WILMS TUMOR

Epidemiology.
Wilms tumor, also designated nephroblastoma, is a complex mixed embryonal neoplasm
of the kidney composed of three elements: blastema, epithelia, and stroma. The incidence
is approximately 8 cases/million children younger than 15 yr of age. It usually occurs in
children between 25 yr of age, although it has also been encountered in neonates,
adolescents, and adults. It comprises approximately 6% of pediatric cancers and is the
second most common malignant abdominal tumor in childhood. It may arise in one or
both kidneys; the incidence of bilateral Wilms tumor is 7%. It may be associated with
hemihypertrophy, aniridia, and other congenital anomalies, usually of the genitourinary
tract. It has also been described in association with a variety of syndromes.
Pathogenesis.
The majority of Wilms tumors cases are sporadic, although 12% of patients have a
family history. Familial predisposition to Wilms tumor is inherited in an autosomal
dominant manner. Familial cases are associated with a decreased age at diagnosis and an
increased frequency of bilateral disease, although these features are not observed in all
families. Congenital anomalies are absent in most families.
One Wilms tumor gene, WT1, located at 11p13, has been isolated. WT1 encodes a zinc
finger transcription factor that is critical for normal kidney development. Roughly 20% of
all Wilms tumors carry WT1 mutations, and most of these mutations are tumor specific.
Wilms tumor patients with associated congenital anomalies frequently carry germline
WT1 mutations. Familial predisposition to Wilms tumor is usually not associated with
WT1 alterations; familial predisposition genes have been localized to 19q13 and 17q.
Histologically, two broad categories have been recognized: favorable and unfavorable.
The favorable type is considered to be the conventional form and usually carries a good
prognosis. It is characterized by blastema, epithelia, and stromal elements devoid of
ectopia or anaplasia. Small amounts of sarcomatous elements in the stroma in an
otherwise favorable type apparently do not adversely influence the prognosis. The
unfavorable subtype is characterized by marked enlargement of the nuclei,
hyperchromatism of the enlarged nuclei, and multipolar mitotic figures. Areas of
anaplasia may be focal or diffuse and predict probable high rates of tumor relapse and
death. It tends to occur in older, nonwhite patients. Clear cell sarcoma is a subtype of the
unfavorable form and usually metastasizes to bone. Rhabdoid tumor, which may
metastasize to the brain, is no longer classified as a subtype of Wilms tumor.
Nodal or other potential metastatic sites are usually the most fruitful areas to identify
anaplasia, which is extremely uncommon in children younger than 2 yr of age. A high
index of suspicion and more thorough sampling of techniques are appropriate if anaplasia
is detected, particularly in older children. The phenomenon is generally not found once
chemotherapy has been administered. Anaplasia related to skeletal muscle cells does not
appear to be associated with an increased incidence of relapse.
Recent studies have shown a remarkable correlation among the DNA content in the cells
of Wilms tumor, histiologic subtype, and treatment outcome. Stem lines of both the
primary tumor and metastases are in the diploid and low aneuploid (hyperdiploid) range.
Tumors with hyperdiploid content are also characteristic of the anaplastic (unfavorable)
varieties and

