Willms tumor

Wilms tumor, or nephroblastoma, is the most common childhood abdominal malignancy. The
median age at diagnosis of Wilms tumor (see the image below) is approximately 3.5 years. With
current multimodality therapy, approximately 80-90% of children with a diagnosis of Wilms
tumor survive.

Signs and symptoms

Clinical findings include the following:
 Asymptomatic abdominal mass (in 80% of children at presentation)
 Abdominal pain or hematuria (25%)
 Urinary tract infection and varicocele (less common)
 Hypertension, gross hematuria, and fever (5-30%)
 Hypotension, anemia, and fever (from hemorrhage into the tumor;
uncommon)
 Respiratory symptoms related to lung metastases (in patients with
advanced disease; rare)

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Practice Essentials
Wilms tumor, or nephroblastoma, is the most common childhood abdominal
malignancy. The median age at diagnosis of Wilms tumor (see the image
below) is approximately 3.5 years. With current multimodality therapy,
approximately 80-90% of children with a diagnosis of Wilms tumor survive.

CT scan of child with a stage

IV Wilms tumor with favorable histology. Note the bilateral pulmonary
metastases.
View Media Gallery
See Wilms Tumor: A Pediatric Oncology Success Story, a Critical Images
slideshow, to help identify the clinical features, staging evaluation, prognostic
factors, and therapeutic options for this disease.
Signs and symptoms
Clinical findings include the following:
 Asymptomatic abdominal mass (in 80% of children at presentation)
 Abdominal pain or hematuria (25%)
 Urinary tract infection and varicocele (less common)
 Hypertension, gross hematuria, and fever (5-30%)
 Hypotension, anemia, and fever (from hemorrhage into the tumor;
uncommon)
 Respiratory symptoms related to lung metastases (in patients with
advanced disease; rare)
Diagnosis
The following lab studies are indicated:
 CBC
 Chemistry profile - Including kidney function tests and routine
measurements of electrolytes and calcium
 Urinalysis
 Coagulation studies
 Cytogenetics studies, including 1p and 16q deletion
Imaging studies are as follows:
 Renal ultrasonography (often the initial study)
 Four-field chest radiography (to detect lung metastases)
 Abdominal and chest CT
 Abdominal MRI
Histologic confirmation in North America is with immediate nephrectomy, with
exploration of the contralateral kidney to ensure that the disease is unilateral,
and lymph node biopsy sampling for staging purposes. Immediate
nephrectomy is not performed in patients with bilateral disease at
presentation.

Children’s Oncology Group staging of Wilms tumors

Stage I tumors have the following characteristics:
 The tumor is limited to kidney and is completely resected
 The renal capsule is intact
 The tumor was not ruptured or biopsied prior to removal
 The vessels of the renal sinus are not involved
 No evidence of tumor is present at or beyond the margins of resection

Stage II tumors have the following characteristics:

 The tumor is completely resected
 No evidence of tumor at or beyond the margins of resection is noted
 The tumor extends beyond the kidney (penetration of renal capsule,
involvement of renal sinus)
Stage III tumors have the following characteristics:
 A residual, nonhematogenous tumor is present following surgery and is
confined to the abdomen
 Positive lymph nodes in the abdomen or pelvis are noted
 Penetration through the peritoneal surface is observed
 Peritoneal implants are present
  Gross or microscopic tumor remains postoperatively, including positive
margins of resection
 Tumor spillage is noted, including biopsy
 The tumor is treated with preoperative chemotherapy
 The tumor is removed in more than 1 piece
Stage IV tumors are characterized by the following:
 Hematogenous metastases (eg, lung, liver, bone, brain) or lymph node
metastases beyond the abdomen or pelvis are noted
Stage V tumors are characterized by the following:
 Bilateral renal involvement by the tumor is present at diagnosis

Etiology
Wilms tumor is thought to be caused by alterations of genes responsible for
normal genitourinary development. Examples of common congenital
anomalies associated with Wilms tumor are cryptorchidism, a double
collecting system, horseshoe kidney, and hypospadias. Environmental
exposures, although considered, seem relatively unlikely to play a role.
WT1 gene
In the early 1970s, Knudson and Strong proposed a genetic model for the
development of Wilms tumor. [2] WT1, the first Wilms tumor suppressor gene
at chromosomal band 11p13, was identified as a direct result of the study of
children with Wilms tumor who also had aniridia, genitourinary anomalies, and
mental retardation (WAGR syndrome). [3]
Karyotypic analysis revealed constitutional deletions within the short arm of 1
copy of chromosome 11. The 11p13 locus was subsequently demonstrated to
encompass numerous contiguous genes, including the aniridia
gene PAX6 and the Wilms tumor suppressor gene WT1, which was cloned in
1990. WT1 encodes a transcription factor critical to normal renal and gonadal
development.
Characterization of this novel tumor suppressor gene has provided insight into
the mechanisms underlying normal kidney development and Wilms
tumorigenesis. The WT1 gene is the specific target of mutations and deletions
in a subset of patients with sporadic Wilms tumors, as well as in the germline
of some children (eg, those with Denys-Drash syndrome) with a genetic
predisposition to develop this cancer. [4]
Additional genetic loci
A second gene that predisposes individuals to develop the Wilms tumor has
been identified (but has not yet been cloned) telomeric of WT1, at 11p15. This
locus was proposed on the basis of studies in patients with both Wilms tumor
and Beckwith-Wiedemann syndrome (BWS), another congenital Wilms-tumor
predisposition syndrome linked to chromosomal band 11p15. [3]
BWS is an overgrowth syndrome characterized by visceromegaly,
macroglossia, and hyperinsulinemic hypoglycemia. In addition, patients with
BWS are predisposed to have several embryonal neoplasms, including Wilms
tumor. Thus far, a few candidate loci for Wilms tumor and BWS have been
proposed. These loci include the insulinlike growth factor II gene
(IGFII), H19 (for an untranslated ribonucleic acid [RNA]), and that encoding for
p57kip2.

