SECTION G Oncology
53 Pediatric Urologic Oncology: Renal and Adrenal
Michael L. Ritchey, MD, Nicholas G. Cost, MD, and Robert C. Shamberger, MD
NEUROBLASTOMA
Neuroblastoma is the most common extracranial solid tumor of
childhood. Unfortunately, more than half of the children are seen
initially with metastatic disease. Neuroblastoma is known to arise from
cells of the neural crest that form the adrenal medulla and sympathetic
ganglia. Tumors may occur anywhere along the sympathetic chain
within the neck, thorax, retroperitoneum, or pelvis or in the adrenal
gland: 75% arise in the retroperitoneum, 50% in the adrenal, and
25% in the paravertebral ganglia. The variety of locations where
these tumors arise and the spectrum of their differentiation result in
a wide range of clinical presentations and behaviors (Brodeur, 1991).
These tumors can undergo spontaneous regression (Brodeur, 1991),
differentiate to benign neoplasms, or exhibit extremely malignant
behavior. Biologic factors have been defined that predict and explain
much of the variance in behavior between tumors.
Epidemiology and Genetics
Incidence
Neuroblastoma accounts for 8% to 10% of all childhood cancers.
In the United States, the annual incidence is 10 cases per 1 million
live births. It is the most common malignant tumor of infancy. A
review of 3666 children enrolled in the cooperative group trials of
the Pediatric Oncology Group and the Children’s Cancer Group
showed a median age at diagnosis of 19 months (Brodeur and Maris,
2006): 36% were infants, 89% were younger than 5 years, and 98%
were diagnosed by 10 years of age.
Genetics
There have been a number of familial cases reported that are pos-
tulated to represent an autosomal dominant pattern of inheritance
(Knudson and Strong, 1972; Robertson et al., 1991). Although the
median age at diagnosis of neuroblastoma is 19 months, in familial
cases it is 9 months (Kushner et al., 1986). At least 20% of patients
with familial neuroblastoma have bilateral adrenal or multifocal
primary tumors, which are unusual in spontaneous cases. The risk for
development of neuroblastoma in a sibling or offspring of a patient
with neuroblastoma is less than 6% (Kushner et al., 1986). Linkage
analysis in seven families with two or more first-degree relatives
affected with neuroblastoma identified a single interval at chromo-
some 16p12-13 with consistent linkage (Maris et al., 2002). This
suggested that a hereditary neuroblastoma predisposition gene may
be located at this site and may explain the familial cases. Subsequent
studies in these familial cases, which account for less than 1% of
patients with neuroblastoma, have identified PHOX2B and ALK as
hereditary predisposition genes (Mosse et al., 2004, 2008).
Constitutional Chromosome Abnormalities
Numerous karyotypic abnormalities have been found in neuroblas-
toma, and these are recognized to have prognostic significance. These
changes occur in the form of chromosomal deletions, translocations,
and cytogenetic evidence of gene amplification. Aneuploidy of the
tumor DNA, an abnormal number of copies of the normal 23
chromosomes, occurs in a significant number of cases (55%) and
is a favorable prognostic indicator when compared with tumors that
have a normal or tetraploid number (Kaneko et al., 1987). Amplifica-
tion of the MYCN oncogene at 2p24 defined as greater than 10
copies of this gene is seen in roughly 20% to 25% of primary
tumors and is an adverse prognostic indicator (Look et al., 1991;
Muraji et al., 1993). It is present in 40% of patients with advanced
stage disease but in only 5% to 10% of children with low-stage
disease (Brodeur et al., 1984). It is associated with rapid tumor
progression and poor outcome from treatment. These findings have
been so striking that neuroblastoma was the first tumor in which
the intensity of chemotherapy for a patient was determined not only
by the stage and histology of the tumor but also by its “biologic
markers,” which were primarily chromosomal (Matthay et al., 1998).
Deletion of the short arm of chromosome 1 (1p) is found in
25% to 35% of neuroblastomas and is an adverse prognostic marker
(Brodeur et al., 1992; Caron et al., 1996). The deletions are of various
lengths, but, in a series of eight cases, a consensus deletion included
the segment 1p36.1-2, suggesting that a tumor suppressor may be
present in this region; although the involved genes have not been
identified conclusively, CHD5 is a strong candidate for this role
(Fujita et al., 2008; Maris et al., 2007; Weith et al., 1989). This deletion
is present in 70% of advanced stage neuroblastoma, and it has been
demonstrated to be an independent prognostic factor (Attiyeh et al.,
2005). There have been reports of constitutional abnormalities
involving the short arm of chromosome 1 (Laureys et al., 1990). It
has been demonstrated that loss of heterozygosity (LOH) at 1p36
and Unb11q is independently associated with a worse outcome in
patients with neuroblastoma (Attiyeh et al., 2005). (Unbalanced
LOH implies LOH at markers on 11q with retention of 11p material,
in contrast with “whole-chromosome” 11 LOH, where there is LOH
at every marker along the chromosome.) Although the 1p deletions
are seen in conjunction with advanced stage and MYCN amplification,
the 11q deletions are rarely seen in tumors with MYCN amplification
but are associated with other high-risk features and are predictive
of poor outcomes in the subset of patients with low-stage disease
without MYCN amplification (Spitz et al., 2006). An additional
genetic abnormality, gain of one to three copies of 17q, often the
result of translocation with chromosomes 1 or 11, has been dem-
onstrated to correlate with more aggressive tumors (Bown et al.,
1999). The break points vary, but the addition of a region from
17q22-qter is common, suggesting that genes replicated in this region
provide an advantage (Schleiermacher et al., 2004). In multivariate
analysis, gain of 17q was the most powerful prognostic factor, followed
by the presence of stage IV disease and deletion of 1p.
Embryology and Spontaneous Regression
In 1963 Beckwith and Perrin coined the term in situ neuroblastoma
for small nodules of neuroblasts found incidentally within the adrenal
gland that are histologically indistinguishable from neuroblastoma.
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1088 PART III Pediatric Urology
In situ neuroblastoma was found during postmortem examination
in 1 of 224 infants younger than 3 months. This represents an
incidence of approximately 40 to 45 times greater than that of clinical
tumors, suggesting that these small tumors regress spontaneously
in most cases. Subsequent studies have shown that these nodules
of neuroblasts are found in all fetuses studied and generally regress
(Ikeda et al., 1981). Neuroblastoma identified by prenatal ultraso-
nography (US) has also been shown to have a clinically favorable
course (Ho et al., 1993).
The concept of in situ neuroblastoma has been used to support
the argument that many neuroblastomas arise and regress spontane-
ously. This concept has been further supported by population-based
studies in Quebec province and in Japan, where prospective screening
of infants for neuroblastoma has been performed based on urinary
catecholamine excretion. An increased number of children were
identified with low-stage neuroblastoma, a higher frequency than
present clinically, but resection of those tumors did not result in a
decrease in the incidence of advanced-stage tumors seen at an older
age (Hayashi et al., 1995; Woods et al., 1996). A subsequent German
Neuroblastoma Screening Study postponed screening until 10 to 19
months of age. Fewer early stage cases were identified, and a greater
frequency of patients with unfavorable clinical and biologic features
were identified, but there was no decrease in the mortality of these
patients (Schilling et al., 2002). Evaluation of adrenal tumors resected
in the neonatal period, whether cystic or solid, showed that in most,
the “biologic markers” were favorable (Kozakewich et al., 1998).
The highly favorable outcome of infants diagnosed with neuroblas-
toma in the population screening studies led to attempts at expectant
observation. These trials demonstrated a high rate of spontaneous
resolution (Yamamoto et al., 1998; Yoneda et al., 2001). Spontaneous
regression of these perinatally identified lesions also has been
demonstrated radiographically (Holgerson et al., 1996). These findings
led to a prospective study by the Children’s Oncology Group (COG)
evaluating treatment of infants with adrenal masses identified in
the perinatal or neonatal period in which expectant observation for
infants with small lesions with favorable catecholamine ratios was
encouraged and is discussed later.
Pathology
Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma display
a spectrum of histologic maturation and differentiation (Fig. 53.1).
A grading classification of neuroblastoma, introduced in 1984 by
Shimada and subsequently modified by him and others as the
A B
Fig. 53.1. (A) Poorly differentiated neuroblastoma with a minimal to moderate amount of neuropil. (B)
Ganglioneuroblastoma with more than 50% of surface area occupied by Schwannian stroma on left.
Lobule contains ganglion cells, immature ganglion cells, and poorly differentiated neuroblasts; only minimal
neuropil is present within lobule. (Photo courtesy Dr. Harry Kozakewich.)
International Neuroblastoma Pathology Classification in 1999, has
helped to define risk-based subtypes of ganglioneuroblastoma and
neuroblastoma (Shimada et al., 1984, 1999a, 1999b). This revised
system has been demonstrated to add independent prognostic
information beyond the contribution of age that is one of the factors
contained in the system (Sano et al., 2006). Ganglioneuroma is a
histologically benign, fully differentiated counterpart of neuroblas-
toma. It is unclear whether ganglioneuroma arises de novo or by
maturation of a preexisting neuroblastoma or ganglioneuroblastoma.
Metastatic lesions from neuroblastoma have been observed to develop
the histology of mature ganglioneuroma, supporting the latter theory
(Hayes et al., 1989).
The Shimada classification is an age-linked histopathologic
classification. One of its important aspects is determining whether
the tumor is stroma poor or stroma rich. Patients with stroma-poor
tumors with unfavorable histopathologic features have a very
poor prognosis (less than 10% survival) (Shimada et al., 1984).
Stroma-rich tumors can be separated into three subgroups: nodular,
intermixed, and well differentiated. Tumors in the latter two categories
more closely resemble ganglioneuroblastoma or immature ganglio-
neuroma and carry a higher rate of survival. The stroma-poor tumors
can be divided into favorable and unfavorable subgroups based on
the patient’s age at diagnosis, the degree of histologic maturation,
and the mitotic rate. When compared with other clinical features,
these histologic patterns were independently predictive of outcome
(Shimada et al., 1984).
In contrast to neuroblastomas, ganglioneuromas are most often
diagnosed in older children and are usually located in the posterior
mediastinum and retroperitoneum, with only a small number arising
in the adrenal glands (Enzinger and Weiss, 1988). Ganglioneuromas
often grow to a very large size before they cause symptoms as a
result of compression of adjacent structures or extension into the
spinal canal (Benjamin et al., 1972; Fig. 53.2). Because survival is
not influenced by extent of resection, it should be used only in those
patients in whom significant symptoms are present, and aggressive
attempts at resection should be avoided (DeBernardi et al., 2008).
Clinical Presentation and Pattern of Spread
The clinical manifestations of neuroblastoma vary widely. Most
children have abdominal pain or a palpable mass, but others are
identified as a result of manifestations of their metastatic disease,
including bone or joint pain and periorbital ecchymosis. Thoracic
lesions may produce respiratory symptoms of cough or dyspnea.
 Chapter 53
Fig. 53.2. MRI of child with thoracic ganglioneuroma extending into the
spinal canal (solid arrow).
Fig. 53.3. MRI demonstrating compression of bowel and bladder by a pelvic
neuroblastoma.
Direct extension of the tumor into the spinal canal may produce
neurologic deficits as a result of cord compression.
Most primary tumors arise within the abdomen (65%); the
frequency of adrenal tumors is slightly higher in children than in
infants. Physical examination often reveals a fixed, hard abdominal
mass. Pelvic neuroblastoma arising from the organ of Zuckerkandl
accounts for 4% of tumors (Haase et al., 1995). Extrinsic compression
of the bowel and bladder can produce symptoms of urinary retention
and constipation (Fig. 53.3).
Metastases are present in 70% of patients with neuroblastoma at
diagnosis and can be responsible for a variety of the clinical signs
and symptoms at presentation. A number of unique paraneoplastic
syndromes have been associated with localized and disseminated
neuroblastoma. Symptoms produced by catecholamine release may
mimic those seen in pheochromocytoma: paroxysmal hypertension,
palpitations, flushing, and headache. Secretion of vasoactive intestinal
peptide (VIP) by the tumor can produce severe watery diarrhea
and hypokalemia (Cooney et al., 1982). Another unusual presenta-
tion of neuroblastoma is acute myoclonic encephalopathy, in which
Pediatric Urologic Oncology: Renal and Adrenal 1089
patients develop myoclonus, rapid multidirectional eye movements
(opsoclonus), and ataxia. It is thought to result from an interaction
of antibodies produced against the neuroblastoma to normal neural
tissues (Connolly et al., 1997; Farrelly et al, 1984). Although this
syndrome is associated with a favorable outcome from an oncologic
perspective (Altman and Baehner, 1976), prolonged neurologic impair-
ment, including learning disabilities and developmental delay, is the
rule in 70% to 80% of these children, and symptomatic therapy is
often required (Mitchell et al., 2002; Rudnick et al., 2001; Russo
et al., 1997). Adrenocorticotropic hormone (ACTH) or steroids are
the basis of most therapy, but other treatments include high-dose
intravenous gamma globulin and cyclophosphamide. A recently
completed protocol of the Children’s Oncology Group evaluated
the efficacy of cyclophosphamide plus steroids randomized to
receive intravenous gamma globulin or not. The addition of IVIG
to prednisone and risk-adapted chemotherapy improved opsoclonus/
myoclonus response (de Alarcon et al., 2018).
Diagnosis
Laboratory Evaluation
When sensitive techniques are used, increased levels of urinary
metabolites of catecholamines, vanillylmandelic acid (VMA) and
homovanillic acid (HVA), are found in 90% to 95% of patients
(Williams and Greer, 1963). Therapy with various modalities produces
a reduction in catecholamine metabolite excretion in most patients
(Gerson and Koop, 1974). These metabolites can be monitored to
detect tumor relapse and response to therapy.
Anemia is noted in children with widespread bone marrow
involvement. Studies suggest that marrow biopsies add substantially
to the detection of marrow involvement by tumor, compared with
marrow aspirates alone (Franklin and Pritchard, 1983). It is recom-
mended that two marrow aspirates and two biopsies be performed
for staging at presentation. In the future, neuroblastoma-specific
immunocytology of marrow aspirates may obviate the need for
marrow biopsies in most patients (Hsiao et al., 1990).
Imaging
Imaging studies play an important role in the evaluation of a child
with neuroblastoma. Plain radiographs may demonstrate a calcified
abdominal or posterior mediastinal mass. Computed tomography
(CT) and magnetic resonance imaging (MRI) provide more infor-
mation about the local extent of the primary tumors and vascular
involvement. Invasion of the renal parenchyma is not common,
but it can be detected radiographically by CT (Albregts et al., 1994).
MRI has advantages over CT in the evaluation of intraspinal tumor
extension, which is common in the paravertebral lesions (see Fig.
53.2), and in demonstrating the relationship between the major vessels
and the tumor (Azizkhan and Haase, 1993; Fig. 53.4). The finding
of intratumoral calcifications, vascular encasement, or both on
preoperative CT may help distinguish neuroblastoma from Wilms
tumor (Dickson et al., 2008). Current Children’s Oncology Group
protocols require a radionuclide meta-iodobenzylguanidine (MIBG)
scan for staging but no longer require the classic skeletal survey or
bone scans. MIBG scans use 123I-MIBG (Geatti et al., 1985), which
is taken up by the adrenergic secretory vesicles of the tumor cells in
primary and metastatic sites. MIBG scintigraphy can determine the
extent of disease and detect tumor recurrence after completion of
therapy (Geatti et al., 1985). 123I-MIBG has been shown to be more
sensitive than either 131I-MIBG or bone scans in detecting tumor
relapse (Kushner et al., 2009). For patients who have non-MIBG
avid tumors, positron emission tomography (PET) scans are used.
Osseous metastatic lesions occur most commonly in the long bones
and skull.
Screening
Mass population screening for neuroblastoma has been widely used
in Japan for more than 20 years (Nishi et al., 1987). The goal of
1090 PART III Pediatric Urology

screening programs is to detect disease at an earlier stage and to
decrease the number of older children with advanced-stage disease,
thereby improving survival. In fact, the children diagnosed as a result
of screening studies have had almost uniformly favorable survival
(>97%) (Suita, 2002). An increased number of infants younger than
1 year of age have been diagnosed through the mass screening program
(Ishimoto et al., 1990), and most of these patients have lower-stage
tumors (Sawada, 1992). Before mass screening, 20% of neuroblastoma
cases were diagnosed before 1 year of age, compared with 55% after
its implementation. However, the number of children older than 1
year of age diagnosed with advanced-stage disease has not decreased.
These results suggest that the aggressive advanced-stage tumors in
older children did not arise from the low-risk tumors seen in the
infants less than 1 year of age.
There are biologic differences between tumors diagnosed by
screening and those detected clinically (Hayashi et al., 1992). In
one review of 48 cases discovered by screening, no tumors were
observed to have amplified MYCN oncogene expression (Ishimoto
et al., 1991), and in a second review of 20 infants, only one who
did poorly had amplification (Hase et al., 2002). Furthermore, 80%
had a diploid chromosome pattern, which is also associated with a
favorable prognosis. On follow-up, all 48 patients were still alive
without tumor. In another series of 357 patients whose tumors were
diagnosed by mass screening, the overall survival rate was 97%
(Sawada, 1992). Given the favorable biologic characteristics of tumors
discovered by screening, it is possible that many would spontaneously
resolve without therapy, particularly given the increased incidence
of neuroblastomas seen in the screened population.
Two large prospective population-based studies were conducted
in the Province of Quebec and in Germany. These studies demon-
strated that urine screening at various ages was successful in identifica-
tion of neuroblastoma, but there was no decrease in the occurrence
of neuroblastoma in older children and its subsequent mortality
(Schilling et al., 2002; Woods et al., 2002).