1712
have enormous complex translocations. They respond poorly to chemotherapy.
CONGENITAL ABNORMALITIES.
Several syndromes, congenital abnormalities, and chromosomal aberrations are
commonly reported in Wilms tumor ( Tables 4911 and 4912 ). WAGR syndrome
comprises Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation.
Patients with this syndrome have a constitutional deletion of chromosome 11p13 where
both the Wilms tumor gene, WT1, and the aniridia gene, PAX6, are located. Denys-Drash
syndrome comprises male pseudohermaphrodism, early-onset renal failure characterized
by mesangial sclerosis, and an increased risk of Wilms tumor. Patients with this
syndrome typically carry a point mutation within the WT1 gene. The BeckwithWiedemann syndrome is characterized by hemihypertrophy, macroglossia, and
visceromegaly, with a risk of developing Wilms tumor of 35%. A variety of 11p15.5
abnormalities have been reported in patients with this syndrome, and it is postulated that
a second Wilms tumor gene, WT2, is located in this region. Other syndromes or
conditions with an increased risk of Wilms tumor include hemihypertrophy, aniridia,
genitourinary anomalies, Pearlman syndrome, Sotos syndrome, neurofibromatosis (von
Recklinghausen disease), and von Willebrand disease. The most common genitourinary
anomalies associated with Wilms tumor are hypoplasia, fusion and ectopia of the kidney,
duplications of the collecting systems, hypospadias, and cryptorchidism.
Clinical Manifestations.
Wilms tumor usually presents as an abdominal mass. It is generally discovered
fortuitously, and it is not uncommon for it to be brought to the mother's attention while
bathing the infant. It may also be identified during a well-child clinical examination.
Renal masses of this type are usually smooth and firm and occasionally may cross the
midline. They vary in size. Some patients may present with abdominal pain and vomiting
and, infrequently, hematuria. Hypertension has also been described and is probably due to
renal ischemia. Occasionally, rapid abdominal enlargement and anemia may occur owing
to bleeding into the renal parenchyma or pelvis. Hematuria has been reported in 1225%
of patients.
Diagnosis.
Any abdominal mass in a child must be considered malignant until diagnostic imaging
and laboratory findings define its true nature. If there is any doubt, biopsy or excision and
histologic verification is the final arbiter. Wilms tumor must be differentiated from a
variety of malignant abdominal and pelvic tumors ( Table 4913 ). Once an abdominal
mass is discovered
TABLE 491-1 -- Syndromes Associated with Wilms Tumor and Their Clinical and
Genetic Characteristics
Syndrome
Clinical Characteristics
Chromosome or other abnormalities
WAGR
Aniridia, genitourinary abnormalities, mental retardation
Del 11p13 (WT1 & PAX6 loci)
Denys-Drash

Early-onset renal failure with renal mesangial sclerosis, male pseudohermaphrodism,

increase risk of Wilms tumor
WT1 mutations
Beckwith-Wiedemann
Organomegaly (liver, kidney, adrenal, pancreas), macroglossia omphalocele,
hemihypertrophy
Uniparental paternal disomy, duplication 11p15.5, loss of imprinting, mutation of
p57KIP57 have been described. Del 11p15.5 (WT2 locus)
May also involve IGF2 and/or H19 genes

TABLE 491-2 -- Genetic Alterations Observed in Wilms Tumors

Gene
Wilms Tumor Characteristic
Frequency
Type of Alteration
WT1
Unselected
~20%
Deletions, truncating mutations, missense mutations in zinc fingerencoding exons
-Catenin
Unselected
~15%
Missense mutations or deletions affecting protein phosphorylation sites
Tumors with WT1 mutations (~20% of total)
~50%
P53
Anaplastic histology (~5% of total)
~80%
Missense and truncating mutations
, a complete physical examination should be performed followed by a complete blood
cell count, liver and kidney function studies, and a search for specific tumor markers
secreted by the suspected tumor. Imaging studies include a flat plate of the abdomen,
ultrasonography, and CT and/or MRI.
CT scan permits confirmation of the intrarenal origin of the mass. It may also provide
information on the extent of tumor, involvement of the inferior vena cava, and integrity
of the contralateral kidney. Tumors enhance slightly after injection of contrast medium,
which is useful to determine the function of the uninvolved kidney in the event that

