poor. In NWTS-4, patients
(risk ratio [RR] ¼ 4.5; P ¼ 0.004), and by cumulative doxoru- were treated with vincristine, dactinomycin, doxorubicin,
bicin dose (RR ¼ 3.2/100 mg/m2; P < 0.001), lung irradiation and RFS, and overall survival was improved versus NWTS-3
(RR ¼ 1.6 for every 10 Gy; P ¼ 0.037), and left abdominal ir- (RFS 71.6% versus 60.2% at 8 years, P ¼ 0.11; OS 83% versus
radiation (RR ¼ 1.8/10 Gy; P ¼ 0.013).185 Preliminary results 66.9% at 8 years, P < 0.01).204 To further improve survival,
suggest that cardiotoxicity is lower with current radiation doses, patients on NWTS-5 with CCSK were treated using regimen
but patients still have a substantial lifetime risk of developing I (see Table 30-2), because etoposide and cyclophosphamide
cardiac disease.183,196 were active against CCSK in preclinical models.205 Four-year
OS for stage I patients was 100%. Stage II, III, and IV had 4-year
Thoracic OS of 88.9%, 94.8%, and 41.7%, respectively. LOH was
Radiotherapy (RT) has been implicated as a major contributor not found in most cases of children with CCSK and is not pre-
to late complications. Acute lung injury is relatively uncom- dictive of outcomes. In the current COG study, patients
mon, occurring in a minority of children.197 The late effects with CCSK are treated according to the high-risk study.
of pulmonary RT include pneumonitis and restrictive lung Patients with stage I disease will continue to be treated with
disease, scoliosis, kyphosis, reduced lung capacity, and sec- regimen I but will not receive radiation therapy. The need to
ondary tumors. In girls, breast hypoplasia and cancer minimize unnecessary therapy in patients with stage I CCSK
have been described.176,177 Paulino and his colleagues is highlighted by the fact that treatment-related deaths in the
reported on the late complications of pulmonary RT in 55 Argani series outnumbered tumor-related deaths, two versus
long-term survivors of WT.176 Two thirds of the patients had one.200 In addition, none of the stage I patients from NWTS-
at least one complication. Forty-three percent had scoliosis or 5 have relapsed, with a median follow-up of more than 4 years.
kyphosis, and 10% developed benign chest tumors (osteochon- To improve survival for children with higher-stage disease,
dromas). Secondary tumors were noted in three patients within they will be treated with revised UH-1 (see Table 30-4).
the lung field (two osteogenic sarcomas of the rib and one breast
cancer), and all succumbed to these tumors. Pulmonary func- RHABDOID TUMOR OF THE KIDNEY
tion was examined by Attard-Montalto and colleagues.177 Sub-
jectively, 63% percent of patients had mild to moderate exercise RTK was initially described in 1978 as a “rhabdomyosarcoma-
intolerance, and objective measurement of vital capacity and to- toid” variant of WT.206 Haas used the term “rhabdoid tumor”
tal lung capacity was decreased compared with age and height in 1981, because of the absence of muscle differentiation.207
predicted values in all. All of the females had breast hypoplasia. RTKs have been reported to occur throughout the body, in-
In another study of long-term survival of females, all developed cluding the brain, liver, soft tissues, lung, skin, and heart.
breast hypoplasia and one had breast cancer.198 RTK accounts for 2% of all renal tumors, and it is the most
aggressive and lethal of all pediatric renal tumors. Clinical fea-
tures that help distinguish an RTK from WT clinically include
Other Renal Tumors the presence of hypercalcemia and diffuse lymphatic and he-
------------------------------------------------------------------------------------------------------------------------------------------------ matogenous spread in a young infant. Tomlinson and her col-
leagues reviewed 142 patients with RTK from NWTS-1 to
CLEAR CELL SARCOMA OF KIDNEY
NWTS-5.208 Age at diagnosis was found to be a highly signif-
CCSK accounts for 3% of renal tumors reported to the COG icant prognostic factor for survival of children with RTK. In-