Fig. 53.4. MRI of pelvic neuroblastoma. The bifurcation of the aorta and iliac
vessels are well delineated, showing the relationship to the mass.
Staging
Staging of neuroblastoma is an important aspect of management.
The stage of the disease is a significant prognostic variable that
determines adjuvant therapy in the cooperative group trials. The
International Neuroblastoma Staging System (INSS) is based on
clinical, radiographic, and surgical evaluation of children with
neuroblastoma (Brodeur et al., 1993; Table 53.1). Earlier staging
systems provided generally comparable results in terms of distinguish-
ing low-stage, good-prognosis disease from high-stage, poor-prognosis
disease. Use of a uniform international system, however, makes
comparison of results from various studies much easier. The biggest
differences arise when the various systems are applied to those with
intermediate-stage disease.
An effort has been made to identify, preoperatively, those tumors
that are resectable without significant surgical risks. The Localized
Neuroblastoma European Study Group (LNESG) defined the
radiographic criteria associated with higher surgical morbidity. They
validated that the criteria’s presence was associated with a lower rate
of complete resection and a greater risk of surgical complications
(Cecchetto et al., 2005). This finding has been confirmed by others
(Simon et al., 2008). The International Neuroblastoma Risk Group
(INRG) Task Force proposed a staging system based on tumor imaging
rather than the extent of surgical resection to address this problem
(Monclair et al., 2009). In this system, localized tumors are graded
as L1 or L2 based on the absence or presence of 1 or more of 20

TABLE 53.1 International Neuroblastoma Staging System

STAGE DEFINITION

1 Localized tumor with complete gross excision with or without microscopic residual disease; representative ipsilateral lymph
nodes negative for tumor microscopically (nodes attached to and removed with the primary tumor may be positive).
2A Localized tumor with incomplete gross excision; representative ipsilateral nonadherent lymph nodes negative for tumor
microscopically.
2B Localized tumor with or without complete gross excision, with ipsilateral nonadherent lymph nodes positive for tumor.
Enlarged contralateral lymph nodes must be negative microscopically.
3 Unresectable unilateral tumor infiltrating across the midlinea, with or without regional lymph node involvement; or localized
unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral extension by
infiltration (unresectable) or by lymph node involvement.
4 Any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin and/or other organs.
4S Localized primary tumor (as defined for stage I, IIA, or IIB), with dissemination limited to skin, liver, and/or bone marrow
(less than 10% tumor) in infants < 1 year of age.

a
The midline is defined as the vertebral column. Tumors originating on one side and crossing the midline must infiltrate to or beyond the opposite
side of the vertebral column.
 Chapter 53 Pediatric Urologic Oncology: Renal and Adrenal 1091

TABLE 53.2 International Neuroblastoma Risk Group (INRG) Classification System

INRG AGE HISTOLOGIC GRADE OF TUMOR 11Q PRETREATMENT

STAGE (MONTHS) CATEGORY DIFFERENTIATION MYCN ABERRATION PLOIDY RISK GROUP
L1/L2 GN maturing A. Very low
GNB intermixed
L1 Any, except NA B. Very low
the above Amp K. High
L2 <18 Any, except NA No D. Low
the above Yes G. Intermediate
≥18 GNB nodular Differen NA No E. Low
neuroblastoma Yes H. Intermediate
Poorly differen NA H. Intermediate
or undifferen Amp N. High
M <18 NA Hyperdiploid F. Low
<12 NA Diploid I. Intermediate
12 to <18 NA Diploid J. Intermediate
<18 Amp O. High
≥18 P. High
MS <18 NA No C. Very low
NA Yes Q. High
Amp R. High

Blank field = any; Diploid – DNA index ≤ 1.0; Hyperdiploid – DNA index > 1.0 and includes near-triploid and near-tetraploid; very-low–risk 5-year EFS
>85%; low-risk 5-year EFS >75% to ≤85%; intermediate-risk 5-year EFS ≥50% to ≤75%; high-risk 5-year EFS <50%; L1 localized tumor confined to
one body compartment and with absence of image-defined risk factors (IDRFs); L2 locoregional tumor with presence of one or more IDRFs; M distant
metastatic disease except stage MS; MS metastatic disease confined to skin, liver, and/or bone marrow in children <18 months of age.
Amp, Amplified; Differen, differentiating; GN, ganglioneuroma; GNB, ganglioneuroblastoma; NA, not amplified; Undifferen, undifferentiating.