nephrectomy is required. MRI may also help define the extent of tumor. Ultrasonography
may also contribute to identification of the tumor and integrity of the inferior vena cava.
Occasionally, angiography may be requested to plan the surgical procedure. Bone scans
are obtained for clear cell sarcoma of the kidney and MRI or CT of the brain in a
malignant rhabdoid tumor.
Radiographic examination of the chest is required to determine the presence of
pulmonary metastases. Pulmonary metastases from Wilms tumor can generally be
identified on conventional radiograph; therefore, CT scans of the lungs are not routinely
obtained. Occasionally, a CT scan demonstrates isolated nodules in patients with normal
chest radiographs; the true nature of these nodules is uncertain.
STAGING.
The staging system frequently utilized was developed by the National Wilms Tumor
Study Group ( Table 4914 ) and correlates with prognosis ( Table 4915 ). Stage I
Wilms tumor is confined to the kidney and, by definition, is completely excised with the
capsular surface intact. Stage II Wilms tumor is also confined to the kidney, although the
capsule is penetrated or tumor is present in the perirenal soft tissue. Stage III Wilms
tumor has postsurgical residual nonhematogenous extension present. Spread is confined
to the abdomen and may involve the perirenal bed, draining lymph nodes, or the
surrounding tissue and organs by contiguity. Stage IV Wilms tumor is characterized by
hematogenous metastases. The metastases generally involve the lungs and occasionally
the liver. Stage V Wilms tumor is designated by bilateral renal involvement.
Treatment.
Surgical extirpation of the tumor should be performed. The patency of the inferior vena
cava should be established before the resection; if it is not patent, preoperative
chemotherapy should be administered. During the operation the contralateral kidney
should be examined to exclude bilateral Wilms tumor. The liver should be inspected for
possible metastases
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TABLE 491-3 -- Differential Diagnosis of Abdominal and Pelvic Tumors in Infants and
Children
Tumor
Age
Clinical Signs
Laboratory Findings
Wilms tumor
Preschool
Unilateral flank mass, aniridia, hemihypertrophy
Hematuria; bone scintigraphy (clear cell sarcoma)
Neuroblastoma
Preschool
Gastrointestinal/ genitourinary obstruction, raccoon eyes, myoclonus-opsoclonus,
diarrhea, skin nodules (infants)

Increased VMA; increased HVA; increased ferritin; stippled calcification in mass. Bone
marrow +
Non-Hodgkin lymphoma
>1 yr
Intussusception in >2-yr-old child
Increased urate; bone marrow +
Rhabdomyosarcoma
All
Gastrointestinal/genitourinary obstruction, sarcoma botryoides, vaginal bleeding,
paratesticular mass
Germ cell/teratoma
Preschool, teens
Girls: abdominal pain, vaginal bleeding
Increased hCG;
Boys: testicular mass, new onset hydrocele
Increased AFP
Sacrococcygeal mass/dimple
Hepatoblastoma
Birth3 yr
Large, firm liver
Increased AFP
Hepatoma
School age, teens
Large, firm liver; hepatitis B, cirrhosis
Increased AFP
VMA = vanillylmandelic acid; HMA = homovanillic acid; hCG = human chorionic
gonadotropin; AFP = a-fetoprotein.

TABLE 491-4 -- Staging System Developed by the Third National Wilms Tumor Study
Group
Stage I
Tumor limited to kidney and is completely excised. Capsular surface intact; no tumor
rupture; no residual tumor apparent beyond margins of excision
Stage II
Tumor extends beyond kidney but is completely excised. Regional extension of tumor;
vessel infiltration; tumor biopsied or local spillage of tumor confined to the flank. No
residual tumor apparent at or beyond margins of excision