Renal complications
Children with Wilms tumor have a minimal risk for impaired renal function,
primarily related to nephrectomy. In selected patients, (ie, those who receive
radiation therapy), function of the remaining kidney can be further
endangered. The development of compensatory postnephrectomy
hypertrophy of the remaining kidney is well documented in patients with Wilms
tumor.
NWTSG data suggest that most patients with unilateral Wilms tumor do not
develop serious, long-term renal complications. By comparison, renal function
can be impaired in those with bilateral disease. The most common cause of
renal failure in patients with bilateral Wilms tumor is bilateral nephrectomy.
Treatment-related injury (eg, radiation-induced damage, surgical
complications) of the remaining kidney is the second leading cause of renal
insufficiency.
In a study of 7950 patients in the National Wilms Tumor Studies (from 1969-
2002), 100 patients, or approximately 1%, developed end-stage renal disease.
The primary risk factors included stromal predominant histology, intralobar
rests, age at diagnosis of younger than 24 months, metachronous bilateral
Wilms tumor, and WT1 mutation etiology. [19] The particularly high frequency
of renal failure associated with metachronous bilateral Wilms tumor was due
to surgery for progressive Wilms tumor.
Hepatic complications
Several cytotoxic agents may damage the liver of patients treated for Wilms
tumor, including dactinomycin and irradiation. Most early reports suggest that
hepatic irradiation is the major etiologic factor in hepatic injury. However,
reports have documented hepatic toxicity with the combination of vincristine
and dactinomycin in nonirradiated children with Wilms tumor, suggesting that
chemotherapeutic agents themselves can also damage the liver.
In the fourth NWTSG report, the incidence of hepatotoxicity was 2.8-14.3% in
patients who did not receive irradiation. The fact that patients who received
less dactinomycin than others (ie, those with relatively low-stage disease) had
a low incidence of 2.8% suggests a dose-related toxicity for dactinomycin.
With the use of currently accepted radiotherapy techniques, radiation-induced
hepatitis is rare in survivors of Wilms tumor.
Some patients with Wilms tumor have developed hepatic veno-occlusive
disease (VOD). VOD is primarily a clinical diagnosis characterized by
hepatomegaly or pain in the right upper quadrant, jaundice, ascites, and
unexplained weight gain. The syndrome occurs in patients with Wilms tumor
undergoing nephrectomy first and in those receiving combination
chemotherapy before surgery, the standard approach that SIOP recommends.
Although treatment for VOD is primarily supportive, the administration of
chemotherapeutic agents can be resumed after the signs of VOD have
disappeared.
Other complications of chemotherapy and radiation therapy
Congestive heart failure is a well-known complication of the administration of
anthracyclines. Therefore, patients with Wilms tumor who receive
anthracyclines, most commonly doxorubicin, should be monitored for cardiac
dysfunction.
Because radiation therapy can affect pulmonary function, monitoring of
pulmonary function is required in patients with metastatic Wilms tumors to the
lung who are treated with bilateral pulmonary irradiation. The total lung
capacity and vital capacity of patients receiving bilateral irradiation can be
expected to decrease by 50-70% of the predicted values.
Women who received whole-abdomen irradiation in childhood can develop
ovarian failure. Data clearly suggest that a high risk of adverse pregnancy
outcomes should be considered in the counseling and prenatal care of women
who received abdominal radiation therapy to treat a Wilms tumor. Male
patients are at risk for testicular failure after whole-abdomen radiation therapy
or certain types of chemotherapy, most notably that involving alkylating
agents.
The effect of radiation therapy to the skeletal system is often predictable.
Although radiation therapy may affect the growth of any given bone, the spine
is most notably affected at doses of 20 Gy. A study from the University of Iowa
showed a dose-response relationship in the induction of scoliosis and in the
dose delivered. Most patients who received doses of more than 24 Gy with
megavoltage beams developed asymptomatic scoliosis. Patients receiving
current doses of 10-12 Gy may have a much reduced likelihood of developing
scoliosis. [20]
Patients who survive Wilms tumor are at risk because inherited disposition
and treatment (eg, chemotherapy, irradiation) can induce second malignant
neoplasms. Most secondary malignant neoplasms reported (eg, bone tumors,
breast and thyroid cancers) have occurred in irradiated areas. Nevertheless,
certain chemotherapeutic agents, including doxorubicin, dactinomycin, and
vincristine, may contribute to an increased risk for secondary malignancies.
Fifteen years after initial diagnosis, the cumulative incidence of a secondary
malignant neoplasm in patients registered with the NWTSG was 1.6% and
increasing. According to NWTSG investigators, abdominal irradiation
increases the risk of a secondary malignant neoplasm and doxorubicin
potentiates the radiation effect. Treatment for relapse further increased the
risk for a secondary malignant neoplasm by a factor of 4-5.
In a study of 2,492 female subjects from the National Wilms Tumor Studies,
Lange and colleagues found that female survivors of Wilms tumor had a 9.1-
fold increased risk of developing invasive breast cancer and had an estimated
cumulative risk of invasive breast cancer at age 40 of 4.5%. A total of 29
cases of invasive breast cancer were identified among 28 participants, all but
four occurring before age 40. [21]
Relative to the general population, the risk was highest among women who
had been treated with chest radiotherapy, who had a 27.6-fold increase and a
cumulative risk at age 40 of 14.8%. Of the women who developed breast
cancer after chest radiotherapy, most received doses of 12 Gy; the remainder
received higher doses. No significant difference was found in breast cancer
rates between women treated or not treated with abdominal irradiation