image-defined risk factors (IDRFs), which are related primarily to
encasement of vessels or nerves. Metastatic tumors are termed stage
M, and MS refers to INSS stage IV-(S) in children younger than
18 months of age, whereas in INSS the age cutoff was 12 months.
These factors were found to be prognostic, and in 661 patients, those
with L1 disease had a greater 5-year event-free survival (EFS) (90
± 3%) compared with those with L2 disease (78 ± 4%, P = 0.001).
A further description of these guidelines has been reported by this
group (Brisse et al., 2011). Although a close correlation between
presence of IDRFs and resectability of the tumor has been reported,
others have not supported this finding (Günther et al., 2011; Rich
et al., 2011). A follow-up from the LNESG of patients with localized
disease demonstrated that the presence of IDRFs is associated with
worse survival rates and higher rates of operative complications
(Monclair et al., 2015). A SIOPEN study of children with unresectable
neuroblastoma demonstrated that the IDRFs remained unchanged
in 50% of patients receiving chemotherapy and that in fact 20%
suffered the appearance of new IDRFs (Avanzini et al., 2017). They
also identified that children with midline perivascular IDRFs had
an increased incidence of operative complications but also lower
EFS and overall survival (OS).
The International Neuroblastoma Risk Group Pretreatment Clas-
sification uses the Risk Group Classification (INRGSS), pathological
findings, stage, age, and several of the biologic markers to best define
the child’s risk for progressive disease (Table 53.2; Cohn et al., 2009).
Although the classification appears complex, it provides the most
accurate assessment of how intense the chemotherapy and radio-
therapy must be to cure the child. The challenge with any staging
system that uses extent of resection as a component, however, is
that a more aggressive approach to a tumor at one institution may
result in a different stage for the child than if treated at another.
Prognostic Factors
Many variables affect the prognosis of neuroblastoma. In addition
to the clinical features, there are now many biologic factors that can
be used to stratify patients for treatment.
Clinical Variables
Age remains an important indicator of outcome, as originally reported
by Breslow (Breslow and McCann, 1971). Children age 1 year or
younger have been recognized historically to have a better survival
than older children (Nitschke et al., 1988). This may be attributed
to the presence of favorable biologic parameters in tumors
diagnosed at this age. Retrospective reviews have suggested that age
is a more “continuous” prognostic variable and that a cutoff of 460
days maximized the outcome difference between the younger and
older patients (London et al., 2005). More recent data from the
INRG suggest that an age at diagnosis cutoff of greater than 18
months is associated with a higher risk of disease recurrence (Moroz
et al., 2011). Teenagers and adults with neuroblastoma have a par-
ticularly indolent and relentless disease (Gaspar et al., 2003; Kushner
et al., 2003). The site of origin is also of significance, with better
survival noted for nonadrenal primary tumors (Haase et al., 1995).
Most children with thoracic neuroblastoma are seen at a younger
age with localized disease and have improved survival even when
corrected for age and stage (Adams et al., 1993). Tumors at this site
are less likely to have MYCN amplification and more likely to have
a DNA index greater than 1.0, both favorable prognostic indicators
(Morris et al., 1995).
Stage of the disease is a powerful independent prognostic
indicator. All stage I patients with complete resection of the
primary tumor survive. Stage II patients also have a favorable
survival prospect, even though there may be incomplete excision
(Matthay et al., 1989). Children with advanced regional disease,
stages III or IV, fare less well and require more intensive treatment.
The proportion of patients with localized, regional, or metastatic
disease is age dependent (Nitschke et al., 1988). The OS for stages
I, II, or IV-S was a range of 75% to 90%, whereas those children
with stage IV disease had a historical 2-year disease-free survival
range of 19% to 30% despite intensive therapy, including bone
marrow transplantation. The outcome for infants younger than 1
year of age is substantially better than for older patients with the
same stage of disease.
1092 PART III Pediatric Urology
Stage IV-S (S meaning special) is a distinct category referring
to infants with small primary tumors and liver, skin, and bone
marrow metastases without radiographic evidence of bone
metastases. This group of patients has a good prognosis, with OS
ranging from 80% to 88%. The INSS criteria later restricted this
stage to children with less than 10% bone marrow involvement
(Brodeur et al., 1993). This stage accounts for 7% to 10% of all cases
of neuroblastoma. Many of these tumors undergo spontaneous
regression (Evans et al., 1987; Haas et al., 1990). In general, the
tumors in infants with stage IV-S neuroblastoma have favorable
prognostic findings not typically seen in children with stage IV disease
(Hachitanda et al., 1991; Nickerson et al., 2000). Poor outcome in
stage IV-S patients is associated with elevated serum neuron-specific
enolase (>100 nmol/mL), ferritin (>280 ng/mL), urinary dopamine
levels (>2500 nmol/mmol creatinine), as well as MYCN amplification
and chromosome 1p deletion (Schleiermacher et al., 2003). Most
deaths in this group are in infants under 2 months of age with
extensive abdominal involvement and respiratory compromise or
disseminated intravascular coagulation (Nickerson et al., 2000).
Biologic Variables
The presence of homogeneously staining regions and double-minute
chromosomes was noted in approximately one-third of neuroblastoma
tumors. These abnormalities are cytogenetic manifestations of gene
amplification, and it was subsequently found that the MYCN oncogene
was mapped to these regions. The association of MYCN amplification
with the pathogenesis of neuroblastoma is unclear, but MYCN
amplification is almost always present at the time of diagnosis
(Brodeur, 1991). Seeger et al. (1985, 1988) showed that MYCN
amplification is associated with rapid tumor progression and a
poor prognosis. Amplification is found in 5% to 10% of patients
with low-stage or stage IV-S (Hachitanda et al., 1991) but in 30
to 40% of those with advanced-stage disease (Brodeur, 1990; Brodeur
and Fong, 1989). The poor prognosis associated with MYCN
amplification is independent of patient age or stage of disease
at presentation (Iehara et al., 2006). However, not all patients with
a poor outcome have MYCN amplification. Many advanced-stage
tumors lack MYCN at diagnosis, and recurrence or progression of
disease develops in most of these patients.
DNA content of tumor cells and ploidy number has been reported
to have prognostic value in patients with neuroblastoma (Cohn
et al., 1990). Studies of DNA content measured by flow cytometry
showed that a “hyperdiploid” karyotype (or increased DNA content)
was associated with a favorable outcome (Kusafuka et al., 1994;
Look et al., 1984). DNA diploidy and tetraploidy were associated
with decreased survival. A review of 2660 children with localized
neuroblastoma registered with the International Neuroblastoma Risk
Group database evaluated tumor ploidy in children with MYCN–
amplified tumors (Bagatell et al., 2009). They reported an improved
prognosis in children with hyperdiploid tumors compared with
diploid tumors. This could be used to identify children for reduction
in the intensity of their therapy. A full INRG analytic cohort of 8800
patients from North America, Europe, and Japan provided an extensive
analysis of the survival implications of multiple genetic characteristics
(Cohn et al., 2009). Again, MYCN status was the most powerful
predictor of EFS and OS along with ploidy, 11q and 1p status, and
to a lesser extent 17q gain.
Deletions of the short arm of chromosome 1 have been found
in 70% to 80% of the near-diploid tumors that have been karyotyped
(Brodeur, 1990; Brodeur and Fong, 1989). Preliminary studies suggest
a correlation between 1p deletion and poor survival (Brodeur and
Fong, 1989; Hayashi et al., 1989). Children currently treated on
protocols of the COG are assigned to a risk group that is determined
by age, stage of disease, MYCN status, histologic grade, and DNA
ploidy (Katzenstein et al., 1998). Other factors that have been
demonstrated to have prognostic significance, although they are often
associated with these genetic abnormalities, include expression of
the gene encoding the high-affinity nerve growth factor receptor
(termed TRKA proto-oncogene) and the low-affinity nerve growth
factor receptor (Tanaka et al., 1995). Both are favorable prognostic
predictors and are inversely related to amplification of MYCN
oncogene (Nakagawara et al., 1993). Lack of expression of CD44
glycoprotein on the tumor cell surface and increased levels of serum
ferritin, serum neuron-specific enolase, and serum lactate dehydro-
genase are adverse prognostic factors (Chan et al., 1991; Silber et al.,
1991). They have not, however, been shown by multivariate analysis
to be independently predictive from age, stage, ploidy, and MYCN
status. Telomere length has also been described as a significant
prognostic parameter, and in a cohort of high-risk patients, it was
the sole significant parameter that identified a group of patients
with a favorable prognosis (Ohali et al., 2006).
Treatment
The treatment modalities primarily used in the management of
neuroblastoma are surgery, chemotherapy, and radiation therapy.
The role of each in individual patients varies depending on tumor
stage, age, and biologic prognostic factors. These can be used to
stratify patients into favorable and unfavorable categories by risk
group (see Table 53.2).
Surgery
The goals of surgery are to establish the diagnosis, stage the
tumor, excise the tumor (if localized), and provide tissue for
biologic studies. Resectability of the primary tumor should take
into consideration tumor location, mobility, relationship to major
vessels and nerves (IDRFs), and overall prognosis of the patient.
Neoadjuvant chemotherapy, given the efficacy of modern agents,
is successful in reducing the size of primary tumors and enhancing
their resectability. Sacrifice of vital structures to achieve resection
at diagnosis should be avoided, particularly in young children in
whom prognosis is excellent.
Low-Risk Disease (Stages I, II, and IV-S). Children with stage
I neuroblastoma have a disease-free survival rate of greater than
90% with surgical excision alone (DeBernardi et al., 1995; Nitschke
et al., 1988; O’Neill et al., 1985). Chemotherapy is indicated only
in the event of recurrence unless the child has MYCN amplification
and unfavorable histology. The Pediatric Oncology Group reviewed
101 children with localized neuroblastoma who had complete gross
excision of the primary tumor (Nitschke et al., 1988). Nine patients
experienced relapse, but 6 were salvaged with chemotherapy. Radiation
therapy has no role in this subset of patients. With current use of
the risk factor grading, those children with recurrence in the past
may be identified now as the small number with adverse biologic
markers. In a comparable study from the Children’s Cancer Group,
374 stage I and II patients were treated primarily by resection (Perez
et al., 2000). EFS and OS for stage I patients were 93 ± 3% and 99
± 1%, respectively, compared with 81 ± 4% and 98 ± 2% for stage
II patients, respectively. Supplemental treatment was required in
only 10% of stage I and 20% of stage II patients, and excellent OS
was achieved in the stage II patients. MYCN amplification, unfavorable
histology, age greater than 2 years, and positive lymph nodes predicted
a lower OS. The Children’s Oncology Group (COG) conducted a
trial of asymptomatic INSS stages 2a and 2b patients treated with
surgery alone (Strother et al., 2012). Chemotherapy on this study
was reserved for patients with symptomatic disease or in those
considered at risk for its development, or those with less than 50%
resection with unresectable progressive disease after surgery. For all
915 enrolled patients, the 5-year EFS and OS were 89% ± 1% and
97 ± 1%. In the cohort with IIb disease, the EFS and OS were sig-
nificantly lower for those with unfavorable histology or diploid
tumors, and OS was significantly lower for those 18 months and
older. The 5-year OS for patients with stage I and IV-S were 99% ±
1% and 91% ± 1%, respectively; 11.1% of patients observed after
surgery experienced recurrence or progressive disease.
Radical resection resulting in removal of normal organs, particularly
the kidney, is not justified in this group of patients. Radiation of
the local tumor bed has been advocated for treatment of residual
disease in stage II cases. However, a review of 156 patients with stage
II neuroblastoma found a 90%, 6-year, progression-free survival rate
 Chapter 53
A B
Fig. 53.5. MRI before and after chemotherapy showing marked reduction in size of right suprarenal
neuroblastoma. (A) Before chemotherapy. (B) After chemotherapy.
regardless of whether radiation therapy was used (Matthay et al.,
1989). Therefore radiation should be reserved for those relapsed
patients who fail to respond to either primary or secondary che-
motherapy. In stage III disease, or in stage II with extensive tumor
around the kidney and renal vessels, preoperative treatment with
chemotherapy significantly decreases the risk of nephrectomy as a
result of resection of the tumor (Shamberger et al., 1998; Fig. 53.5).
The generally favorable behavior of IV-S disease has been explained
by our current knowledge of the significance of biologic markers.
The majority of these infants have tumors with entirely favorable
markers, explaining their favorable behavior. However, a small
fraction have adverse markers; these children have progressive
disease that often is fatal. Resection of the primary tumor is not
mandatory (Evans et al., 1987; Nickerson et al., 1985). Although
excellent survival has been reported after surgery (Martinez et al.,
1992), information regarding histologic prognostic factors was not
available for all of these patients. In a review of 110 infants with stage
IV-S disease, the entire cohort had an estimated 3-year survival rate
of 85% ± 4% (Katzenstein et al., 1998). This rate was significantly
decreased to 68% ± 12% for infants whose tumors were diploid;
to 44% ± 33% for those with MYCN amplification; and to 33% ±
19% for those with unfavorable histology. There was no statistical
difference in survival rate for infants who underwent complete
resection of their primary tumor compared with those who had
partial resection or only biopsy (Katzenstein et al., 1998; Nickerson
et al., 2000; von Schweinitz et al., 2002). Patients with extensive
metastatic disease and MYCN amplification represent a high-risk
group (Martinez et al., 1992). These patients should be considered
for a more intensive treatment with multimodal therapy, according
to the risk group classification (see Table 53.2) (Schleiermacher et al.,
2003). Those with favorable biologic markers and no symptoms
can be followed with supportive care and limited chemotherapy.
Intensive chemotherapy is reserved for those with adverse markers,
although these infants do poorly even with therapy.
Perinatal Neuroblastoma. Based on the favorable outcomes of
infants identified with neuroblastoma from the screening studies
discussed earlier and the favorable biology of these tumors, a prospec-
tive study was performed by the COG to assess the outcome of
expectant observation for neuroblastoma in young infants. Infants
were enrolled who were under 6 months of age with small adrenal
masses (≤16 mL in volume if solid or ≤65 mL if the mass was at
least 25% cystic) and no evidence of spread beyond the primary
Pediatric Urologic Oncology: Renal and Adrenal 1093
tumor (Nuchtern et al., 2012) was found. Serial abdominal sonograms
and urinary catecholamine levels were obtained during a 90-week
interval. A 50% increase in the volume of the mass, urine catecholamine
values, or the homovanillic acid–to–vanillylmandelic acid ratio greater
than 2 were referred for surgical resection: 87 infants were enrolled,
83 families elected observation, and 4 chose immediate surgery.
Sixteen infants on the observation arm ultimately had surgery; 8
had INSS stage I neuroblastoma, 2 had higher-stage neuroblastoma
(IIB and IV-S), 2 had a low-grade adrenocortical neoplasm, 2 had
adrenal hemorrhage, and 2 had extralobar pulmonary sequestration.
The 2 adrenal cortical tumors were resected because of a greater than
50% increase in tumor volume. The 3-year EFS for a neuroblastoma
event was 97.7% ± 2.2% within the entire cohort of infants. The
3-year OS was 100% with a median follow-up of 3.2 years. Following
this protocol, 81% of the infants avoided resection, supporting the
role of expectant observation in this selected population. Based on
the success of the first trial with fairly restrictive entry criteria, a
follow-up study was developed in which infants can be enrolled
who are under 12 months of age at presentation with suspected
lesions at any site that are under 5 cm in greatest diameter. For
non-adrenal primary tumors, MIBG update in the tumor or elevated
catecholamine levels must be present. Similar indications for surgical
intervention are used from the initial study. Until this approach is
established as safe, infants should be managed in this manner only
if enrolled in a therapeutic study.
Intermediate and High-Risk Disease (Stages III and IV). There
is debate regarding the extent of surgical resection required for stage
III lesions. A report from the Children’s Cancer Group of 58 patients
with stage III disease found that 8 of 12 patients with initial complete
excision, and 12 of 14 with subsequent resection of the primary
tumor, were long-term survivors (Haase et al., 1989). This result
contrasts with only 9 of 32 survivors among patients in whom
complete tumor excision could not be accomplished. Significant
morbidity was reported in association with the surgical procedures,
including 21 major complications. The Italian Cooperative Group
for Neuroblastoma found that complete resection after chemotherapy
of extensive unresectable neuroblastoma was associated with improved
survival, compared with partial resection only (Garaventa et al.,
1993). Similar results have been noted by others (Fischer et al.,
2017; LeTourneau et al., 1985; O’Neill et al., 1985; Powis et al.,
1996). It has been suggested by some that even children with stage
III disease do not need cytotoxic therapy if the biologic marker
1094 PART III Pediatric Urology
MYCN amplification is not present (Kushner et al., 1996). These
results are not widely accepted, however, and confirmatory studies
are required before this policy can be widely adopted.
Children with bulky pelvic tumors generally do well even with
limited residual disease (LeClair et al., 2004). Extensive surgery at
this site has been associated with long-term neurologic sequelae;
thus the extent of resection must be balanced against this morbidity
(Cruccetti et al., 2000).
A study from the COG of intermediate-risk patients attempted
to decrease the intensity of therapy while maintaining outcomes
(Baker et al., 2010). Criteria for enrollment into this study included
intermediate-risk neuroblastoma without MYCN amplification,
including infants younger than 365 days of age with stage III or IV
disease, children older than 365 days of age who had stage III tumors
with favorable histopathological features, and infants who had stage
IV-S disease with a diploid DNA index or unfavorable histopathologi-
cal features. Children received four active agents in this study:
cyclophosphamide, doxorubicin, carboplatin, and etoposide. They
received 4 cycles if they had favorable biology or 8 cycles if they
had unfavorable biology. Radiotherapy was used only for progressive
disease or in patients with an unresectable primary tumor with
unfavorable prognostic features. The 3-year estimate of OS for the
entire group was 96% ± 1%; 98% ± 1% for those with favorable
biologic features, and 93% ± 2% for those with unfavorable biologic
features. These findings supported the reduction in therapy for this
cohort of patients. Complete data regarding surgical intervention
were available in 235 patients. Gross total resection was achieved
in 89 patients, near total resection (>90% of the tumor) in 51, major
resection (>50% of the tumor) in 26, and limited resection (≤50%
of the tumor) in 54. No significant difference was demonstrated
in OS according to the extent of resection (complete vs. incomplete;
P = 0.37); 28% of patients had one or more complications.
A report from Memorial Sloan Kettering Cancer Center of children
with stage III, non-MYCN–amplified disease with gross residual
disease after initial surgery demonstrated that these patients could be
safely observed and maintained excellent OS without use of cytotoxic
therapy (Kushner et al., 1996). Similar results were found in the
German neuroblastoma 97 study, in which infants with stage II or
III MYCN non-amplified tumors who had incomplete resections
were observed after surgery without chemotherapy. Regression of
the residual masses without additional treatment was seen in 32 of
55 patients. Tumors that recurred or progressed were responsive to
therapy with a 3-year OS rate of 98% (Hero et al., 2008).
Unfortunately, more than half of all newly diagnosed patients
with neuroblastoma have high-risk disease. There is conflicting
evidence regarding the benefit of extensive resection in children with
stage IV disease between studies that support (Adkins et al., 2004;
Chamberlain et al., 1995; DeCou et al., 1995; Haase et al., 1991;
Koh et al., 2005; Kuroda et al., 2003; LaQuaglia et al., 1994, 2004;
LeTourneau et al., 1985; McGregor et al., 2005; Tsuchida et al., 1992;
Vollmer et al., 2017; von Allmen et al., 2005; Yokoyama et al., 1995)
and those that refute that approach (Adams et al., 1993; Castel et al.,
2002; Kaneko et al., 1997; Kiely, 1994; Losty et al., 1993; Matsumura
et al., 1988; McGregor et al., 2005; Simon et al., 2013; Sitarz et al.,
1983; von Schweinitz et al., 2002). In a retrospective review, Kiely
(1994) compared the results of radical tumor resection with those
of more conventional surgery in patients with stages III and IV disease.
He found no difference in survival between 46 patients treated with
radical surgical procedures and 34 patients treated with more
conventional surgery. Shorter et al. (1995) also did not find any
evidence that the extent of surgical resection had an impact on the
survival of stage IV patients. Simon et al. (2013) reported the results
of the German cooperative trial NB97 that evaluated the role of
surgery (upfront and post-neoadjuvant therapy) in patients older
than 18 months with stage IV disease: 278 patients were evaluated.
Their data suggested that neither upfront surgery nor operations
performed post neoadjuvant therapy produced a positive impact on
EFS, local progression-free survival, or OS. In contrast, von Allmen
et al. (2005) reported on the local control of 76 patients treated at
two institutions with the same treatment protocol and a consistent
surgical approach. They found that aggressive surgery followed by
local radiotherapy provided excellent local tumor control with no
isolated local relapse in patients who had greater than 90% resection
(60 of 76 children).
Subsequently, von Allmen et al. (2017) reviewed 220 patients
treated on the COG study A3973 with high-risk neuroblastoma. In
this cohort the blinded radiographic central imaging review for
completeness of resection was compared with the surgeon’s assess-
ment. Concordance between surgeon’s assessments and the radio-
graphic assessment was low, 63%. Nonetheless, the clinical assessment
of resection extent of greater than or equal to 90% (in 154 patients)
compared with resection of less than 90% (in 66 patients) after
adjustment for MYCN amplification or diploidy was associated with
longer EFS and lower clinical incidence of local progression but had
no effect on OS. In these nonrandomized studies, it has been difficult
to determine whether improved survival in those with complete
resection has been due to the more favorable intrinsic biology of
the tumor, allowing resection or truly because of the completeness
of resection. LaQuaglia has assessed the results in 33 non-redundant
studies, which provided adequate surgical data for analysis of survival
(LaQuaglia et al., 2014). The analysis included 2599 patients for the
survival analysis and 412 in the analysis of local progression. Meta-
analysis revealed that the relative risk of mortality for stage III and
IV patients who had more than 90% resection was 0.67 (95% CI
0.59–0.77) compared with those with a lesser resection. For stage
IV patients alone the relative risk was 0.75 (95% CI 0.62–0.92). The
relative risk of local recurrence or progression in patients with stage
IV disease was 0.38 (95% CI 0.27–0.53) for those undergoing extensive
primary resection compared with those who did not.
As the intensity of the therapy increases (including the use of
autologous bone marrow transplantation) and control of distant
metastasis improves, the impact of maximal local control may become
apparent. The combination of gross total resection and external
beam irradiation has achieved local control in 84% to 90% of children
(Kushner et al., 2001; Wolden et al., 2000). In another series of
reports, intensive chemotherapy followed by double autologous bone
marrow transplantation, aggressive surgical resection, and radiotherapy
has achieved an OS of 56% and a local recurrence rate of only 2.6%
(Marcus et al., 2003; von Allmen et al., 2005).
Usually the safest approach for advanced tumors is to defer
resection until after initial chemotherapy (Berthold et al., 1989;
Black et al., 1996; LaQuaglia et al., 1994; Shamberger et al., 1991;
Shochat, 1992). The tumors are smaller and firmer, with less risk
of rupture and hemorrhage after chemotherapy, resulting in a
decreased rate of complications, particularly nephrectomy (Sham-
berger et al., 1998; see Fig. 53.5). One specific complication
encountered after resection of extensive tumor surrounding the celiac
axis and the superior mesenteric artery is diarrhea (Kiely, 1994). It
is thought to result from resection of the autonomic nerves to the
gut found anterior to the aorta at the base of the superior mesenteric
artery and the celiac axis (Rees et al., 1998). The second frequent
complication after extensive resection is chylous ascities resulting
from resection of the involved retroperitoneal lymph nodes. This is
generally a self-limited problem, but initial extensive abdominal
distention may require intervention (Qureshi et al., 2016). Preopera-
tive chemotherapy does appear to increase the proportion of children
able to achieve a complete resection (Adkins et al., 2004).
Surgery usually is performed 13 to 18 weeks after initiation of
chemotherapy, allowing three to four courses of treatment (Azizkhan
and Haase, 1993). Some tumors remain inoperable even after
chemotherapy.
Infants under 1 year of age with extensive local disease or stage
IV disease make up a special subset of patients. They have historically
fared much better than children older than 1 year of age with
comparable disease, but not as well as infants with stage IV-S disease.
It is now recognized that biologic markers can be used to identify
which infants have high-risk disease and require intensive therapy
and which will have intermediate-risk disease requiring less intensive
therapy. The SIOPEN Infant Neuroblastoma European Study reported
120 infants with localized tumors and no MYCN amplification who
were deemed unresectable based on IDRFs (Rubie et al., 2011). These
infants were treated with low-dose cyclophosphamide and vincristine
 Chapter 53
(VCR) repeated once to three times every 2 weeks until surgical
excision could be safely performed. Infants with either one threatening
symptom or an insufficient response were given carboplatin and
etoposide (CaE) sometimes followed by vincristine, cyclophospha-
mide, and doxorubicin. Seventy-nine received the two-drug therapy
with VCR and 49 received CaE because of insufficient response.
Thirty-two infants had threatening symptoms and of these 30 received
CaE. Anthracyclines were used in 46 infants. Surgery was performed
in 102 infants leading to gross surgical excision in 93. Relapse occurred
in 12 patients (9 local and 3 distant). The 5-year OS and EFS were
99% ± 1% and 90% ± 3%, respectively. The low-dose chemotherapy
without an anthracycline was effective in 62% of these infants with
an unresectable tumor and no MYCN amplification.
In a large cohort (134 infants), MYCN amplification, serum ferritin,
Shimada histopathologic classification, and bone marrow involvement
by immunocytology were analyzed. Although each factor had
prognostic significance by univariate analysis, only MYCN amplifica-
tion was significant by multivariate analysis; the EFS for infants
without MYCN amplification was 93% ± 4% versus 10% ± 7% in
those with amplification despite intensive therapy (Schmidt et al.,
2000).
Clinical trials in Europe evaluated these infants without MYCN
amplification and achieved excellent survival (OS of 97.6% at 2
years) without chemotherapy in those with primaries extending across
the midline or a positive skeletal survey (DeBernardi et al., 2009).
Infants with overt metastases to the skeleton, lung, and central nervous
system (CNS) were treated with a minimum of four chemotherapy
courses and achieved a 2-year OS of 95.6%.
Chemotherapy
A variety of multiagent treatment regimens have been developed to
treat high-risk patients with neuroblastoma that use a combination
of intensive induction therapy, myeloablative consolidation therapy
with stem cell support, and biologic therapy to control minimal
residual disease. The goal of this treatment intensification in a
sequence of protocols is better disease control, and 5-year survival
rates have gone from less than 15% to 30% to 40% (Philip et al.,
1997). Although initial response rates are improving, with a prolonged
time to progression of disease, relapse continues to be a major
problem. A meta-analysis of 44 trials showed a correlation between
dose intensity and treatment efficacy including improved response