Stage III
Residual nonhematogenous tumor confined to the abdomen. Lymph node involvement of
hilus, periaortic chains, or beyond; diffuse peritoneal contamination by tumor spillage;
peritoneal implants of tumor; tumor extends beyond surgical margins microscopically or
macroscopically; tumor not completely removable because of local infiltration into vital
structures
Stage IV
Deposits beyond stage III (e.g., lung, liver, bone, brain)
Stage V
Bilateral renal involvement at diagnosis
, although CT, MRI, or ultrasonography may have identified metastases preoperatively.
The retroperitoneal lymph nodes should be examined and suspicious nodes sampled for
tumor involvement. Every attempt should be made to avoid spillage of tumor.
Most centers utilize chemotherapy guidelines provided by the National Wilms Tumor
Study Group. For stage I and II, favorable histology tumors, vincristine and dactinomycin
are administered. For stage III, favorable histology, vincristine, dactinomycin, and
doxorubicin are administered. Radiation therapy is also administered to the tumor bed. In
stage IV, favorable histology, vincristine, dactinomycin, and doxorubicin are
administered. In addition, radiation therapy is administered to the sites of known disease,
particularly the lungs. If tumor in the liver is present, surgical resection as opposed to
radiation therapy may be considered. Resistant tumors that fail to respond to
chemotherapy and radiation, or tumors that recur, may be considered for surgical
resection and alternate (investigational) chemotherapy.
In the unfavorable histology subtype, vincristine, dactinomycin, doxorubicin, and
cyclophosphamide are administered. Treatment is more aggressive and usually
incorporates radiation therapy to the tumor bed and sites of established metastases. Clear
cell sarcoma of bone has responded to a combination of cisplatin, doxorubicin, and
radiation therapy. Additional therapy with cyclophosphamide or ifosfamide may also be
considered.
INOPERABLE WILMS TUMOR.
Chemotherapy is administered for all Wilms tumors that appear inoperable. In these
circumstances the diagnosis is usually established by percutaneous needle biopsy. The
selection of chemotherapy is dictated by histologic criteria: for favorable histologic
subtypes, vincristine and dactinomycin are utilized for stages I and II and vincristine,
dactinomycin, and doxorubicin for stages III and IV. Tumors of the unfavorable variety
are treated with vincristine, dactinomycin, doxorubicin, and cyclophosphamide. In most
instances a reduction in tumor size will be obtained. The prognosis for inoperable tumors
treated with chemotherapy, surgery, and, if required, radiation therapy is generally
favorable, with survival rates of more than 50%.
BILATERAL WILMS TUMOR.
Chemotherapy for bilateral Wilms tumor is identical to that employed for inoperable
tumors and is utilized to render the tumor amenable to surgical extirpation. This may
comprise unilateral nephrectomy and contralateral partial nephrectomy or bilateral partial
nephrectomies. These maneuvers permit ablation of viable neoplasm and conservation of

renal tissue. Surgical procedures are dictated by the extent of tumor and response to
chemotherapy. Postoperatively, chemotherapy and, not infrequently, radiation therapy are
administered. Occasionally, preoperative radiation is also utilized. These therapeutic
strategies have yielded survival rates of 6085%.
SALVAGE CHEMOTHERAPY.
Patients may relapse during or after treatment with conventional therapy. Such patients,
particularly those with favorable hematology, can often be salvaged with alternate
treatment. In these circumstances, combination chemotherapy with vincristine,
doxorubicin (Adriamycin), cyclophosphamide, and dactinomycin (Actinomycin D)
(VACA) or ifosfamide, carboplatin, and etoposide (ICE) may be attempted. High-dose
chemotherapy with bone marrow rescue has also been employed. A multidisciplinary
strategy with surgery, radiation therapy, and chemotherapy will generally yield the best
result.
Prognosis.
Major prognostic factors are tumor size, stage, and histology (see Table 4915 ). The
prognosis is worse in patients with a larger tumor (>500?g), advanced stage (III and IV),
and unfavorable histologic subtype. Nonetheless, Wilms tumor
1714
TABLE 491-5 -- Wilms Tumor: Survival by Histology and Stage
Histology/Stage
Survival 2 Yr (%)
Survival 4 Yr (%)
Favorable I
98
97
Favorable II
96
94
Favorable III
91
88
Favorable IV
88
82
Anaplastic I
89
89
Anaplastic IIIV
56
54
Modified from Wilms' tumor: Status report, 1990. By the National Wilms' Tumor Study
Committee. J Clin Oncol 1991;9:87787.

constitutes a paradigm of successful multidisciplinary treatment; more than 60% of

patients with all stages generally survive. Stages I through III have a cure rate varying
from 8898%.