studies. Each year, approximately 20 new cases of CCSK are di- fants have a dismal prognosis, whereas older children have a
agnosed in the United States. CCSK was recognized as a distinct slightly more favorable outcome. Higher tumor stage and
clinicopathologic entity by Kidd in 1970.199 CCSK has been de- presence of a central nervous system (CNS) lesion were also
scribed as nests of ovoid, epithelioid, or spindled cells separated predictive of a poor rate of survival. Unfortunately, these tu-
by fibrovascular tissue with a “chicken wire” pattern of small mors tend to present at an advanced stage and are resistant
blood vessels. Most tumors show evidence of this “classical” pat- to chemotherapy.209 RTK is associated with second primary
tern, but other reported histologic patterns seen include myxoid, tumors in the brain, including cerebellar medulloblastomas,
sclerosing, cellular, epithelioid, palisading, spindle-cell, stori- pineoblastomas, neuroblastomas, and subependymal giant
form, and anaplastic patterns.200 Immunohistochemistry is cell astrocytomas.210
438 PART III MAJOR TUMORS OF CHILDHOOD
Grossly, the tumors are solid, unencapsulated, and often
have extensive hemorrhage and necrosis. The tumors are very
invasive. Microscopically, they consist of sheets of cells showing
nuclear pleomorphism and characteristic morphologic features
of open vesicular nuclei, prominent nucleoli, and scattered
hyaline eosinophilic cytoplasmic inclusions composed of inter-
mediate filaments in a “whorled” pattern. At present, no single
immunohistochemical stain or profile is considered to represent
a diagnostic criterion. Recently, genetic abnormalities of the
hSNF5/INI1 tumor suppressor gene on chromosome 22 have
been shown to be characteristic for both renal and extrarenal
rhabdoid tumors; the gene is important for chromatin remodel-
ing. For all other renal tumors, except RTK, immunohistochem-
ical staining for the wild-type integrase interactor 1 (INI-1)
protein shows nuclear positivity. In renal and extrarenal rhab-
doid tumors, this is absent.211 This antibody is being evaluated
for its diagnostic utility in the current COG renal tumor study.
Both SIOP and COG/NWTSG have reported poor out-
comes for children with RTK.208,212 The outcomes by stage
from NWTS-5 are stage I ¼ 50.5%, stage II and III ¼
33.3%, stage IV ¼ 21.4%, stage V ¼ 0%. Children with
RTK, on the current COG study, will be treated using revised
UH-1 if they are stage I to IV and have no measurable disease
after surgery. If they have measureable disease (stage III, IV),
they will receive a vincristine/irinotecan “window,” followed
by revised UH-2 if they have a partial or complete response
(see Table 30-2). The rationale for this treatment strategy
was based on reviewing the outcomes from the intergroup
rhabdomyosarcoma (IRS) studies and several case reports that
documented the successful treatment of advanced or meta-
static rhabdoid tumor of the kidney.213–215
RENAL CELL CARCINOMA
RCC in childhood accounts for 5% to 8% of all pediatric and
adolescent renal malignancies. They are more common than
clear cell sarcoma of the kidney and malignant rhabdoid.1
The median age at presentation in children is 9 years. By
age 15, RCC becomes as common as WT (Fig. 30-10). In
the pediatric population, there have been limited therapeutic
studies with no randomized controlled trials. Similar to WT,
children with RCC generally present with an asymptomatic
abdominal mass, although hematuria is a frequent finding.216
Imaging studies cannot differentiate RCC from other solid
RENAL CANCER AGE-SPECIFIC INCIDENCE RATES BY TUMOR
SEER 1975-1995
20
0.1
Wilms’ tumora
Average annual rate
15 Renal cell carcinoma
per million
18.3
10
0.1
5 Congenital mesoblastic nephroma (CMN) is the most frequent
5.6
0.4
0 0.8
<5 5 to 9 10 to 14 15 to 19
Age at diagnosis (years)
FIGURE 30-10 Incidence of renal cell carcinoma and Wilms’ tumor by
age. SEER, Surveillance, Epidemiology, and End Results (Program).