and survival (Cheung et al., 1991).
An induction regimen developed at Memorial Sloan-Kettering
Cancer Center has been widely used in subsequent protocols. It used
cycles of cyclophosphamide, vincristine, and doxorubicin alternating
with cycles of cisplatin and etoposide. In their single institution
study Kushner et al. (1994) reported complete response rate of 63%
and a complete plus very good partial response rate of 87% in 24
patients. The dose intensification of chemotherapy required for local
tumor control results in significant myelosuppression, limiting the
amount of therapy that can be given. This has prompted the use of
autologous bone marrow transplantation after sublethal chemotherapy
or total-body irradiation. The use of marrow-ablative chemoradio-
therapy followed by autologous marrow reinfusion has resulted in
complete remission in up to 50% of patients with stage IV disease
(Dinndorf et al., 1992; Grupp et al., 2000; Matthay et al., 1995;
Moss et al., 1987; Mugishima et al., 1994; Seeger et al., 1991).
However, a significant problem is the risk for late relapse. The random-
ized clinical trial of the German Society of Paediatric Oncology and
Hematology of high-risk neuroblastoma showed improved EFS at
3 years with myeloablative therapy and autologous stem cell rescue
compared with maintenance chemotherapy (Berthold et al., 2005).
These results were similar to those of the COG study (Matthay et al.,
1999). Unfortunately, the OS rates were not statistically different in
either study at initial report. An update of the latter study, however,
reveals that the 5-year OS of the patients receiving the autologous
bone marrow transplant was improved (Matthay et al., 2009).
A subsequent study by the COG addressed the issue of the need
for “purging” of the bone marrow before return to the patient to
remove any potential remaining neuroblastoma cells (Kreissman
Pediatric Urologic Oncology: Renal and Adrenal 1095
et al., 2013). This study was terminated when interim analysis showed
no difference in outcome between the two groups. A further study
addressed the benefit between a single versus a paired autologous
transplant to see if additional intensification would improve outcome.
It was demonstrated that tandem versus single myeloablative therapy
improves 3-year EFS in children with high-risk neuroblastoma (Park
et al., 2016).
Recent trials in COG have piloted a strategy of using non–cross-
resistant chemotherapy to further improve induction response rates.
Topotecan, a topoisomerase-1 inhibitor has shown activity against
neuroblastoma in phase I and II trials. In a COG feasibility trial
high-dose topotecan was added to the Memorial Sloan-Kettering
induction backbone (Park et al., 2011). Thirty-one patients were
enrolled and the combination was well tolerated without unexpected
toxicity. Fifteen of 31 patients (48%) achieved a complete or very
good partial response. This regimen was added in a non-randomized
fashion in the large phase III trial between single and tandem
transplantation.
The presence of osseous disease has long been recognized as an
adverse prognostic finding, particularly after induction therapy. A
multivariate analysis of 549 patients with high-risk neuroblastoma
in the European Bone Marrow Transplantation Solid Tumor Registry
demonstrated that persistent cortical bone lesions (P = 0.004) and
bone marrow involvement (P = 0.03) were the only independent
adverse prognostic factors (Ladenstein et al., 1998). More recent
retrospective studies of patients treated on COG A3973 assessed a
“semiquantitative” MIBG score using the Curie scoring system. Patients
who had a Curie score greater than 2 at the end of induction (n =
52) had a significantly decreased EFS compared with patients who
had Curie scores of 2 or less (3-year EFS 15.4% ± 5.3% vs. 44.9%
± 3,8%, P < 0.001) (Yanik et al., 2013). This finding was particularly
stark for patients with MYCN amplification (6 patients), in whom
3-year EFS was 0.
The presence of bulky disease results in increased failure. Tumor
debulking with surgery or radiation therapy is warranted before
autologous bone marrow transplantation. There are many questions
yet to be resolved about this modality of treatment. Toxicity of bone
marrow transplantation can be lethal, and the long-term complications
in patients with successful transplantation are unknown. However,
these risks are acceptable given that long-term survival is difficult
to achieve without such intensive therapy.
Additional new agents in phase I and II trials for relapsed neu-
roblastoma include temozolomide and irinotecan (Kushner et al.,
2006; Rubie et al., 2006; Simon et al., 2007). As efficacy is established,
they will be advanced into clinical trials for high-risk tumors with
a goal to improve the overall outcome.
New Innovative Biologic Therapies
Double autologous bone marrow transplantation has allowed the
use of myeloablative therapies, but the maximum benefit to that
approach has been reached. 13-cis-retinoic acid produces differentia-
tion of neuroblastoma in cell cultures including cultures of recurrent
tumors. It was given for a 6-month period after cytotoxic therapy
in children with advanced-stage disease and significantly decreased
the frequency of relapse (Matthay et al., 1999). Long-term follow-up
has shown that the 5-year OS was improved (Matthay et al., 2009).
Antibody therapy against the GD2 disialoganglioside cell surface
marker uniformly expressed in neuroblastoma has been shown to
be an effective adjuvant therapy in combination with granulocyte-
macrophage colony-stimulating factor and interleukin-2 along with
13-cis-retinoic acid after autologous bone marrow transplant compared
with 13-cis-retinoic acid alone (Yu et al., 2010). More recent studies
have combined antibody therapy with a “backbone” of irinotecan
and temozolomide, a pair of newer agents not included in front-line
therapy. In one study these agents were combined with either antibody
to GD2 or temsirolimus, an mTOR inhibitor that has a role in regula-
tion of protein synthesis and cell proliferation (Mody et al., 2017).
In this randomized study of relapsed patients the combination with
the antibody to GD2 was effective but the mTOR inhibitor had a
very low response rate. Newer “humanized” antibodies are also being
1096 PART III Pediatric Urology
tested to see if they are more effective and if they can minimize the
pain produced by the current antibody, which can limit the extent
of treatment. Studies are also in preparation to evaluate the use of
the GD2 antibody in front-line therapy.
A new synthetic retinoid, fenretinide, which has produced apoptosis
rather than differentiation in neuroblastoma cell lines, is also in
clinical trials for maintenance therapy. It has been shown to be
effective against some neuroblastoma cell lines that are resistant to
13-cis-retinoic acid.
Other avenues of treatment in current phase I and phase II trials
include vaccine and antiangiogenic therapy. Vaccines have been
developed against the GD2 antigen, but they are in early stages of
testing. Inhibition of angiogenesis is another appealing avenue of
therapy in this very vascular tumor, particularly once there is minimal
residual disease, although efficacy has not yet been established in
phase 1 or 2 studies.
Another modality in the treatment of metastatic neuroblastoma
is the use of 131I-MIBG (Hutchinson et al., 1992). The finding that
the primary tumor and metastatic areas take up this radiotracer
suggested the possibility that therapeutic doses can be delivered to
the tumor. Preliminary analysis indicates that objective responses
do occur in terms of reduction of tumor volume, even in previously
heavily treated patients (Howard et al., 2005; Matthay et al., 2007).
Significant myelosuppression is seen with dose escalation, however,
and stem cell support is required. It has not yet been tested as an
“up-front” therapy.
Radiotherapy
Radiotherapy is effective for local control in neuroblastoma, and
risk of local relapse can be correlated with the biologic markers.
Although irradiation has not provided a benefit in low-stage tumors,
it has increased local control in children with advanced stage IV or
bulky stage III tumors (Castleberry et al., 1991; Evans et al., 1996;
Matthay et al., 1989). A randomized control trial to evaluate the
efficacy of local control between radiotherapy alone and surgery has
not been performed. Doses of external beam irradiation used have
ranged between 15 and 30 Gy, depending on the patient’s age, location
of the tumor, and extent of residual disease.
Intraoperative radiation therapy has been used for patients with
unresectable disease. This technique has the advantage of delivering
a higher dose of radiation to the operative field while sparing normal
adjacent tissues (Leavey et al., 1997). Although its use has been
promoted, it has not been convincingly demonstrated to improve
control when compared with external beam irradiation (Haas-Kogan
et al., 2000).
Spinal Cord Compression
Extension of tumor into the spinal canal produces symptoms of
spinal cord compression in up to 5% of patients presenting with
neuroblastoma (DeBernardi et al., 2001), whereas up to 13% of
patients have radiographic evidence of extension into the spinal
canal (Plantaz et al., 1996). These children have been treated by
decompressive laminectomy, radiotherapy, or chemotherapy. Neu-
rologic outcome has been similar by all modalities and, unfortunately,
patients presenting with severe motor deficits generally recover little
function (DeBernardi et al., 2001; Katzenstein et al., 2001). Because
of the delayed complications of scoliosis after laminectomy, current
recommendations are to initiate treatment with chemotherapy and
reserve laminectomy for children with progressive neurologic deteriora-
tion (Katzenstein et al., 2001). Radiotherapy is now generally avoided,
because of its adverse effect on growth of the spine.
WILMS TUMOR
Wilms tumor, or nephroblastoma, is the most common primary
malignant renal tumor of childhood. It is an embryonal tumor that
develops from remnants of immature kidney. Treatment of patients
with nephroblastoma has been extensively investigated in a number
KEY POINTS: NEUROBLASTOMA
• Neuroblastoma is the most common e tracranial solid
neoplasm in children.
• hildren 1 months of age or younger have a better
survival rate than older children. This may be attributed to
more favorable biologic parameters in tumors diagnosed
at this age.
• omplete surgical resection is curative for low-stage
disease.
• MYCN amplification, found in 20% of patients with
primary tumors, is associated with tumor progression. This
poor prognosis is independent of patient age and tumor
stage. Additional biologic markers of poor prognosis have
been defined and treatment protocols are currently based
on these factors.
of large randomized clinical trials in North America and Europe.
The focus of the most recently completed trials was on reducing the
morbidity of treatment for low-risk patients, reserving more intensive
treatment for high-risk patients for whom survival remains poor. This
section outlines current recommendations for treatment and reviews
the latest developments in the biology of Wilms tumor.
Epidemiology
Wilms tumor accounts for approximately 6% to 7% of all childhood
cancers. It is the most common renal tumor of childhood, accounting
for 95% of all kidney cancers in children under the age of 15 in the
United States (Ali et al., 2012; Howlader et al., 2013). According to
the Surveillance, Epidemiology, and End Results (SEER) registry, the
average annual age-adjusted incidence rate of Wilms tumor is 8.0
per million (Bernstein et al., 1999; Breslow et al., 1993). More than
80% of cases are diagnosed before 5 years of age, with a median
age of 3.5 years. Nevertheless, older children and occasionally even
adults can be affected (Ali et al., 2012; Arrigo et al., 1990; Kalapurakal
et al., 2004a). The median age at diagnosis is lower in children with
bilateral Wilms tumor (Breslow et al., 1993) and those with a
syndromic predisposition to Wilms tumor (Kalish et al., 2017). Wilms
tumor presents at an earlier age among males with both unilateral
and bilateral tumors.
In North America, Wilms tumor is slightly more frequent in
females than in males. With regard to ethnicity, the incidence of
Wilms tumor is lower in East Asian populations and higher in black
populations compared with the incidence reported for North American
and European Caucasians (Axt et al., 2011; Breslow et al., 1994;
Fukuzawa et al., 2004). The fact that such variations exist more
closely associated with race than geography suggests that environ-
mental risk factors likely play a minor etiologic role, certainly in
comparison with adult epithelial cancers (Breslow et al., 1993). Black
children often have a more advanced stage of disease at presentation,
but it is not clear if this is related to tumor biology or reflects delays
in diagnosis resulting from impaired access to health care (Axt et al.,
2011). Data also exist on the very poor survival outcomes of children
in Africa with Wilms tumor; however, as with the data on black
children in North America it is still unclear what contribution tumor
biology plays relative to other known barriers to care (Paintsil et al.,
2015). Several epidemiologic studies have investigated occupational,
environmental, and lifestyle factors as risk factors for Wilms tumor.
Although some studies have suggested that a number of parental
and prenatal exposures may be associated with an increased risk of
Wilms tumor, very few have been established conclusively (Breslow
et al., 1993; Shrestha et al., 2014).
Biology/Genetics
Children with Wilms tumor have been extensively studied to determine
the role of genetic alterations in tumor development (Gadd et al., 2012).
We now recognize that the majority of Wilms tumors arise from somatic
 Chapter 53
TABLE 53.3 Gene Mutations in Wilms Tumors
SOMATIC OR
GENE (CHROMOSOME) FREQUENCY GERMLINE
IGF2 (11p15) 70% Both
WTX (Xq11) 20% Somatic only
WT1 (11p13) 20% Both
CTNNB1 (3p21) 15% Somatic only
TP53 (17p13) 4% all tumors Both
70% anaplastic
mutations restricted to tumor tissue and a much smaller percentage
originate from germline mutations (Dome and Huff, 2016; Ruteshouser
et al., 2008; Scott et al., 2012). It is apparent that several genetic events
result in Wilms tumorigenesis and that the Knudson two-hit model of
cancer formation does not explain most cases (Knudson and Strong,
1972). In 10% to 15% of individuals with Wilms tumor, the cause
is considered to be a germline pathogenic variant or an epigenetic
alteration occurring early during embryogenesis (see 11p15-Related
Wilms Tumor). These may or may not be associated with a known
congenital malformation syndrome or hereditary cancer syndrome.
Approximately 1% to 2% of individuals with Wilms tumor have at
least one relative also diagnosed with Wilms tumor (familial Wilms
tumor); however, although germline variants that are likely pathogenic
have been identified in some families, they are still not known for
the majority of individuals. The most commonly reported germline
genetic and epigenetic variants in individuals with Wilms tumor
involve WT1 and the 11p15.5 locus. A growing number of variants
in other genes have been reported. In some cases, the estimated of
risk of Wilms tumor with these variants is high, but the variant or
syndrome is so rare in the general population that only a handful of
individuals with Wilms tumor have ever been reported (Dome and
Huff, 2016). A number of genes have been identified that play a role
in the development of Wilms tumor (Table 53.3).
WT1
The first gene mutation described in Wilms tumor was WT1 with
somatic and germ-line mutations noted. The identification and
subsequent cloning of WT1 resulted from cytogenetic observations
of gross deletions at chromosome 11p13 in patients with the
WAGR (Wilms tumor, Aniridia, Genital anomalies, mental Retarda-
tion) syndrome. These children were shown to have heterozygous
germline deletions at 11p13 (Riccardi et al., 1978). Subsequent
molecular analysis of the DNA mapping of this specific region led
to the identification of the WT1 in 1990 (Bonetta et al., 1990; Call
et al., 1990). WT1 mutations are often associated with β-catenin
(CTNNB1) mutations, defining a specific genetic subset of Wilms
tumor (Li et al., 2004; Royer-Pokora et al., 2008). This subset has
been called the ideal type I Wilms tumor (Breslow et al., 2006). It
is characterized by a stromal predominant favorable histology,
intralobar nephrogenic rests, early onset of Wilms tumor, and geni-
tourinary abnormalities in males. Wilms tumors from patients with
Wilms tumor-aniridia-urogenital abnormalities-mental retardation
(WAGR) and Denys–Drash syndrome (DDS) belong to this subtype
of tumors.
Aniridia, found in 1.1% of Wilms tumor patients, arises from
deletion of PAX6, which lies within approximately 0.6 Mb of WT1
(Vasilyeva et al., 2017). Aniridia patients with visible (microscopic)
chromosomal deletions that include WT1 were noted to be prone
to the development of Wilms tumor (Muto et al., 2002). FISH analysis
of aniridia patients has been used to identify submicroscopic deletions
of WT1 and is also a useful predictor of Wilms tumor development
(van Heyningen et al., 2007). Wilms tumor will develop in approxi-
mately 40% to 70% of aniridia patients with deletions of WT1.
Conversely, aniridia patients with normal WT1 do not develop Wilms
tumor (Grenskov et al., 2001; van Heyningen et al., 2007).
Pediatric Urologic Oncology: Renal and Adrenal 1097
The WT1 gene is important for normal kidney and gonadal
development. WT1 encodes a zinc finger transcription regulating
mesenchymal to epithelial transition in kidney development (Dressler,
1995; Pritchard-Jones, 1990). WT1 is necessary for ureteric bud
outgrowth and is also important in nephrogenesis. Targeted mutation
of the WT1 gene in mice results in failure of kidney and gonadal
development (Kreidberg et al., 1997). The Denys-Drash syndrome
(DDS) is the specific association of male pseudohermaphroditism,
renal mesangial sclerosis, and nephroblastoma (Drash et al., 1970).
The syndrome is caused by point mutations in the zinc-finger DNA
binding region of WT1 (Coppes et al., 1993). More than 90% of
DDS patients harbor germline point mutations in only one WT1
allele (Coppes et al., 1992; Pelletier et al., 1991). Therefore the WT1
mutation acts dominantly with respect to genitourinary abnormalities.
The fact that the phenotype resulting from these heterozygous muta-
tions is far more severe than that resulting from constitutional deletion
of one WT1 allele (i.e., WAGR patients) suggests that the Denys-Drash
mutations do not result in inactivation of the WT1 protein, but
rather in the production of a dysfunctional WT1 protein. It is
postulated that this abnormally expressed protein alters regulation
of transcription and urogenital development. The majority of these
patients progress to end-stage renal disease. Nephropathy usually
occurs early in life and renal biopsy demonstrates mesangial sclerosis.
Some WT1 mutations can lead to an incomplete DDS phenotype,
with varying degrees of genitourinary anomalies, renal pathologies,
and penetrance of Wilms tumor (McTaggart et al., 2001). Although
XY individuals have been reported most often, the DDS has been
reported in genotypic/phenotypic females. WAGR and DDS patients
are more likely to have bilateral tumors and are diagnosed at a
younger age (Breslow et al., 2003, 2006).
This risk for renal insufficiency in DDS is shared by children with
WAGR and children with genitourinary abnormalities, all associated
with a WT1 mutation (Diller et al., 1998). WAGR patients and those
with genitourinary abnormalities have an increased risk of renal
failure if they survive into puberty (Breslow et al., 2000, 2005).
Genitourinary anomalies (renal fusion anomalies, cryptorchidism,
hypospadias) are present in 4.5% of patients with Wilms tumor
(Breslow et al., 1993). The incidence of WT1 mutations in patients
with Wilms tumor not associated with any genitourinary abnormality
is approximately 2% (Little et al., 2004). Studies of non-tumoral
renal tissue in children with WAGR and DDS have demonstrated
smaller glomerular diameters than controls (Dahan et al., 2007). This
suggests a specific defect of WT1 function during renal development
that leads to subsequent deterioration in renal function with age.
WT1 was originally considered to be a classic tumor suppressor
gene, and the loss of both copies or mutations of this gene would
lead to Wilms tumor development (Rauscher, 1993). Although this
may be the case for some tumors, only 20% of patients with Wilms
tumor have a mutation in the germline or in tumor tissue (Diller
et al., 1998; Ruteshouser et al., 2008). It is well established that
most constitutional cancer syndrome mutations, including WT1,
are associated with younger age of onset. The median age of onset
in children with somatic WT1 mutations was 14 months. It is
postulated that WT1 mutations are associated with a more rapid
progression to Wilms tumor than other molecular abnormalities
(Scott et al., 2012).
WTX
Another tumor suppressor gene, WTX, is targeted by somatic mutations
in up to 30% of cases of Wilms tumor, the most common type of
pediatric kidney cancer (Rivera et al., 2007). Most tumors have
deletions of the entire WTX gene, but one-third of WTX-mutated
Wilms tumors carry truncating mutations or missense mutations.
The functional importance of the missense alterations is unclear,
because the missense alteration can be present in normal tissue from
the same patient, whereas the deletion and truncation mutations
are always specific to the tumor. The location of WTX on the X
chromosome is of particular interest because it is inactivated by a
monoallelic, or “single-hit” event rather than by the classical biallelic
inactivation of autosomal tumor suppressor genes. It targets the
1098 PART III Pediatric Urology
single X chromosome in males and the active X chromosome in
females with tumors and occurs at comparable frequencies in males
and females alike. Initially it was reported that tumors caused by
WTX mutations lack WT1 mutations. Subsequently, it has been
observed that WTX mutations occur with equivalent frequency in
tumors with or without mutations in WT1 and CTNNB1 (Ruteshouser
et al., 2008). WTX, like WT1, appears to play a role in the Wnt/
beta-catenin signaling pathway. Mutations in WT1, WTX, and CTNNB1
provide the genetic basis for about one-third of Wilms tumors
(Bahrami et al., 2018).
11p15
Additional molecular alterations are observed at the chromosome
11p15 locus, which contains a cluster of imprinted genes (Koufos
et al., 1989; Mannens et al., 1990). LOH or loss of imprinting (LOI)
on 11p15 occurs in up to 70% of tumors (Scott et al., 2012). A WT2
locus has been postulated in 11p15, but so far, the respective gene
has not been identified. This region is known to harbor genes for
the Beckwith-Wiedemann syndrome (BWS) and other syndromes
with overgrowth features (Koufos et al., 1989). These include
hemihypertrophy, which may occur alone or as part of the BWS,
Perlman, Soto, and the Simpson-Golabi-Behmel syndromes (Neri
et al., 1998; Perlman et al., 1975). Most cases of BWS are sporadic, but
up to 15% exhibit heritable characteristics with apparent autosomal
dominant inheritance. The BWS critical region on 11p15 includes two
domains of imprinted genes located in proximity in band 11p15.
Imprinting center region 1 (ICR1) regulates the expression of IGF2 and
H19; and center 2 (ICR2), which regulates the CDKN1C, KCNQ10T1,
and KCNQ1. These imprinting centers are differentially methylated
on the paternal and maternal allele, leading to expression of only
one parent-specific allele (Choufani et al., 2013).
Wilms tumor associated with epigenetic alterations in the 11p15
region has been termed the ideal type II Wilms tumor (Breslow
et al., 2006). A type II Wilms tumor is characterized by a limited
nephrogenic differentiation and a mostly blastemal or epithelial-type
histology; patients develop tumors at a later age and have a heavier
birth weight. The risk of nephroblastoma in children with BWS
and hemihypertrophy is estimated to be 4% to 10%; 21% of
children have bilateral disease (Beckwith, 1996; Debaun and Tucker,
1998; Porteus et al., 2000). The mean age at diagnosis of Wilms
tumor in BWS and hemihypertrophy patients is similar to that of
the general Wilms tumor population (Breslow et al., 1993). Adre-
nocortical neoplasms and hepatoblastoma also occur with increased
frequency in BWS. Children with BWS found to have nephromegaly
(kidneys greater than or equal to the 95th percentile of age adjusted
renal length) are at the greatest risk for the development of Wilms
tumor (Debaun et al., 1998). Investigators have been able to correlate
genetic changes to identify which BWS patients are at risk for Wilms
tumor development (Bliek et al., 2004; Brioude et al., 2013; DeBaun
et al., 2002). An increased Wilms tumor risk is observed only in
BWS patients with ICR1 gain of methylation and 11p15 uniparental
disomy. In contrast, the tumor risk is lower in BWS with ICR2 loss
of methylation and CDKN1C mutations.
Familial Wilms Tumor
As noted earlier, 1% to 2% of Wilms tumor patients have a family
history of Wilms tumor (Breslow et al., 1996; Ruteshouser and Huff,
2004). Familial cases have an earlier age of onset and an increased
frequency of bilateral disease. Two familial Wilms tumor genes have
been localized (Ruteshouser and Huff, 2004). FWT1 is located at
17q12-q21 and FWT2 at 19q13.4 (McDonald et al., 1998; Rahman
et al., 1996). Penetrance of these genes appears to be moderate, and
these genes do not follow the typical tumor suppressor gene pattern
of loss of heterozygosity (Strong, 2003).
Other Chromosomal Abnormalities
Mutations of the tumor suppressor gene TP53 are frequently encountered
genetic events in human cancer (Hollstein et al., 1991). TP53 mutations
are detected in 50% to 75% of patients with anaplastic histology Wilms
tumor (Bardeesy et al., 1994, Ooms et al., 2016). It has been suggested
that a favorable histology tumor may progress to an anaplastic tumor
by acquiring a disruption of TP53 function in a group of selected cells
(Natrajan et al., 2007). The TP53 mutations also have been correlated
with advanced stage disease (Malkin et al., 1990; Sredni et al., 2001). A
recent report from COG on TP53 mutations in diffuse anaplastic Wilms
tumor noted improved relapse-free survival in those with advanced
stage disease who had wild-type TP53 (Ooms et al., 2016).
Loss of the long arm of chromosome 16 has been found in
approximately 20% of Wilms tumors (Maw et al., 1992), suggesting
the presence of a gene at 16q involved in the biology of Wilms
tumor. Similarly, loss of the short arm of chromosome 1p has been
found in approximately 10% of cases (Grundy et al., 1994). LOH
at 1p and 16q are associated with an increased risk of tumor
relapse and death (Grundy et al., 1994, 2005; Wittman et al., 2007).
Confirming the utility of LOH of 16q and 1p to predict outcome
was one of the major objectives of the fifth National Wilms Tumor
Study (NWTS) (see discussion later). LOH of chromosome 11q is
noted in approximately 20% of tumors. LOH of 11q is 3 to 4 times
more frequent in anaplastic tumors (Wittman et al., 2007). There
is a correlation with tumor recurrence and death but only for tumors
that lost the entire long arm of chromosome 11. Combined LOH
(at 1p and 16q) was used to risk-stratify patients with favorable-
histology Wilms tumor (FHWT) on the most recently completed
COG renal tumor studies. COG Study AREN 0533 intensified therapy
for those stage III and IV FHWT and demonstrated that therapeutic
intensification improved EFS and OS (Dix et al., 2015; Fernandez
et al., 2018). However, this is of limited clinical importance because
only approximately 5% of all FHWT patients have combined LOH.
Gain of 1q has also been identified to be another genetic change
associated with outcome (Gratias et al., 2013, 2016; Segers et al.,
2013). 1q gain has the potential to be a more clinically significant
factor because it is consistently noted in one-fourth of FHWTs. It is
important to note that 1q gain and LOH at 1p and 16q are not
independent events. LOH at 1p and 16q often arises through
chromosomal translocations that also result in 1q gain. After stratifica-
tion for stage of disease, 1q gain was associated with a significantly
increased risk of disease recurrence and worse OS (Gratias et al.,
2016). Future studies will likely investigate the ability of 1q gain to
be used to risk-stratify patients for therapeutic intensification.
COG investigators have evaluated a large cohort of FHWTs for
global gene expression patterns; WT1, CTTNNB1, and WTX mutation;
and 11p15 copy number and methylation patterns. They identified
five subsets of tumors showing distinct differences in their clinical
and pathological features. One unique subset was epithelial Wilms
tumor in infants that lacked WT1, CTTNNB1, and WTX mutations
and nephrogenic rests, and none had recurrence of tumor. COG
investigators hope to use this type of information to develop specific
treatment strategies for different subsets of patients based on biology
(Gadd et al., 2012; Sredni et al., 2009).
Screening
Screening with serial renal sonograms has been recommended
in children at high risk for development of Wilms tumor. Review
of most studies suggests that 3 to 4 months is the appropriate
screening interval. The frequency of screening does not change as
the patient ages; the rate of tumor growth is expected to be the same
in older children. Tumors detected by screening will usually be at
a lower stage (Choyke et al., 1999; Green et al., 1993; Kalish et al.,
2017). No studies have demonstrated that early detection has
improved patient survival. Early detection can provide an opportunity
for nephron-sparing surgery, because these children are at an increased
risk for bilateral disease. The smaller tumors found on screening
studies are more amenable to renal-sparing surgery (Romao et al.,
2012; Fig. 53.6). A recent report from the American Association for
Cancer Research Childhood Cancer Predisposition Workshop recom-
mended that screening be performed when a condition has a Wilms
tumor incidence of greater than 1% (Table 53.4; Kalish et al., 2017).
Others have recommended screening when the Wilms tumor incidence
 Chapter 53 Pediatric Urologic Oncology: Renal and Adrenal 1099

A B
Fig. 53.6. Small renal tumor found on serial screening. (A) Ultrasound shows solid lesion just pushing
out from the cortex. (B) CT demonstrates that lesion is amenable to renal-sparing surgery.

TABLE 53.4 Syndromes Associated With Development of Wilms Tumor

SYNDROME GENES LOCUS WILMS TUMOR RISK

HIGH RISK
WAGR WT1 11p13 50%
Denys-Drash WT1 11p13 50%
Fanconi anemia D1 BRCA2 13q12.3 >20%
Perlman Unknown >20%
Mosaic variegated aneuploidy BUB1B 15q15 >20%

MODERATE RISK
Beckwith-Wiedemann WT2 IGF2, H19 5%–10%
Hemihypertrophy WT2 IGF2, H19 5%
Frasier WT1 11p13’ 5%–10%
Simpson-Golabi-Behmel GPC3 Xq26 10% (in males)

LOW RISK
Li-Fraumeni p53 17p13 Low
Neurofibromatosis NF1 17q11 Low
Sotos NSD1 5q35 Low
Trisomy 18 Unknown 18 Low
Bloom BLM 15q26 Low

is greater than 5% (Scott et al., 2006a,b). Although there is emerging
evidence of different cancer risks based on genetic or epigenetic
subgroups for certain syndromes, and several European countries
now use subgroup-specific recommendations for WT screening
particularly in BWS, these practices have not yet been adopted in
North America (Mussa et al., 2016). Ultrasound surveillance is recom-
mended until 7 years of age. For patients with BWS/IHH, trisomy
18, and SGBS, screening for hepatoblastoma is also required. They
need full abdominal ultrasound and simultaneous serum AFP
screening every 3 months starting at birth (or at the time of diagnosis)
and continuing through the child’s fourth birthday.
Screening of the contralateral kidney after nephrectomy for
unilateral Wilms tumor is also recommended (D’Angio et al., 1993).
Infants younger than 12 months found to have nephrogenic rests
(NRs) in the resected kidney are at the greatest risk for metachronous
tumors (Coppes et al., 1999). Ultrasound surveillance is performed
from time of diagnosis until 5 years of age, with a frequency of every
3 to 4 months.
CT or MRI should be performed if ultrasonography demonstrates
a suspicious lesion. Nonmalignant renal lesions—for example, renal
cysts—do occur at an increased rate in children with BWS, and recogni-
tion of these is important to avoid unnecessary nephrectomy when
new lesions are identified on screening ultrasonography (Borer et al.,
1999; Choyke et al., 1999).
Pathology
Pathologists have made important contributions to the study of the
clinical behavior and biology of Wilms tumor (Beckwith and Palmer,
1978; Gadd et al., 2012, 2017; Perlman et al., 2011; Ravenel et al.,
2001; Schmidt and Beckwith, 1995; Vujanic et al., 2002, 2010; Weeks
et al., 1987; Zuppan et al., 1991). Wilms tumor is characterized by
wide histologic diversity, and thus the classification of these childhood
tumors can be difficult. As noted in the discussion earlier, correlation
of the pathologic findings with genetic events is improving our
understanding of the development of Wilms tumor.
1100 PART III Pediatric Urology
Fig. 53.7. Typical Wilms tumor with blastemal, epithelial, and stromal components.
Favorable Histology Wilms Tumor
Wilms tumor usually compresses the adjacent normal renal paren-
chyma, forming a pseudocapsule composed of compressed, atrophic
renal tissues. This intrarenal pseudocapsule can be helpful to dis-
tinguish Wilms tumor from NRs and other renal tumors. The texture
of the tumors varies depending on the predominant histologic pattern.
Many are soft and friable with necrotic or hemorrhagic areas frequently
noted. This consistency increases the risk of intraoperative tumor
rupture during primary nephrectomy. Most Wilms tumors are
unicentric, but 12% are multicentric unilateral tumors (Breslow et al.,
1988a). Extrarenal Wilms tumor arising in the retroperitoneum and
elsewhere are rare and are thought to arise from displaced metanephric
elements or mesonephric remnants. Wilms tumor is derived from
primitive metanephric blastema (Beckwith and Palmer, 1978). In
addition to expressing a variety of cell types found in a normal
developing kidney, Wilms tumor often contains tissues such as skeletal
muscle, cartilage, and squamous epithelium. These heterotopic cell
types likely reflect the primitive developmental potential of meta-
nephric blastema that is not expressed in normal nephrogenesis.
“Classic” Wilms tumor is characterized by islands of compact
undifferentiated blastema and the presence of variable epithelial
differentiation in the form of embryonic tubules, rosettes, and
glomeruloid structures separated by a significant stromal component
(Fig. 53.7). The proportion of each of these components varies from
infrequent to abundant within and among individual tumors.
However, some Wilms tumors are not triphasic but have only biphasic
or even monomorphous patterns, and the latter can present diagnostic
difficulty (Schmidt and Beckwith, 1995). Wilms tumors with
predominantly epithelial differentiation have a low degree of
aggressiveness, and the majority are stage I tumors (Beckwith
et al., 1996; Gadd et al., 2012; Vujanic and Sandstedt, 2010). However,
these tumors may be more resistant to therapy if they are seen
initially as advanced stage disease.
Anaplastic Wilms Tumor
Identification of tumors with unfavorable histologic features such
as anaplasia was an important milestone accomplished by the inclu-
sion of the central pathological review of the National Wilms Tumor
Study Group protocols (Beckwith and Palmer, 1978; Bonadio et al.,
1985; Zuppan et al., 1991). It has allowed progressive use of adjuvant
therapies in the sequential studies based on the risk and response
of the various pathological tumor types. Anaplasia is characterized
by the presence of three abnormalities: nuclear enlargement to three
or more times the diameter of the adjacent cells, hyperchromasia
of enlarged nuclei, and abnormal mitotic figures. Anaplasia is rarely
seen in tumors of patients younger than 2 years of age at diagnosis
(incidence about 2%), but its presence increases to a relatively stable
incidence of about 13% in those older than 5 years of age (Bonadio
et al., 1985; Green et al., 1994). Anaplasia is associated with
resistance to chemotherapy. The presence of anaplasia has clearly
been demonstrated to carry a poor prognosis even when the
tumor is apparently confined to the kidney, stage I (Dome et al.,
2006). Anaplasia has been further divided into focal and diffuse
patterns to reflect further the different prognosis of anaplasia that
is present throughout the kidney or in an extrarenal location (Faria
et al., 1996). The later age at diagnosis and the general absence of
anaplasia from nephrogenic rests suggests that anaplasia develops
from Wilms tumor cells that acquire additional genetic lesions
(Williams et al., 2011). As mentioned earlier, approximately 50% of
anaplastic Wilms tumors harbor TP53 mutations.
Pathology After Preoperative Chemotherapy
The International Society of Paediatric Oncology (SIOP) studies
have made some important observations on the histology of Wilms
tumor after preoperative chemotherapy. They have performed an
assessment of the tumor response after preoperative chemotherapy
in terms of tumor volume and histology. The relative proportions of
histologic subtypes of WT differ following preoperative chemotherapy
when compared with those reported after primary surgical resection
(Weirich et al., 2001). Stromal and epithelial predominant tumors
are found more often after chemotherapy. These histologic subtypes
may demonstrate a poor clinical response to therapy but have an
excellent prognosis if the tumor is completely excised (Verschuur
et al., 2010). The proportion of blastemal predominant tumors is
decreased after chemotherapy, indicating some response of this
tumor type to the preoperative chemotherapy. However, patients
with blastemal predominant tumors after chemotherapy have a
high rate of relapse (Reinhard et al., 2004b). Tumor progression
during therapy occurred in 5% of patients enrolled in SIOP 93-01 (Ora
et al., 2007). These patients were documented to have decreased OS.
As an embryonal tumor, nephroblastoma may differentiate into
more mature mesenchymal tissue types, such as skeletal muscle,
after chemotherapy. Chemotherapy and radiation may induce
cytodifferentiation of Wilms tumor cells or select for the survival
of less mitotically active cells. In follow-up biopsies, the presence
of rhabdomyomatous differentiation can confound the histologic
diagnosis. Furthermore, these differentiated tumors appear to be
more resistant to chemotherapy, thus surgical excision is considered
the treatment of choice (Seifert et al., 2012).
SIOP classifies tumors with complete tumor necrosis after preopera-
tive chemotherapy as “low risk.” The blastemal element commonly
responds very dramatically to chemotherapy. The degree of tumor
necrosis after chemotherapy has a positive correlation with the
proportion of blastemal component and a negative correlation
with proportion of epithelial component in pre-chemotherapy
biopsy samples (Taskinen et al., 2017). Unfortunately, if not
responsive to therapy and there is blastemal predominance in
residual tumor specimens after pre-surgical chemotherapy, this
predicts worse survival outcomes (Reinhard et al., 2004b). Children
with stage I “low-risk” tumors after post-chemotherapy nephrectomy
receive no further chemotherapy (Boccon-Gibod et al., 2000). Tumors
with diffuse anaplasia and blastemal predominance after chemo-
therapy are classified as “high risk.” SIOP “intermediate risk” tumors
comprise all other histologies.
Nephrogenic Rests
More than one-third of kidneys resected for Wilms tumor (regardless
of those receiving preoperative chemotherapy or not) contain precur-
sor lesions known as NRs (Beckwith, 1993; Beckwith et al., 1990;
Vujanić et al., 2017). Nephrogenic rests have a varied natural history
and most do not form Wilms tumor. A rest can undergo maturation,
sclerosis, involution, or complete disappearance. NRs have also been
detected in 1% of kidneys in infants on postmortem examination;
a much higher incidence than that of Wilms tumor. Therefore most
apparently undergo involution (Beckwith, 1998). It has been recently
postulated that epigenetic changes and relative methylation affect
Wilms tumor evolution from its precursor NRs, which may be useful
 Chapter 53
to differentiate between these tissues and potentially predict which
NRs will become Wilms tumors (Charlton et al., 2015).
NRs can be separated into two fundamentally distinct catego-
ries, perilobar nephrogenic rests (PLNRs) and intralobar nephrogenic
rests (ILNRs) (Beckwith et al., 1990). These two types of NRs are
distinguished by their location within the renal lobe. Relative posi-
tion within the lobe is a direct reflection of the chronology of the
embryologic development of the kidney. PLNRs are found only in
the lobar periphery, which is elaborated late in embryogenesis,
whereas ILNRs are found anywhere within the lobe, as well as
the renal sinus and the wall of the pelvicaliceal system. Therefore
ILNRs are generally believed to be the result of earlier gestational
aberrations (Beckwith, 1998). ILNRs are commonly stroma rich and
intermingle with the adjacent renal parenchyma. PLNRs are usually
subcortical, sharply demarcated, and contain predominantly blastema
and tubules. Of particular interest is the observation that PLNRs are
usually found in children with BWS, linked to 11p15, whereas ILNRs
are typically seen in children with aniridia, WAGR, and DDS or other
features associated with WT1. The age at diagnosis is lower for Wilms
tumor associated with WT1 mutations and those arising in association
with ILNR. These tumors have a stromal-predominant histology
with varying degrees of rhabdomyogenesis (Fukuzawa et al., 2008).
Multiple rests in one kidney usually implies that NRs are present
in the other kidney (Beckwith et al. 1990). Children younger than
12 months of age diagnosed with Wilms tumor who also have NRs,
in particular PLNRs, have a markedly increased risk of developing
contralateral disease and require frequent and regular surveillance
for several years (Coppes et al., 1999). Surveillance is also recom-
mended for those diagnosed after 12 months of age who have NRs
(D’Angio et al., 1993). The occurrence of metachronous Wilms tumor
in patients previously treated with conventional chemotherapeutic
regimens suggests that nephrogenic rests are not always eradicated.
NRs display a spectrum of appearances. Hyperplastic NRs can
produce a renal mass that can be mistaken for a small Wilms tumor
(Beckwith, 1998). Incisional biopsy of a hyperplastic rest is of little
value in distinguishing this lesion from a Wilms tumor, unless the
interface between the rest and normal kidney is included. Wilms tumor
has a pseudocapsule at the interface with the normal parenchyma
compressing the normal elements. The appearance of the lesion can
provide some help in distinguishing between NR and Wilms tumor.
The Wilms tumor will have a spheric shape, whereas hyperplasic rests
retain the appearance of the original rest and are more elliptical or
lenticular in shape. MRI may be of some value in distinguishing
between the two lesions, but this must be confirmed prospectively in
large numbers of patients (Hoffer, 2005; Rohrschneider et al., 1998).
Nephroblastomatosis refers to the presence of multiple neph-
rogenic rests. Diffuse overgrowth of PLNRs may produce a thick
rind that enlarges the kidney but preserves its original shape
(Fig. 53.8). Patients with nephroblastomatosis are prone to Wilms
tumor development, and bilateral lesions are common. Perlman
et al. (2005) have reviewed 52 cases of diffuse hyperplastic perilobar
nephrogenic rests reported to the National Wilms Tumor Study Group
(NWTSG) pathology center. Wilms tumor developed in 23 patients
at a median of 30 months. Of children receiving adjuvant therapy
at diagnosis, 17/33 (52%) developed a Wilms tumor. There was an
increased incidence of anaplasia noted in tumors that developed
after chemotherapy in patients with nephroblastomatosis (Perlman
et al., 2005).
Preoperative Evaluation and Staging
The majority of children (>85%) are symptomatic at presentation
with either an abdominal mass, abdominal pain or hematuria
(Pritchard-Jones et al., 2016). Less commonly an asymptomatic
abdominal mass is discovered incidentally by a family member or
primary care physician. A small percentage of tumors are diagnosed
by screening. A higher proportion of stage I and II tumors (72.7%)
are noted in those who are asymptomatic at diagnosis compared
with those who are symptomatic (52.9%).
The mass may be extremely large relative to the size of the child
and is not necessarily confined to one side. Approximately 20% of
Pediatric Urologic Oncology: Renal and Adrenal 1101
Fig. 53.8. Typical appearance of diffuse hyperplastic perilobar nephrogenic
rest with thick rind compressing the normal renal tissue centrally.
children with Wilms tumor have hematuria at diagnosis, and 25%
will have hypertension at diagnosis that can be caused by elevated
plasma renin levels (Maas et al., 2007). Gross hematuria warrants
further evaluation including a cystoscopy and retrograde pyelogram
at the time of nephrectomy to rule out tumor extension into the
collecting system (Ritchey et al., 2008). Other symptoms include
fever, anorexia, and weight loss in 10% of patients. Rarely, children
may have acute abdominal pain from tumor rupture into the
peritoneal cavity or bleeding within the tumor. There is limited
evidence that patterns of diagnosis may differ by medical specialty
and that delays in diagnosis can adversely affect survival outcomes
(Pritchard-Jones et al., 2016).
Compression or invasion of adjacent structures may result in an
atypical presentation. A persistent varicocele in the supine position
or hepatomegaly may be reflective of inferior vena cava (IVC) obstruc-
tion from tumor thrombus. Atrial thrombus may manifest as
hypertension or congestive heart failure. Such symptoms are found
in less than 10% of patients with intracaval or atrial tumor extension
(Ritchey et al., 1988; Shamberger et al., 2001). During the physical
examination, it is important to assess for signs of associated Wilms
tumor syndromes such as aniridia, hemihypertrophy, and genito-
urinary anomalies.
Emergent operation is not necessary unless there is evidence of
active bleeding or tumor rupture. The preoperative laboratory evalu-
ation of a child with an abdominal mass should include a complete
blood count, liver enzymes, and serum electrolytes, including blood
urea nitrogen, creatinine, and calcium. Because as many as 8% of
newly diagnosed patients with Wilms tumor will have acquired von
Willebrand disease, coagulation studies should be considered (Baxter
et al., 2009). This includes prothrombin time and partial thrombo-
plastin time, which may be normal in the presence of von Willebrand
disease. This defect can generally be corrected preoperatively with
the administration of 1-desamino-8-d-arginine-vasopressin (DDAVP)
but may require IVIG or plasmapheresis (Callaghan et al., 2013).
Generally, this acquired defect and coagulopathy will be reversed
with surgical removal of the tumor or with preoperative chemotherapy
(Baxter et al., 2009; Blanchette and Coppes 2009).
Imaging
All solid renal tumors of childhood have some common radio-
graphic features (Miniati et al., 2008; Smets and de Kraker, 2010).
Therefore Wilms tumors cannot be reliably distinguished from other
renal tumors (e.g., renal cell carcinoma [RCC], or clear cell sarcoma
of the kidney [CCSK]). In the SIOP-9 study, 5.4% of patients in
whom preoperative chemotherapy for Wilms tumor was commenced
before diagnostic biopsy were found on nephrectomy to have renal
1102 PART III Pediatric Urology
malignancies other than Wilms tumor or benign renal conditions
(Tournade et al., 2001). In the United Kingdom Children’s Cancer
Study Group (UKCCSG), 12% of renal tumors clinically and radio-
graphically consistent with Wilms tumor were found to have some
other diagnosis on biopsy (Vujanic et al., 2003). Other clinical
parameters can provide some clues to the diagnosis. The development
of a renal tumor in a child known to have aniridia, hemihypertrophy,
or other syndromes associated with an increased incidence of
nephroblastoma is most likely to be a Wilms tumor. Bilateral or
multicentric tumors are more typical of Wilms tumor, but renal
lymphoma can manifest in this fashion. Congenital mesoblastic
nephroma (CMN) is the most likely diagnosis in a neonate with a
renal mass. However, favorable-histology (FH) Wilms tumor and
rhabdoid tumor of the kidney (RTK) can also manifest in the first
few months of life (LeClair et al., 2005; Ritchey et al., 1995). The
renal origin of the mass is usually apparent on CT, but it can be
mistaken for neuroblastoma.
The clinical presentation—that is, as abdominal pain with tumor
rupture—can create confusion regarding the preoperative diagnosis.
In 2.5% of NWTS-3 patients, there was an erroneous diagnosis before
surgical exploration (Ritchey et al., 1992). Most of these children
did not have any preoperative imaging studies performed, and this
group of patients had an increased incidence of surgical complications.
This emphasizes that defining the exact histology is not as important
as establishing that the child has a solid renal tumor, allowing the
surgeon to plan for a major cancer operation. These events are now
rare with modern imaging and the almost universal use of CT and
MRI for preoperative evaluation.
Ultrasonography is recommended as first-line imaging in children
with an abdominal mass. This demonstrates the solid nature of the
lesion, and it can also help triage appropriate subsequent imaging
such as chest CT at the same time as abdominal cross-sectional
imaging and avoid unnecessary scans such as a noncontrasted CT
abdomen. Doppler ultrasonography may be able to exclude intracaval
tumor extension that occurs in 4% of Wilms tumor patients (Ritchey
et al., 1988; Shamberger et al., 2001). However, properly phased CT
has been shown to more reliably identify all clinically significant
extension of tumor into the IVC when compared with ultrasonography
(Khanna et al., 2012).
All patients should undergo either CT of the abdomen and
pelvis with oral and intravenous contrast or MRI of the abdomen
and pelvis with gadolinium. MRI avoids radiation but typically
requires anesthesia or sedation in young children. These imaging
modalities can further define the extent of the lesion (Fig. 53.9;
Hoffer, 2005; McDonald et al., 2012; Schenk et al., 2008). This allows
improved preoperative planning by evaluating for extrarenal spread
of disease, the relationship of the tumor to adjacent visceral structures,
and the presence of synchronous tumors in the contralateral kidney.
Fig. 53.9. CT scan of a Wilms tumor that demonstrates preoperative rupture
with perirenal hemorrhage.
Routine exploration of the contralateral kidney at the time of
nephrectomy is not necessary when preoperative imaging with
CT or MRI demonstrates a normal contralateral kidney (Ritchey
et al., 2005).
The role of imaging studies in renal tumor staging continues to
be defined. The COG found that CT has moderate specificity but
poor sensitivity in the detection of preoperative tumor rupture
(Khanna et al., 2013). Ascites beyond the cul-de-sac was most strongly
associated with tumor rupture. If the preoperative imaging could
accurately detect local extension of tumor beyond the renal capsule
or into regional lymph nodes, it would obviate concerns regarding
staging in patients treated with preoperative therapy. The local tumor
burden (e.g., regional lymph node involvement) determines the
intensity of the chemotherapy regimen and whether a child receives
abdominal irradiation. Regional adenopathy can be identified on
CT or MRI, but enlarged retroperitoneal benign lymph nodes are
common in children, and correlation between pathologic findings
and lymph node evaluation at surgical exploration in Wilms tumor
patients has found significant false-positive and false-negative error
rates (Lubahn et al., 2012; Othersen et al., 1990). Positron emission
tomography (PET) has not been shown to have any advantages over
conventional imaging modalities in preoperative assessment of Wilms
tumor (Misch et al., 2008). Detection of extrarenal tumor extension
into the perirenal fat and into adjacent structures is also problematic.
Therefore determination of inoperability should be made at surgical
exploration.
The lung is the most common site of distant metastasis in
children with Wilms tumor. Preoperative chest CT with or without
contrast is performed to rule out pulmonary metastases. The clinical
significance of lung nodules detected on CT scan alone is controversial
(Green, 2016; Grundy et al., 2012; Meisel et al., 1999; Owens et al.,
2002; Smets et al., 2012). CT will clearly detect more lesions than
a standard chest radiograph, but not all of these lesions represent
metastases (Ehrlich et al., 2006). Some reports have suggested that
treatment of such patients with dactinomycin (actinomycin D [AMD])
and vincristine (VCR) is sufficient without the need for DOX or
pulmonary radiation (Grundy et al., 2012; Smets et al., 2012). Others
have found an increased risk of pulmonary relapse if more intensive
treatment is not given (Owens et al., 2002). The most recent round
of renal tumor studies from COG prospectively investigated this
issue and found no statistical significant decrease in EFS or OS in
children with favorable histology Wilms tumor who lacked LOH at
1p and 16q and who had complete resolution of their lung nodules
after 6 weeks of VCR, AMD, and doxorubicin and thus then omitted
lung radiation (Dix et al., 2014).
Imaging surveillance after treatment of the primary tumor is
recommended to detect tumor recurrence. COG studies advocate
for periodic chest CT and either CT or MRI of the abdomen. However,
some have begun to question the value of these studies and whether
they will detect relapse early enough to improve survival (McHugh
and Roebuck, 2014). Many patients will have clinical symptoms
related to relapse before imaging detection. Omitting even the pelvic
portion of the abdominal CT can significantly reduce the radiation
exposure without compromising detection of relapse (Kaste et al.,
2013; Mirza et al., 2015).
CCSK and rhabdoid tumor of the kidney (RTK) have a propensity
to metastasize to the skeleton (D’Angio et al., 1993; Seibel et al.,
2018). Bone scans are recommended after the histologic diagnosis
is confirmed (Feusner et al., 1990). Cranial CT or MRI is performed
on all children with CCSK or with RTK, because both are associated
with intracranial metastases (Gooskens et al., 2014; Tomlinson et al.,
2005; Weeks et al., 1989).
Staging
The most important determinants of outcome in children with
Wilms tumor are the histopathology and tumor stage. Accurate
staging of Wilms tumor allows treatment results to be evaluated and
enables universal comparisons of outcomes. The current staging
system used by the COG (Table 53.5) is based primarily on the
surgical and histopathological findings. Examination for extension
 Chapter 53
TABLE 53.5 Staging System of the Childrens
Oncology Group
STAGE
I Tumor confined to the kidney and completely
resected. The renal capsule is intact and the
tumor was not ruptured prior to removal. No renal
sinus extension. There is no residual tumor.
II Extracapsular penetration but is completely
resected. Renal sinus extension or extrarenal
vessels may contain tumor thrombus or be
infiltrated by tumor.
III Residual nonhematogenous tumor confined to the
abdomen: lymph node involvement, any tumor
spillage, peritoneal implants, tumor beyond
surgical margin either grossly or microscopically,
or tumor not completely removed.
IV Hematogenous metastases to lung, liver, bone,
brain, etc.
V Bilateral renal involvement at diagnosis.
through the capsule, residual disease, vascular involvement, and
lymph node involvement are essential to properly assess the extent
of the tumor at presentation.
Stage I tumors are limited to the kidney and completely resected.