renal tumors. RCC in children can be divided into two broad
pathologic groups.217 The first is the classical clear cell histol-
ogy. This includes the adult-type RCC with 3p25 (VHL locus)
genetic abnormalities and tumors in patients with tuberous
sclerosis. In addition, there is a unique genetic subtype of clear
cell that presents in adolescents and young adults, accounting
for nearly one third of all cases. These tumors are character-
ized by the chromosomal translocations involving the TFE3
gene on Xp11.2217–219 or the TFEB gene on 6p21.220,221
The abnormal gene fusions produce protein dysregulation
and result in overexpression of either TFE3 or TFEB transcrip-
tion factors, which contribute to tumor pathogenesis. Immu-
nohistochemistry can detect aberrant expression for TFE3 or
TFEB and can thus be useful in establishing the diagno-
sis.221,222 In addition, these translocation-positive RCCs have
been described as second malignancies following previous
chemotherapy.223,224
The second subgroup of pediatric RCCs are the papillary
RCCs.225–227 Papillary renal cell carcinoma appears more fre-
quently than classical clear cell. Other RCC cell types include
chromophobe or collecting duct types.228 Renal medullary
carcinomas are rare, but highly aggressive, malignancies that
are associated with sickle cell hemoglobinopathy.229,230 Ap-
proximately 25% of pediatric RCCs are not able to be classified
because of atypical histologic features.217
Complete tumor resection is the most important determi-
nant of outcome in RCC.228 Younger age at diagnosis is
also a favorable prognostic factor. It has been suggested that
regional lymph node involvement does not portend the same
grave prognosis as it does in adult renal cell carcinoma; how-
ever, because this impression was reached based on only
13 patients, further evaluation is required.231 Data collected
from RCC patients enrolled on NWTS-5 showed 5-year OS
survival rates by stage: stage I 92.5%, stage II 73%, stage III
55%, and stage IV 9%. Similar to adult RCC, prognosis
worsens with increasing stage, although direct comparisons
of adult and pediatric data are confounded by the finding that
most reviews of pediatric RCC used the modified Robson
staging system rather than the tumor-node-metastasis
(TNM) system. Neither chemotherapy nor radiation therapy
have demonstrated activity in adult or pediatric patients with
metastatic RCC. To address this lack of knowledge and expe-
rience, for the first time these tumors will be addressed in a
COG protocol. To enable comparison with adult tumors,
the staging system proposed by the World Health Organiza-
tion will be used. The relatively good survival rate for children
with localized RCC combined with the relative inefficacy of
the known adjuvant therapies support treating children with-
out adjuvant therapy. However, the provision of adjuvant che-
motherapy is at the discretion of the local physicians. A major
future thrust will be to identify novel agents with activity
against RCC.
CONGENITAL MESOBLASTIC NEPHROMA
renal neoplasm of newborns and young infants, accounting
0.7
0.4 for 5% of all renal tumors.129,232–234 The median age at diagnosis
is 2 months. In 1967, Bolande and colleagues were the first to
describe the tumor as a separate entity from WT.234 CMN are
firm on gross examination, and the cut surface has the yellow-
ish gray trabeculated appearance of a leiomyoma. To date,
 CHAPTER 30 WILMS’ TUMOR 439

three histologic subtypes have been described. The classical or cellular and mixed, which had the same risk of recurrence.
type, first identified by Bolande (24% of cases), cellular type Stage III disease was the second factor associated with recur-
(66% of cases), and mixed type (10% of cases) showing both rence. Intrarenal and renal sinus vascular invasion correlated
classical and cellular patterns.235 The classical variant is char- with increased potential for recurrence; however, the correla-
acterized by leiomyomatous histology, with spindle cells in tion did not achieve independent statistical significance. Other
bundles, rare mitoses, and the absence of necrosis. It is histo- clinical or pathologic features previously suggested as prognos-
logically similar to infantile myofibromatosis. The cellular var- tic factors, including age at diagnosis, were not proven to be of
iant consists of solid, cellular, sheetlike growth pattern of oval additional prognostic significance. This study concluded that
or round cells with little cytoplasm and frequent mitoses and the most important risk factors for recurrence in CMNs are
necrosis, which resembles infantile fibrosarcoma. The mixed the presence of a cellular histologic component and stage III
type of congenital mesoblastic nephroma features areas resem- disease. However, in none of these reports has the efficacy of
bling both classical and cellular morphologies.235–237 The re- adjuvant therapy been established.
lationship between mixed CMN and the two main histologic
subtypes is not clear.238 SOLITARY MULTILOCULAR CYST AND
The observation that classical CMN is similar to infantile
CYSTIC PARTIALLY DIFFERENTIATED
myofibromatosis and cellular CMN resembles infantile fibro-
sarcoma suggests that these may be two distinct entities, and NEPHROBLASTOMA
genetic studies provide evidence in support of this hypothesis. Cystic renal tumors are a diagnostic and therapeutic challenge
Cellular CMN is characterized by the t(12;15) translocation, (Fig. 30-11). Cystic nephroma (CN), cystic partially differen-
resulting in the ETV6-NTRK3 fusion gene, a genetic change tiated nephroblastoma (CPDN), and cystic WT (CWT) are a
that has not been identified in classical CMN, but is character- spectrum with CN at the benign end, CWT at the malignant
istic of infantile fibrosarcoma.238,239 This led to the hypothesis end (these must have both a solid and cystic component),
that cellular CMN is an intrarenal occurrence of infantile fibro- and CPDN in the intermediate position. The three types can-
sarcoma, whereas classic CMN reflects intrarenal fibromatosis. not be differentiated using imaging techniques and can be
The cloning of the resulting gene fusion has allowed the devel- confused with cystic clear cell sarcoma and cystic mesoblastic
opment of molecular detection assays for this subtype of con- nephroma.254 Multicystic dysplastic kidney can generally be
genital mesoblastic nephroma. The absence of the fusion distinguished radiographically from the other entities, be-
product in classical congenital mesoblastic nephroma corre- cause it lacks any normal renal parenchyma that the other
lates with its demonstrated absence in infantile myofibroma- lesions should contain.255
tosis. The challenge then is to explain the existence of the
mixed lesions.