However, evidence for tumor extension can be subtle. Tumor invasion
of blood and lymphatic vessels in the renal sinus is the first sign of
spread outside the kidney in stage II tumors (Weeks et al., 1987).
Penetration through the renal capsule is the next most common
finding of extrarenal spread. Clear demonstration of tumor cells in
the perirenal fat is required to document capsular penetration. Any
tumor spill leads to a stage III designation because of the increased
risk for local tumor recurrence (Ehrlich et al., 2013; Shamberger
et al., 1999). On the COG biology and banking study AREN 03B2,
the distribution by stage for patients with FHWT tumors was stage
I, 19%; stage II, 20%; stage III, 35%; stage IV, 18%; and stage V, 8%
(Mullen et al., 2014). Patients with anaplastic tumors are more likely
to present with stage III or IV disease than those with FHWT tumors
(Dome et al., 2006).
Prognostic Factors
As the treatment regimens for children with Wilms tumor have
become more effective, the ability of retrospectively determined
prognostic factors to predict outcomes is diminished. Traditional
staging factors (e.g., tumor size, histology, and lymph node metastases)
relied upon in the past to predict risk for tumor progression or
relapse are now less able to stratify FH patients for treatment. Clinical
cancer trials incorporate biologic factors that predict tumor behavior
to stratify patients for treatment.
Chromosomal Abnormalities. As noted earlier, LOH for a portion
of chromosome 16q and/or 1p has been noted in 20% of Wilms
tumors. This is associated with an increased risk for relapse (Grundy
et al., 1994, 2005; Messahel et al., 2009; Wittman et al., 2007). This
difference in outcome is independent of histology and stage. NWTS-5
patients with stage I or II FH tumors with LOH of either 1p or 16q
had an increased risk of relapse and death in comparison with patients
lacking LOH at either locus (Grundy et al., 2005). The risks of relapse
and death for patients with stage III or IV FH tumors were increased
only with LOH for both regions.
Patients enrolled in the recently published COG renal tumor
protocols were selected for more intensive treatment if the tumor
demonstrated LOH for 1p and 16q. Compared with historical controls,
they found that intensification of treatment improved EFS for stage
Pediatric Urologic Oncology: Renal and Adrenal 1103
III FHWT displaying LOH of 16q and 1p (Dix et al., 2015). Treatment
was likewise intensified for stage I and II patients, with DOX added
to VCR/ACT-D, although this did not significantly affect outcome.
As mentioned earlier, gain of 1q has also been identified to be a
related genetic change associated with oncologic outcome (Gratias
et al., 2013, 2016; Segers et al., 2013). Future studies will likely expand
the investigative thread from the prior generation of COG renal
tumor studies to look at treatment intensification for those with
FHWT and gain of 1q because only approximately 5% of FHWT
will have combined LOH, whereas at least 25% will have gain of 1q.
A number of other markers have been evaluated to predict tumor
recurrence including several immunohistochemical markers. It appears
that most of the markers that are predictive of tumor progression
are found in the blastemal component of the tumor (Ghanem et al.,
2013; Routh et al., 2013). These markers will have to be evaluated
in larger numbers of patients to determine their usefulness for risk
stratification.
Treatment
Surgical Considerations
The initial therapy for most children with Wilms tumor is radical
nephrectomy. Nephrectomy is generally performed via a trans-
peritoneal approach. The surgeon is responsible for determining
the extent of tumor. Accurate staging is essential for the subsequent
determination of the need for radiation therapy and the appropriate
chemotherapy regimen. Thorough exploration of the abdominal
cavity is necessary to exclude local tumor extension, liver and nodal
metastases, or peritoneal seeding. Exploration of the contralateral
kidney is no longer mandated before nephrectomy if the preoperative
CT or MRI demonstrates a normal kidney (Ritchey et al., 2005). The
renal vein and IVC are palpated to exclude intravascular tumor
extension before vessel ligation. Wilms tumor extends into the IVC
in approximately 6% of cases and may be clinically asymptomatic
in more than 50% (Ritchey et al., 1988; Shamberger et al., 2001).
The adrenal gland can be spared without increasing the risk for
tumor spill or recurrence if it is not in proximity to the tumor (Kieran
et al., 2013a). Selective sampling of regional lymph nodes is an
essential component of local tumor staging. Formal retroperitoneal
lymph node dissection is not mandated (Othersen et al., 1990;
Shamberger et al., 1999). En bloc resection yields a lower rate of
positive lymph nodes compared with separate sampling (Stewart
and Bruny, 2015). In a review of NWTS-4 and -5 patients, 12.5% of
patients did not have lymph node sampling performed (Kieran et al.,
2012). The likelihood of having a positive lymph nodes is greater
when more lymph nodes were sampled, emphasizing the importance
of the surgeon and surgical quality in accurately staging Wilms tumor
(Kieran et al., 2012; Saltzman et al., 2018). Future studies will likely
mandate more specific nodal sampling patterns to standardize surgical
staging across institutions and individual surgeons.
The other major responsibility when performing a nephrectomy
for Wilms tumor is complete removal of the tumor without con-
tamination of the operative field. Gentle handling of the tumor
throughout the procedure is mandatory to avoid tumor spillage. A
COG study reported intraoperative tumor spillage in 9.7% of patients
undergoing primary nephrectomy (Gow et al., 2013). Multivariate
analysis demonstrated that spillage was more common with right-sided
tumors and larger tumors. Avoiding tumor spillage has a real impact
on patient outcomes because these patients have an increase in local
abdominal relapse (Shamberger et al., 1999). Shamberger et al.
(1999) identified risk factors for local tumor recurrence as tumor
spillage, unfavorable histology, incomplete tumor removal, and
absence of any lymph node sampling. This study included stage
II and III disease. The risk of recurrence was highest in those patients
with stage II disease. More recent COG studies have treated all spill
patients as stage III. Review of these patients shows that the greatest
risk of recurrence in stage III patients are positive lymph nodes,
combined LOH, or residual disease (Ehrlich et al., 2013; Fernandez
et al., 2018). Tumor spillage was not predictive of recurrence likely
resulting from the increased therapy currently given to these patients.
1104 PART III Pediatric Urology
There have been several reports of laparoscopic or robotic
nephrectomy for Wilms tumor. This is usually done in conjunction
with preoperative chemotherapy and is likely more feasible after the
tumor is reduced in size (Duarte et al., 2014; Romao et al., 2014;
Varlet et al., 2014; Warmann et al., 2014). Experience with open
nephrectomy after chemotherapy has shown that these tumors are
less prone to tumor spillage (Powis et al., 2013). Although pre-
chemotherapy laparoscopic nephrectomy has been reported, many
more cases will have to be performed to determine if there is an
increased risk of tumor spillage, residual disease, or surgical complica-
tions (Barber et al., 2009; Cost et al., 2015).
Removing a large renal tumor in a small child is associated with
some morbidity. NWTS-4 patients undergoing primary nephrectomy
had an 11% incidence of surgical complications (Ritchey et al., 1999).
The most common complications encountered are hemorrhage and
small bowel obstruction (Ritchey et al., 1992, 1993a, 1999). Factors
that have been associated with an increased risk for surgical complica-
tions are higher tumor stage, tumor size greater than 10 cm, incorrect
preoperative diagnosis, thoracoabdominal incision, intracaval tumor
extension, and resection of other visceral organs.
Preoperative chemotherapy may influence surgical complication
rates by producing tumor shrinkage. A report from the UKCCSG
compared the complication rate for patients undergoing immediate
nephrectomy compared with delayed nephrectomy performed after
6 weeks of chemotherapy (Powis et al., 2013). They found significantly
fewer complications in those undergoing delayed nephrectomy (1%
vs. 5.8%). They also noted a much higher rate of tumor rupture/
spill in those undergoing immediate nephrectomy (14.6% vs. 0).
This is similar to the rate of intraoperative tumor spill after immediate
nephrectomy reported by the COG (Gow et al., 2013).
Cooperative Group Trials
Multiple randomized clinical trials have been conducted by the
NWTSG, COG, SIOP, and the UKCCSG to determine the appropriate
role for each of the therapeutic modalities available. Patients are
stratified into different treatment groups based on stage and pathology.
The goals of these trials are to decrease the intensity of therapy for
most patients in an effort to prevent late sequelae of treatment while
maintaining excellent OS.
National Wilms Tumor Study Group. The NWTSG was formed
in 1969 to study Wilms tumor. The early NWTSG studies, NWTS-1
(1969–1973) and NWTS-2 (1974–1978), showed that the combina-
tion of VCR and AMD was more effective than the use of either drug
alone. The addition of doxorubicin (DOX) was found to improve
survival for stage III and IV patients, and postoperative flank irradiation
was unnecessary for stage I patients (D’Angio et al., 1976, 1981). A
major achievement of the early trials was identification of prog-
nostic factors that allowed stratification of patients into high-risk
and low-risk treatment groups. Patients with positive lymph nodes
and diffuse tumor spill were found to be at increased risk of
abdominal relapse and therefore considered stage III and given
postoperative irradiation. One of the most important findings
was the identification of the unfavorable histologic features that
have a very adverse impact on survival.
NWTS-3 (1979–1986) demonstrated that stage I and II patients
could be treated with 18 weeks of AMD and VCR without irradiation
(D’Angio et al., 1989). For stage III FH patients, 10.8 Gy of abdominal
irradiation was shown to be as effective as 20 Gy in preventing
abdominal relapse if DOX was added to VCR and AMD. NWTS-4
(1987–1994) proved that treatment durations of 6 months produced
comparable outcomes to 15 months of therapy for patients with
stages II to IV/FH tumors (Green et al., 1998). The NWTSG has
assessed the impact of postoperative irradiation on flank recurrence
and survival (Breslow et al., 2006; Green et al., 2014; Kalapurakal
et al., 2010). The investigators found that abdominal recurrence rates
after tumor spillage were significantly higher among patients treated
with two- or three-drug chemotherapy without RT. Irradiation with
10 Gy appeared to be successful in reducing tumor recurrence rates
after tumor spillage, and 20 Gy even more so. Although radiation
did decrease the incidence of flank recurrence, there was only an
increase in OS for stage II patients with tumor spillage. This was
attributed to a lower post-recurrence mortality in unirradiated patients.
The overall risk for relapse is low in stage II FH with spillage; the
risks of late effects of intensified treatment must be weighed against
benefit of decreased relapse (Green et al., 2014).
NWTS-5 (1995–2003) was a single-arm therapeutic trial. One of
the major aims of the trial was to confirm the utility of LOH for
chromosomes 16q and 1p to predict increased risk of tumor relapse
and death (Grundy et al., 2005). Another objective was to evaluate the
efficacy of treatment regimens for anaplastic histology Wilms tumor.
Stage I patients with anaplastic tumors were treated with AMD and
VCR, but this resulted in a low 4-year EFS of 69.5% (Dome et al.,
2006). A new intensified chemotherapy regimen used for patients with
stage II to IV diffuse anaplasia did not result in an improved survival.
In NWTS-5, children less than 2 years of age with stage I FH
tumors weighing less than 550 g were defined as very low-risk Wilms
tumors (VLRWT) did not receive chemotherapy after nephrectomy.
This portion of the study was closed early when the number of
tumor relapses exceeded the limit allowed by the design of the study
(Green et al., 2001a). A long-term review of this cohort was completed
comparing the outcomes to similar patients treated with postoperative
AMD and VCR (Shamberger et al., 2010). The 5-year EFS for surgery
alone was 84% compared with 97% for the treated group, but the
5-year OS was equivalent between the two groups at 98% and 99%,
respectively (P = 0.70). There is a trade-off between more intensive
therapy and its potential long-term sequelae required for the 16%
of children who relapse versus the avoidance of any postoperative
chemotherapy in the majority. As noted earlier, COG investigators
hope to use biologic prognostic factors to select patients who do
not require adjuvant therapy. All VLRWT registered on NWTS-5 who
did not receive adjuvant chemotherapy were analyzed for LOH at
11p15 and for WT1 mutation. LOH, as determined by 11p15 methyla-
tion analysis, was significantly associated with relapse in VLRWT as
were WT1 abnormalities (Perlman et al., 2011). If these results are
validated in an independent cohort of patients, it would be worthwhile
to conduct a clinical trial that uses molecular genetic factors rather
than the arbitrarily defined clinical factors of patient age and tumor
weight to identify patients with stage I FHWT who do not require
adjuvant therapy. It is anticipated that such a trial would expand
the number of patients who would be candidates to be treated with
surgery only.
Children’s Oncology Group. The first generation of COG studies
(2006–2013) grouped patients by risk for recurrence (very low, low,
standard, and high). The COG again examined the role of surgery-only
treatment for patients with stage I FHWT in which the tumor and
kidney weighed less than 550 g and patient’s age was less than 2
years. This further demonstrated the success in a surgery-only approach
for those with very low risk FHWT. The 4-year EFS was 89.7% and
OS was 100% (Fernandez et al., 2017). This will likely prompt future
study of expanding those approaches offered surgery-only.
Children with stage I or II FHWT and LOH of 1p and 16q were
treated with VCR, AMD, and DOX without radiotherapy. Patients
with stage III FHWT disease without LOH of 1p and 16q were treated
with VCR, AMD, and DOX and irradiation of the flank or abdomen.
These risk-stratified stage III patients enjoyed an excellent outcome
with 4-year EFS of 88% and OS of 97% (Fernandez et al., 2018).
The COG evaluated a response-based approach for management of
children with pulmonary metastases. Those with resolution of the
pulmonary lesions on chest CT after 6 weeks of chemotherapy were
continued on treatment with VCR, AMD, and DOX. These patients
who were termed “rapid complete responders” had a 4-year EFS of
79.5% and OS of 96.1% that was not statistically inferior to historical
standards; this suggests that these risk-adapted patients may be able
to avoid lung radiation (Dix et al., 2018). Patients who did not
have resolution of the pulmonary lesions by week 6 received more
intensive chemotherapy and pulmonary irradiation. These patients
were termed “slow incomplete responders” and intensification to
regimen M led to an improved outcome with 4-year EFS of 88.5%
and OS of 95.4% (Dix et al., 2018).
A specific study was focused on those with “high-risk” renal tumors.
Children with stage I to III focal anaplastic histology Wilms tumor
 Chapter 53
A B
Fig. 53.10. (A) CT of a Wilms tumor that was pretreated with chemotherapy. (B) After 6 weeks of che-
motherapy, the tumor is much smaller in size.
(AHWT) and stage I diffuse AHWT were treated with AMD, VCR,
DOX, and abdominal irradiation. Patients with stage II, III, or IV
(no measurable disease) diffuse AHWT, stage IV focal AHWT, stage
IV clear cell sarcoma, and stage I to III malignant rhabdoid tumor
were treated with a new chemotherapy regimen to try to improve
OS. Publication of these trial data is still pending.
International Society of Paediatric Oncology. In the randomized
clinical trials conducted by SIOP, preoperative therapy is given before
surgery. This approach usually results in tumor shrinkage (Fig. 53.10),
reducing the risk of intraoperative rupture or spill (Lemerle et al.,
1976). A greater number of patients have “post-chemotherapy stage
I” tumors resulting from disappearance of micrometastases after
neoadjuvant therapy. This was thought to be a significant advantage
in terms of decreasing morbidity of treatment, particularly the late
effects of radiotherapy.
Early SIOP studies evaluated pre-nephrectomy XRT (Lemerle et al.,
1976). SIOP-5 (1976–1980) showed that 4 weeks of AMD and VCR
were as effective as pre-nephrectomy XRT in avoiding surgical tumor
rupture and increasing the proportion of patients with low stage
disease (Lemerle et al., 1983). SIOP-6 (1980–1987) demonstrated
that patients with “post-chemotherapy stage I” disease can safely
be treated with 18 weeks of AMD and VCR (Tournade et al., 1993).
However, patients with “post-chemotherapy stage II” tumors and
negative lymph nodes were found to have a higher rate of abdominal
relapse if postoperative irradiation was omitted (Tournade et al.,
1993). An anthracycline was subsequently added for treatment of these
children. SIOP-6 confirmed the need for a three-drug chemotherapy
regimen after nephrectomy for patients with “post-chemotherapy stage
II” lymph node positive and stage III tumors. SIOP-9 (1987–1993)
demonstrated that the relapse rate for stage II patients with negative
lymph nodes without radiation therapy was reduced with epirubicin
(Tournade et al., 2001). This study also demonstrated that treatment
with VCR and AMD for 4 weeks versus 8 weeks had comparable rates
of stage distribution and tumor shrinkage in patients with stage I and
III disease. The majority of tumor shrinkage was noted in the first
4 weeks of therapy. Radiotherapy was limited to patients with stage
II node-positive and III disease resulting in 18% of patients being
irradiated (Graf et al., 2000). There were 59 children with stage I to IV
tumors who had complete tumor necrosis induced by chemotherapy,
and 98% of these children had no evidence of disease at 5 years
(Boccon-Gibod et al., 2000).
The SIOP 93-01 study (1993–2001), evaluated a reduction in
postoperative therapy for patients with stage I intermediate risk
and anaplastic Wilms tumor (deKraker et al., 2004; Reinhard et al.,
2004b). Patients were randomized to receive either 4 or 18 weeks of
Pediatric Urologic Oncology: Renal and Adrenal 1105
postoperative chemotherapy with AMD and VCR. Two-year EFS was
91.4% after 4 weeks and 88.8% after 18 weeks of therapy, demonstrating
that survival can be maintained while shortening the duration of
post-nephrectomy therapy. Patients with stage II or III with low- or
intermediate-risk histology received 4 weeks of dactinomycin and
VCR before surgery (Graf et al., 2012). Postoperative chemotherapy
consisted of dactinomycin, VCR, and epirubicin/doxorubicin for 27
weeks. Flank or whole-abdomen irradiation was given for stage III.
With a median follow-up of 8 years, 5-year EFS was 90% and OS 95%.
Patients with blastemal type histology had a worse prognosis with 62%
EFS at 5 years. They made up only 10% of patients but contributed to
one-third of the relapses and deaths. The other important prognostic
factors were a large tumor volume at surgery and stage III disease.
The SIOP 2001 study asked the question whether patients with
stage II and III intermediate-risk histology Wilms tumors could be
safely treated without an anthracycline. Data from SIOP 93-01 had
suggested that survival was not adversely affected when nonviable
tumor was identified in the renal sinus and/or perirenal fat after
preoperative chemotherapy (Vujanic et al., 2009). Between 2001 and
2009, 583 patients were randomized (Pritchard-Jones et al., 2015).
For stage II or stage III intermediate-risk histology Wilms tumor,
2-year EFS was 92.6% for patients treated with DOX and 88.2% for
treatment excluding DOX. OS was 96.5% and 95.8%, respectively.
The SIOP group uses the response of the tumor to preoperative
chemotherapy in their risk stratification (Vujanic et al., 2002). This
includes not only percentage of necrosis but also on the predominant
cell type in the residual viable tumor component. Patients with
high-risk blastemal tumors continue to receive treatment with DOX,
including stage I tumors (van den Heuvel-Eibrink et al., 2015). The
intensified treatment for the latter patients yielded improved OS in
SIOP 2001 with EFS of 96% (OS 100%) compared with EFS of 71%
(OS 90%) in SIOP 93-01.
United Kingdom Children’s Cancer Study Group. The UKCCSG
has conducted several trials using prenephrectomy chemotherapy
but, unlike SIOP, they perform biopsy before treatment (Mitchell
et al., 2000; Pritchard et al., 1995; Pritchard-Jones et al., 2003). This
is done to avoid giving chemotherapy to infants and children with
benign tumors, which accounts for 1% of lesions thought to be
Wilms tumor on imaging studies (Tournade et al., 2001). The other
reason to perform biopsy is to avoid giving inappropriate chemo-
therapy to non–Wilms tumors, which often require more intensive
therapy. The UKW3 trial noted a 12% incidence of non–Wilms tumors
in patients with the typical features of Wilms tumor on imaging
study (Vujanic et al., 2003). The UKW1 and UKW2 studies evaluated
the single-agent VCR for treatment of stage I FH tumors (Mitchell
1106 PART III Pediatric Urology
et al., 2000; Pritchard et al., 1995). The OS of 96% compares well
with two-drug chemotherapy, but age greater than 4 years was
considered an adverse prognostic factor (Pritchard-Jones et al., 2003).
The UKW3 trial randomly assigned patients to either immediate
surgery or to 6 weeks preoperative chemotherapy and then delayed
surgery (Mitchell et al., 2006). EFS and OS at 5 years were similar
in the two groups. Around 20% of survivors avoided treatment with
doxorubicin or radiotherapy because of favorable stage distribution
after preoperative therapy. They concluded, like the SIOP group,
that all children with non-metastatic Wilms tumor should receive
chemotherapy before tumor resection.
Adult Wilms Tumor
Wilms tumor occasionally occurs in adults. Earlier reports suggested
that the outcome for adults with Wilms tumor was poor and that
they require more intensive therapy (Arrigo et al., 1990). More recent
reviews of adult patients with FH Wilms tumor have found improved
survival compared with prior reports (Ali et al., 2012; Kalapurakal
et al., 2004a; Reinhard et al., 2004a). The recommendation is that
adult patients receive stage-appropriate combined modality therapy.
Relapse
A uniform approach for the treatment of tumor relapse was used in
NWTS-5. Patients with relapsed Wilms tumor may be divided into
risk groups according to OS rates after salvage therapy (Spreafico
et al., 2009). Children with non-anaplastic Wilms tumor who relapse
after therapy with only VCR and/or AMD are considered standard
risk and have survival rates in the 70% to 80% range (Green et al.,
2007). Patients with non-anaplastic Wilms tumor who relapse after
therapy with three or more agents are called high risk and have
survival rates in the 40% to 50% range (Malagolowkin et al., 2008).
The very high-risk group includes recurrent anaplastic or blastemal-
type Wilms tumor and have survival rates in the 10% range (Reinhard
et al., 2008). Further studies are needed to determine the optimal
treatment strategies for the “high risk” and “very high-risk” groups
and to define the role of high-dose myeloablative chemotherapy
and stem cell rescue (Ha et al., 2013).
Preoperative Chemotherapy (COG Recommendations)
On the COG renal tumor protocols, treatment is dependent on
surgical and pathological staging after immediate nephrectomy. There
are, however, some situations in which preoperative chemotherapy
is recommended. These include children for whom renal-sparing
surgery is planned (Blute et al., 1987), tumors inoperable at surgical
exploration (Ritchey et al., 1994), and tumor extension into the IVC
above the hepatic veins (Ritchey et al., 1993b; Shamberger et al.,
2001; Szavay et al., 2004). The last two conditions are associated
with an increased risk for surgical complications if primary nephrec-
tomy is performed (Ritchey et al., 1992).
Inoperable Tumors. The surgeon, not the oncologist or radio-
therapist, must make the determination that a tumor is inoperable.
This decision should not be based on preoperative imaging studies,
which can overestimate local tumor extension. As noted earlier,
not all renal masses in children represent Wilms tumor (Vujanic
et al., 2003). If the tumor is found to be unresectable, pretreatment
with chemotherapy almost always reduces the bulk of the tumor
and renders it resectable (Grundy et al., 2004; Ritchey et al., 1994).
Patients who are staged with imaging studies alone and receive
preoperative chemotherapy before nephrectomy are also at risk for
understaging (Tournade et al., 1993). Patients enrolled in COG
studies determined to have an inoperable tumor are treated as
stage III disease (Dome et al., 2015). The number of patients in
North America treated with preoperative chemotherapy has increased
over time. On NWTS-3, only 5.4% of patients were treated as inoper-
able (Ritchey et al., 1994). For the recently completed COG AREN0532
and AREN0533 studies, approximately 20% of patients with overall
stage III disease and 40% of patients with overall stage IV disease
underwent delayed nephrectomy (Dome et al., 2015).
Repeat imaging is performed after 6 weeks of chemotherapy.
Experience in SIOP has shown that the majority of reduction (48%) in
tumor volume occurs in the first 4 weeks of therapy (Tournade et al.,
2001) but that reduction extends out through 8 weeks (62%). After
there has been adequate shrinkage of the tumor, definitive resection
can usually be completed. A clinically good response (by imaging)
is usually associated with a pathologically good response in terms
of regressive histologic changes (Weirich et al., 2001; Zuppan et al.,
1991). The converse is not always true. The distribution of histologic
subtypes is different after preoperative chemotherapy compared with
primary surgery, with differentiation of the tumor occurring after
chemotherapy. Stromal- and epithelial-predominant tumors are found
more often after treatment with preoperative chemotherapy. These
histologic subtypes may demonstrate a poor clinical response to
therapy but have an excellent prognosis if the tumor is completely
excised. Patients with progressive disease have a poor prognosis, and
these patients require treatment with a more intensive chemothera-
peutic regimen (Ora et al., 2007; Ritchey et al., 1994).
Bilateral Wilms Tumors. Synchronous bilateral Wilms tumors
occur in 5% to 7% of children with Wilms tumor (Blute et al.,
1987; Coppes et al., 1989; Montgomery et al., 1991). Children with
bilateral tumors should not undergo initial radical nephrectomy.
These children should receive preoperative chemotherapy with the
goal of tumor shrinkage and renal-sparing surgery (Blute et al., 1987;
Coppes et al., 1989; Hamilton et al., 2011; Kumar et al., 1998).
Preservation of renal tissue is important to decrease the incidence
of renal failure, which approaches 15%, at 15 years after treatment
in patients with bilateral Wilms tumor (Breslow et al., 2005; Ritchey
et al., 1996). The most common cause for renal failure was the need
for bilateral nephrectomy for persistent or recurrent tumor in the
remaining kidney after initial nephrectomy. Complete nephrectomy
can be avoided in the majority of patients if a careful protocol is
followed and the surgery is performed by surgeons experienced in
renal-sparing techniques (Davidoff et al., 2008; Fuchs et al., 2011).
The recently completed COG protocol (AREN0534) recommended
that patients with bilateral Wilms tumor receive 6 weeks of chemo-
therapy before surgery. Biopsy was not required if the radiographic
picture was consistent with Wilms tumor. Tumor response was assessed
after 6 weeks with CT or MRI to determine the reduction in tumor
volume and feasibility of partial resection. Patients with tumors
amenable to renal-sparing procedures were allowed to proceed with
surgery. Tumors not responding to therapy required bilateral open
biopsy to determine histology. Open biopsies are recommended
because they are more accurate than percutaneous needle biopsies
when assessing for anaplasia, and bilateral biopsies are recommend
because anaplasia is found to be discordant between the two
kidneys in 83% of children (Hamilton et al., 2006). Biopsy is
necessary because imaging cannot predict the histology of the tumor
based on changes in volume of the tumor after chemotherapy (Olsen
et al., 2004; Weirich et al., 2001). Failure to achieve a reduction in
volume is likely a result of tumor differentiation (Fig. 53.11) (Ander-
son et al., 2002; Shamberger et al., 2006; Weirich et al., 2001).
Differentiated tumors may show a poor clinical response to therapy,
but they have an excellent prognosis if the tumor is completely
excised. If renal-sparing surgery is not feasible, additional chemo-
therapy is then given based on the biopsy findings, but all patients
were recommended to undergo surgical resection within 12 weeks
of starting therapy. Continuing treatment beyond 12 weeks will not
likely provide any additional reduction in tumor burden.
At the time of second-look surgery, partial nephrectomy or wedge
excision of the tumor is preferred with an attempt to achieve negative
margins. Radical nephrectomy may be needed in a kidney with
extensive tumor involvement. The kidney with the lower tumor
burden is addressed first. Tumor enucleation may be considered in
lieu of a formal partial nephrectomy. This is often needed for large
centrally located tumors when removal of a margin of renal tissue
would compromise the vascular supply to the kidney (Cozzi et al.,
1996; Horwitz et al., 1996). The concern is that enucleation will be
more likely to result in positive surgical margins. For FH tumors,
adjuvant therapy may still achieve a good outcome (Cozzi et al.,
1996; Davidoff et al., 2008; Horwitz et al., 1996). However, if there
 Chapter 53
A B
Fig. 53.11. Patient with bilateral tumors who was treated with chemotherapy. (A) CT before treatment. (B) CT
after 12 weeks of chemotherapy, revealing only minimal decrease in the size of the tumors. Bilateral partial
nephrectomies were performed, revealing mature tumor elements with rhabdomyoblastic differentiation.
Fig. 53.12. Postoperative image from patient shown in Fig. 53.11. Demon-
strates that the kidneys have pretty near normal volume after resection of
the bilateral tumors.
is anaplasia in the resected specimen, a positive margin will adversely
affect survival and requires additional resection. Even when large
bilateral masses remain after initial chemotherapy, a high percentage
of children can be successfully managed with renal-sparing surgery
(Davidoff et al., 2008). It is easy to underestimate the amount of
renal parenchyma that can be salvaged as a result of compression
by the tumor; therefore nephron-sparing surgery should be considered
in all patients (Fig. 53.12). One concern regarding enucleation of
large centrally located tumors is the potential for positive surgical
margins. Kieran et al. (2013b) reported a 23% incidence of positive
surgical margins in a cohort of 21 patients with bilateral Wilms
tumor undergoing renal-sparing surgery. They did not demonstrate
an increased risk of local recurrence, but this was a small number
of patients, with all receiving 10.5-Gy flank radiation.
The COG AREN0534 study enrolled 195 patients with bilateral
Wilms tumor (Ehrlich et al., 2017). Of the 189 evaluable patients,
84.0% underwent definitive surgical treatment (partial or complete
nephrectomy or wedge resection in at least one kidney) by 12 weeks
after initiation of chemotherapy. Thirty percent of those patients
who achieved definitive surgical resection within the 12-week specified
aim did so by the 6-week evaluation point. Surgical approaches
included unilateral total nephrectomy with contralateral partial
nephrectomy (48%), bilateral partial nephrectomy (35%), unilateral
Pediatric Urologic Oncology: Renal and Adrenal 1107
total nephrectomy (10.5%), unilateral partial nephrectomy (4%),
and bilateral total nephrectomies (2.5%). The 4-year EFS and OS
were 82.1% and 94.9%, respectively. This is compared with 4-year
EFS and OS of 56% and 80.8% on NWTS-5.
Bilateral nephrectomies and dialysis are rarely required when the
tumors fail to respond to chemotherapy and radiation therapy. This
is the most common cause of renal failure in patients with bilateral
Wilms tumor (Ritchey et al., 1996). Fortunately, anephric patients
can still be administered chemotherapy with some modifications
(Feusner et al., 2008). The recommended interval between successful
completion of treatment of the Wilms tumor and renal transplantation
varies (Kist-van Holthe et al., 2005; Penn, 1979). Some advocate a
waiting period of 2 years to ensure that the patient does not develop
metastatic disease; others have found that a 1-year interval is sufficient
(Gregoriev et al., 2012). Patients who develop renal failure after
renal-sparing surgery should have removal of the remaining renal
tissue before transplant to prevent tumor recurrence after starting
immunosuppression (Kubiak et al., 2004).
All patients treated for bilateral Wilms tumor require close long-
term follow-up. SIOP investigators noted that late relapses have
occurred in patients with bilateral Wilms tumor more than 4 years
after treatment and recommended long-term follow-up (Coppes
et al., 1989). These patients should also have frequent assessment
of renal function, urine protein, and blood pressure.
Partial Nephrectomy for Unilateral Tumors. There have been a
number of papers examining the role of parenchymal-sparing
procedures in children with unilateral Wilms tumors (Cost et al.,
2012; Haecker et al., 2003; McLorie et al., 1991; Wilde et al., 2014;
Zani et al., 2005). The primary motivation for this approach is concern
about late occurrence of renal dysfunction after unilateral nephrec-
tomy. However, the incidence of renal failure after nephrectomy
for most children with unilateral Wilms tumor is low, 0.6% at
20 years after treatment (Breslow et al., 2005; Lange et al., 2011).
The risk of renal failure is higher for patients with genitourinary
anomalies, DDS, and WAGR. As noted earlier, this is a result of
mutation of WT1, which is necessary for normal renal development.
Syndromic patients are more likely to have smaller tumors identified
on screening studies that are more amenable to renal-sparing surgery
(Romao et al., 2012; Scalabre et al., 2016).
Most Wilms tumors are too large at diagnosis to allow partial
nephrectomy. After preoperative chemotherapy, partial nephrectomy
can be performed in 10% to 15% of patients. However, this higher
percentage is only achieved if the clinician is more aggressive in
proceeding with nephron sparing surgery (NSS). The SIOP 2001
study restricted NSS for polar or peripherally non-infiltrating tumors
(Wilde et al., 2014). They reported that 3% of tumors met the criteria
1108 PART III Pediatric Urology
for NSS. Only the occasional case of Wilms tumor will involve a
lesion small enough to allow partial nephrectomy at diagnosis—for
example, tumors detected on screening studies for Beckwith-
Wiedemann syndrome and aniridia (see Fig. 53.6). Even in the young
children with very-low–risk stage I tumors, it is estimated that less
than 10% of children would be amenable to partial nephrectomy
(Ferrer et al., 2013). As noted earlier, there are concerns regarding
staging after chemotherapy, requiring some patients to receive added
therapy to prevent local recurrence. Another concern is the increased
risk for local recurrence after partial nephrectomy (Haecker et al.,
2003; Horwitz et al., 1996; Wilde et al., 2014). Patients who develop
intra-abdominal relapse have a markedly decreased survival (Sham-
berger et al., 1999).
The COG AREN0534 study also included a renal-sparing protocol
for select patients with unilateral Wilms tumors known to be at risk
for bilateral disease or at increased risk for renal failure. These patients
were managed with a strict surgical protocol to minimize risk for
residual disease (Cozzi et al., 2004). The protocol required that the
lesion be completely excised with a margin of normal renal paren-
chyma. These patients should not undergo partial nephrectomy if
the tumor cannot be removed at stage I. Patients with high-risk
histologic patterns such as anaplasia or persistent blastemal-
predominant tumor after chemotherapy should be treated with
complete nephrectomy because these tumors have resistance to
chemotherapy (Reinhard et al., 2004b). Results of AREN0534 for
patients with unilateral tumors have not been published.
Late Effects of Treatment
The 5-year survival rate for childhood cancers has increased over
the past decades to more than 80%. Achieving these high cure rates
requires exposure of normal healthy tissue to potential harm with
many organ systems subject to the late sequelae of anticancer therapy.
These survivors are at increased risk for numerous chronic health
conditions, hospitalizations, and reduced productivity because of
health problems (Phillips et al., 2015). Clinicians must be aware of
the spectrum of problems that face children as they grow into adult-
hood. Our understanding of late effects in Wilms tumor survivors
has been advanced through several large studies. The NWTSG Late
Effects Study followed patients treated in NWTS-1 to NWTS-5. The
original Childhood Cancer Survivor Study (CCSS) was a retrospectively
ascertained cohort of childhood cancer survivors diagnosed from
1970 to 1986. More than 14,000 survivors were surveyed and followed
for long-term health outcomes. Because of the significant changes
in therapy for children with cancer over the past 30 years, a second
group of about 10,000 survivors diagnosed between 1987 and 1999
were also recruited for the study. Similar efforts are also conducted
in other countries, some of which are population-based cohort studies
(Wong et al., 2016).
The CCSS reported a cumulative incidence of 65% for all chronic
health conditions in Wilms tumor survivors at 25 years after
completion of therapy (Termuhlen et al., 2011). These rates continue
to increase with longer periods of follow-up (Phillips et al., 2015).
The cumulative incidence of severe (grades 3 or 4) chronic health
conditions was 24% (Termuhlen et al., 2011).
Mortality
The NWTSG Late Effects Study showed that survivors remain at
elevated risk for death compared with the general population for
many years after their original diagnosis (Cotton et al., 2009). A
more recent report from the CCSS has shown that mortality for
survivors of childhood cancer has decreased for those patients treated
in the 1990s compared with the early 1970s (Armstrong et al., 2016).
This is attributed to changes in therapy (e.g., reduction the number
of patients exposed to radiotherapy or anthracyclines).
Fertility and Pregnancy
Gonadal radiation can produce hypogonadism and temporary
azoospermia in boys (Kinsella et al., 1989). The severity of damage
is radiation dose dependent. The Leydig cells are more radioresistant
than the germ cells, but higher doses can produce damage, resulting
in inadequate production of testosterone. This can result in delayed
sexual maturation. Chemotherapeutic agents can also adversely affect
testicular function (Mustieles et al., 1995). Pelvic irradiation and
exposure to alkylating agents are risk factors for ovarian failure and
premature menopause in female Wilms tumor survivors (Green et al.,
2009). Very few pregnancies have been reported in patients who
received whole abdominal radiation therapy (Green et al., 2010).
Pregnancy complications were evaluated extensively through the
NWTSG. The offspring of irradiated female patients are at risk for
low birth weights and premature birth. Radiation portals that include
the pelvis and doses exceeding 20 Gy increase the risk of miscarriage
(Kalapurakal et al., 2004b). Wilms tumor survivors treated with
abdominal radiotherapy are also at increased risk of hypertension
complicating pregnancy (Reulen et al., 2017).
Second Malignancies
An increased incidence of second malignant neoplasms has been
noted in children treated for Wilms tumor. There is a 1% cumulative
incidence at 10 years postdiagnosis, and a rising incidence thereafter
(Breslow et al., 1988b, 2010; Taylor et al., 2008). One of the greatest
risk factors is prior irradiation, and most tumors occur in the radiation
field (Bassal et al., 2006; Breslow et al., 1988b; Taylor et al., 2008).
The incidence of leukemia is highest during the first 5 years after
Wilms tumor treatment. The incidence of solid tumors increases
with longer periods of follow-up (Lee et al., 2015).
Cardiac Effects
The risk of cardiotoxicity in Wilms tumor survivors has been carefully
studied. In a review of patients entered in NWTS-1, NWTS-2, NWTS-3,
and NWTS-4, the frequency of congestive heart failure was 4.4%
among DOX-treated patients who received this drug as part of their
initial chemotherapy regimen (Green et al., 2001b). The risk was
increased if the patient received whole-lung or left-flank irradiation.
Only one patient with congestive heart failure received a DOX
cumulative dose below 150 mg/m2, which is used in contemporary
North American treatment regimens. However, subclinical cardiotoxic-
ity was not assessed, and it is possible that clinical effects with
modern regimens will become apparent with longer follow-up. The
British CCSS has found that cardiac problems were the second most
common cause of mortality more than 30 years after Wilms tumor
diagnosis (Wong et al., 2016).
Other Renal Tumors
Clear Cell Sarcoma of the Kidney
CCSK accounts for 3% of renal tumors reported to the NWTSG. The
tumor derives its name from the clear cytoplasm of the predominant
cell type (Schmidt and Beckwith, 1995). Important predictors of
improved survival are lower stage, younger age at diagnosis, treat-
ment with DOX, and absence of tumor necrosis (Argani et al., 2000).
The addition of doxorubicin improved OS and relapse-free survival
(Argani et al., 2000; D’Angio et al., 1989; Seibel et al., 2004). Patients
with stage I tumors (using the current criteria of absence of renal
sinus invasion) had a 98% survival rate. Unlike anaplastic Wilms
tumor, even stage I CCSK lesions are associated with increased rates
of relapse and require postoperative irradiation. Long-term follow-up
of CCSK patients is needed because 30% of relapses occurred more
than 3 years after diagnosis and some as late as 10 years. Unlike Wilms
tumor, CCSK is associated with bone and brain metastases. Bilateral
involvement has thus far not been reported, nor has the presence of
Wilms tumor associated congenital anomalies such as aniridia or
hemihypertrophy. Patients with CCSK were treated on NWTS-5 with
a regimen combining VCR, DOX, cyclophosphamide, and etoposide
in an attempt to further improve the survival of this high-risk group.
However, outcomes for patients with CCSK treated on NWTS-5 were
similar to that seen on NWTS-4 (5-year RFS and OS of 79% and 89%,
 Chapter 53
respectively) (Seibel et al., 2018). Stage was found to be highly predictive
of outcome; 5-year RFS rates for stages I, II, III, and IV on NWTS-5
were 100%, 88%, 73%, and 29%, respectively. Similar outcomes have
been reported by SIOP investigators (Furtwangler et al., 2013).
Rhabdoid Tumor of the Kidney
RTK is the most aggressive and lethal childhood renal tumor that
accounts for 2% of renal tumors. RTK and CCSK occur in renal
and extrarenal locations, suggesting an origin from a non–organ-
specific mesenchymal cell. These tumors are characterized by loss
of function of the SMARCB1/INI1/SNF5/BAF47 gene in chromosome
band 22q11.2 (Biegel et al., 1999). Consistent with its role as a
tumor suppressor gene, tumors arise after inactivation of both alleles
of SMARCB1. Germ-line alterations of the SMARCB1 gene are found
in one-third of the patients (Eaton et al., 2011). Germ-line mutations
of INI1 have been identified in renal rhabdoid tumors. Staining for
the products of the INI1 gene can be useful because rhabdoid tumor
of the kidney is consistently negative (Hoot et al., 2004).
Typical clinical features include early age of diagnosis (median
age <16 months), advanced stage, resistance to chemotherapy, and
high mortality (Amar et al., 2001; Tomlinson et al., 2005). Younger
age at diagnosis is an adverse prognostic factor. RTK is distinguished
by its propensity to metastasize to the brain (D’Angio et al., 1993).
There is no standard therapy for RTK. Intensification of therapy with
high-dose chemotherapy and autologous stem-cell transplantation
have not yielded improved survival (Furtwangler et al., 2018).
Congenital Mesoblastic Nephroma
CMN is the most common renal tumor in infants with a mean
age at diagnosis of 3½ months (Howell et al., 1982; van den
Heuvel-Eibrink et al., 2008). This is the most common renal tumor
diagnosed on antenatal ultrasound (LeClair et al., 2005). Congenital
mesoblastic nephroma is a very firm tumor on gross examination,
and the cut surface has the yellowish-gray trabeculated appearance
of a leiomyoma. There are three histologic subtypes: classic, cellular,
and mixed (showing areas of classical and cellular). The classic
subtype, characterized by interlacing sheets of bland spindle cells,
resembles infantile fibromatosis. The cellular variant, with a solid
sheet-like growth pattern and frequent mitoses, is virtually identical
histologically to congenital fibrosarcoma (Beckwith, 1986; Gormley
et al., 1989; Joshi et al., 1986). Both tumors have a similar transloca-
tion that fuses the ETV6 (TEL) gene from 12p13 with the 15q25
neurotrophin-3 receptor gene, NTRK3 (Argani et al., 1998; Vokuhl
et al., 2017). A SIOP/GPOH showed that patients with cellular type
CMN who have translocation-positive tumors had a significantly
superior RFS (5-year RFS: 100% vs. 73%). In CMN, tumor induction
is postulated to occur at a time when the multipotent blastema is
predominately stromagenic (Snyder et al., 1981; Tomlinson et al.,
1992). WT1 is not expressed in CMN (Tomlinson et al., 1992).
The most important aspect of CMN is the usually excellent
outcome with radical surgery only (Howell et al., 1982). The tumor
can extend into the hilar or perirenal soft tissue; therefore complete
surgical resection is important (Beckwith, 1986). Local recurrence and
metastasis can occur particularly with the cellular variant of CMN
(Fitchey et al., 2003; Gormley et al., 1989; Joshi et al., 1986). The
risk of recurrence is thought to be less in children under 3 months of
age at diagnosis, but metastases have been reported in a few infants
(Heidelberger et al., 1993). Neither chemotherapy nor radiation therapy
is routinely recommended (Howell et al., 1982), but consideration
for adjuvant treatment should be given to patients with cellular vari-
ants that are incompletely resected (Gormley et al., 1989). There are
reports demonstrating response of inoperable and recurrent tumors
to chemotherapy (Loeb et al., 2002; McCahon et al., 2003).
Solitary Multilocular Cyst and Cystic Partially
Differentiated Nephroblastoma
Solitary multilocular cyst, or multilocular cystic nephroma, is an
uncommon, benign renal tumor. Fifty percent of multilocular
Pediatric Urologic Oncology: Renal and Adrenal 1109
cysts are found in young children, usually boys. The second peak
incidence occurs in young adult women (Eble and Bonsib, 1998;
Luithle et al., 2007). Although the majority of cases of multilocular
cystic renal disease have been unilateral, there are rare reports of
bilateral cases (Ferrer and McKenna, 1994). The gross appearance
of the tumor is its most distinguishing feature. The cut surfaces reveal
a well-encapsulated multilocular tumor composed of various-size
cysts compressing the surrounding renal parenchyma. This tumor
is distinguished by the finding of only mature cell types within the
septa of the cyst wall. Multilocular cystic nephroma is cured by
nephrectomy, but recurrence has occurred after incomplete excision
by partial nephrectomy. If partial nephrectomy is considered, frozen
section is indicated to exclude cystic partially differentiated nephro-
blastoma (CPDN) or clear cell sarcoma, which can occasionally have
a similar appearance.
Another entity reported in the literature with similar features is
CPDN. The majority of these lesions occur in the first 2 years of life
(Blakely et al., 2003; Joshi and Beckwith, 1989; Luithle et al., 2007).
Eble and Bonsib (1998) recommend that multilocular cystic nephroma
and CPDN be considered the same entity. They are indistinguishable
radiographically. Histologic examination reveals that blastemal cells
or nephrogenic rests may be found in the septa of both tumors.
Surgery is curative in almost all patients with recurrence being the
result of incomplete resection (Blakely et al., 2003; Eble and Bonsib,
1998). In a review of 21 children with cystic partially differentiated
nephroblastoma (CPDN) reported to the NWTSG, there was 100%
survival. Eight were treated with surgery alone (Blakely et al., 2003).
Thirteen patients received postoperative chemotherapy, including
two patients with stage II disease.
Metanephric Adenofibroma
Another tumor with prominent stromal features that can resemble
CMN is metanephric adenofibroma (Arroyo et al., 2000). The epi-
thelial component of these tumors can range from inactive meta-
nephric adenoma to Wilms tumor. Other lesions contain areas
morphologically identical to papillary renal cell carcinoma. This
uncommon entity may be derived from ILNR (Arroyo et al., 2000).
Metanephric adenofibromas with a composite Wilms tumor com-
ponent occur at a young age (mean of 12 months) similar to other
ILNR-related Wilms tumors that develop in patients with DDS and
aniridia. None of these tumors have recurred after nephrectomy, but
all have been treated with Wilms tumor chemotherapy.
Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common renal malignancy
in the second decade of life. Only 5% of RCCs occur in children
(Broecker, 1991; Geller et al., 2015; Hartman et al., 1982). An
abdominal mass is the most common presentation, but hematuria
is more common than in Wilms tumor (Broecker, 1991). Imaging
studies cannot differentiate RCC from other solid renal tumors. There
is a higher incidence of papillary RCC in children (Renshaw et al.,
1999; Selle et al., 2006). However, the most common histology of
RCC in children and adolescents, at approximately 50%, is
translocation-associated RCC (Geller et al., 2015). These tumors,
typically seen in adolescence or young adults, are genetically
unique in that they have chromosome translocations involving
a common breakpoint in the TFE3 gene located at Xp11.2 (Bruder
et al., 2004). These tumors differ from adult RCC in that immuno-
reactivity for epithelial markers is reduced or absent. There is also
an increased risk of lymph node involvement (40%–50%), and
presentation is at a higher stage than adult RCC (Geller et al., 2015).
Another type of RCC more often seen in children is renal medullary
carcinoma found in patients with sickle cell hemoglobinopathy
(Swartz et al., 2002). The median age at presentation is 13 years,
but it can be found in much younger children. It is a highly lethal
tumor. A recent report from COG noted that 22 of 25 patients (88%)
with renal medullary carcinoma in their Biology and Banking Study
(AREN03B2) were diagnosed with stage IV disease at diagnosis
(Sandberg et al., 2017).
1110 PART III Pediatric Urology