CYSTIC NEPHROMA
Clinically, most children with CMN have an excellent prog-
nosis and are cured with a radical nephroureterectomy with CN is an uncommon benign renal lesion that occurs most
lymph node sampling.236,240 However, CMN tends to grow commonly in children younger than 24 months of age, with
into the hilar and perirenal soft tissue, and recurrence or me- a male to female ratio close to 2:1. A second peak incidence
tastases are seen.241,242 In 1973, the first reports of local recur- occurs in adults around 30 years of age, with an 8:1 female
rences in children with CMN appeared in the literature.243–245 to male predominance.255–258 Grossly, these masses are
Since then, metastasis to the lung, liver, brain, and heart have
been reported.245–249 Recurrence and metastatic disease has
lead to a debate concerning the need for adjuvant therapy
to prevent these rare events in a subset of patients versus
the risks of this therapy in infants.237,241
Subsequent investigations demonstrated that recurrences
were seen preferentially in either the cellular or the mixed
subtypes. Other suggested risk factors for recurrence included
age (more than 3 months of age), stage (stage III resulting
from incomplete surgical resection), and vascular inva-
sion.250,251 In 2006, the German Pediatric Oncology Group
published their experience with 50 children with CMNs, sug-
gesting that a subgroup of children more than 3 months of
age with stage III cellular CMN tends to develop recurrences
more often supporting the earlier findings.252 Alternatively,
Perlman and colleagues evaluated 396 cases of CMN from
the database of the J.B. Beckwith Developmental Renal Tumor
Collection.253 Thirty CMNs were known to have recurred
(7.6% overall recurrence rate and 9.3% recurrence rate for tu-
mors with a cellular histologic component). Recurrences took
place within 1 year of diagnosis (range, 2 to 11.5 months); 20
were local, 8 were metastatic, and 2 were both local and
metastatic. None of the classical CMNs recurred, including
18 that were known or suspected to have residual disease. Re-
currences were confined to tumors with a cellular component FIGURE 30-11 A magnetic resonance scan of a cystic nephroma.
440 PART III MAJOR TUMORS OF CHILDHOOD
well-encapsulated multilocular tumors composed of various-
sized cysts with thin septations that compress the normal kid-
ney. Microscopically, the identifying feature is that of mature
well-differentiated cell types within the septa of the cyst wall.
There are no blastemal or embryonal elements.254,255 Most
cases are unilateral, but some are bilateral.259 Although CN
is benign, cases have been reported with pleuropulmonary
blastoma as well. The relationship between these two entities
is undefined.260,261
CYSTIC PARTIALLY DIFFERENTIATED
NEPHROBLASTOMA
Cystic partially differentiated nephroblastoma is a multilocular
cystic WT composed entirely of cysts separated by delicate
septa. The majority of these lesions occur in the first 2 years
of life.256,262,263 Cystic partially differentiated nephroblastoma
is usually well circumscribed and sharply demarcated from
the adjacent normal kidney. It can be large (up to 18 cm in di-
ameter) and may produce visible abdominal distention. This
neoplasm is composed entirely of variably sized cysts; unlike
CN, the septal stroma contains small foci of blastema, primitive
or immature epithelium, and/or immature-appearing stromal
cells.264,265 In addition, skeletal muscle fibers are commonly
present in cystic partially differentiated nephroblastoma.
Both COG/NWTSG and SIOP have reported their experi-
ences with CN and CPDN.262,266,267 In the NWTSG study,
21 patients were evaluated.262 Thirteen patients received che-
motherapy, and 8 patients did not. In the chemotherapy
group, the distribution by stage was 10 children with stage
I, 2 children with stage II, and 1 child with stage V. The
8 no-chemotherapy patients were all stage I with a 100% sur-
vival. The SIOP evaluated 14 patients with diagnoses of cystic
nephroma (7 patients) and cystic partially differentiated
nephroblastoma (7 patients). Two patients received preopera-
tive chemotherapy. Primary nephrectomy was performed in
12 patients. Two patients underwent partial nephrectomy.
In 1 child, postoperative chemotherapy was administered.
None of the patients had progression of disease or recurrence.
Overall survival was also 100%.267 There is some concern
about doing partial nephrectomies because of recurrences af-
ter incomplete excision as well as distinguishing this tumor
from other malignant lesions.267,268
The complete reference list is available online at www.
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