Complete tumor resection is the most important determinant

of outcome in RCC. Raney et al. (1983) found that all children
with stage I lesions survived, and others have reported 64% to 80%
survival for stage I and II tumors (Aronson et al., 1996; Castellanos
et al., 1974; Dehner et al., 1970). Partial nephrectomy has been
used in pediatric patients with RCC, but outcome data are limited
(Cook et al., 2006). Younger age at diagnosis is a favorable prognostic
factor (Raney et al., 1983). Regional lymph node involvement does
not portend the same poor prognosis as adult renal cell carcinoma
(Geller and Dome, 2004). Geller et al. (2008) reported that patients
with TFE+ translocation and positive nodes were found to have 93%
survival at a median follow-up of 4.3 years. However, others have
noted higher rates of relapse (Perlman, 2010). Like RCC in adults,
these tumors are generally not responsive to chemotherapy or radia-
tion therapy, although case reports of successful adjuvant treatment
have been published (Chowdhury et al., 2013).

Angiomyolipoma
Renal angiomyolipoma is a hamartomatous lesion that is only rarely
seen in childhood. The majority of adult patients have sporadic
angiomyolipomas. In children, they are most commonly detected
in patients with the tuberous sclerosis complex (TSC), and presenta-
tion is more often bilateral in these patients (Bissler et al., 2016;
Ewalt et al., 1998; Warncke et al., 2017). Angiomyolipoma develops
in 50% to 80% of patients with TSC. The lesions progressively enlarge
through childhood with an apparent growth spurt in teenagers and
young adults. Warncke et al. (2017) noted increase annual growth
in those TSC patients older than 11 years and those with AMLs
smaller than 2 cm in size. Annual ultrasounds are recommended
with consideration of MRI for those older than 11 years and having
lesions smaller than 2 cm. Other renal lesions found in the TSC
include simple cysts, polycystic kidney disease, and RCC. Renal cysts
occur in up to 30% of patients with TSC. Mutations of one of two
genes on chromosome 9 (TSC1) and chromosome 16 (TSC2) are
found in 85% of TSC patients (Crino et al., 2006). It has been
postulated that these genes act as tumor suppressor genes and that
the LOH of TSC1 or TSC2 may explain the progressive growth pattern
of renal lesions seen in these patients (Henske, 2004).
Patients with angiomyolipomas resulting from tuberous sclerosis
are at risk for hemorrhage and impaired renal function (Bissler et al.,
2016). For many years, the threshold diameter for intervention has
been more than 4 cm. Recent data in adult patients with sporadic
angiomyolipoma suggest that intervention can be delayed until the
diameter exceeds 6 cm (Kuusk et al., 2015). The International TSC
Consensus Group recommends intervention for lesions larger than
3 cm in diameter (Kingswood et al., 2016). Lesions in TSC patients
that are larger than 3 cm and enlarging appear to be at greatest risk
for bleeding. The first-line treatment for children with growing
lesions (Fig. 53.13) is with mTOR inhibitor, and embolization or
surgery are second-line treatments.
The main problems with embolization are risks of damage to
infarction of normal adjacent renal parenchyma and risk of short-term
complications and that it will not prevent other smaller lesions from
progressing. Repeat intervention is required in 35% of patients
undergoing embolization (Kuusk et al., 2015). Embolization is
reserved for patients with active bleeding.
TSC1 or TSC2 mutations in patients with TSC give rise to hyper-
activation of the mTOR pathway. The first mTOR inhibitor studied
for TSC patients was sirolimus. The renal studies all showed that
sirolimus was very effective at preventing enlargement of the lesions
and also significantly reducing their size, while the medication was
Fig. 53.13. Angiomyolipoma of the right kidney in a patient with tuberous
sclerosis.
taken continuously. When discontinued after 12 months, the angio-
myolipomata started to enlarge again, demonstrating that the mTOR
inhibitors must be continued (Bissler and Kingwood, 2016).
A randomized placebo-controlled trial (EXIST-1) reported that
42% of patients had at least a 50% reduction in total volume of
angiomyolipoma after treatment with everolimus compared with 0
of placebo (Bissler et al., 2013). The patients were all age 18 years
or older. An extended follow-up study (EXIST-2) has shown that
14% of patients will experience some progression of the angiomyo-
lipomas (Bissler et al., 2017). No renal bleeding or nephrectomies
were reported.
Some lesions are fat poor, and differentiation from other renal
tumors—for example, RCC—on imaging studies can be difficult
(Hindman et al., 2012). In some cases, biopsy of the lesion may be
needed to confirm diagnosis of angiomyolipoma before proceeding
with treatment. Nephron-sparing approaches are recommended in
children with TSC because of the presence of multiple, bilateral
lesions and the risk of development of new lesions.
KEY POINTS: RENAL TUMORS
• eletions of WT1, located on chromosome 11p, are found
in patients with aniridia and Wilms tumor. Mutations of
WT1 occur in DDS.
• ocal recurrence is increased in ilms tumor patients with
local tumor spillage, and this is not classified stage III
disease. The 2-year survival rate after local recurrence is
43%.
• Patients with bilateral ilms tumor should be treated with
preoperative chemotherapy. This will allow more patients
to undergo renal-sparing surgery in an attempt to decrease
the risk of renal failure.
• MN is the most common renal tumor in infants.
REFERENCES
The complete reference list is available online at ExpertConsult.com.