WILMS TUMOR
Wilms tumor, or nephroblastoma, is the most common renal malignancy in children and accounts for 7% of all malignancies in this age group. In the United States, approximately 500 to 600 new cases are diagnosed each year. Most are diagnosed in children between the ages of 2 and 4 years, with more than 80% of cases diagnosed before 5 years of age. Over the past several decades, there has been a substantial improvement in the prognosis of these tumors, with the overall survival rate now 90%.
GENETICS, PRESENTATION, AND RADIOGRAPHIC FINDINGS OF WILMS TUMOR
PATHOGENESIS
Wilms tumors are believed to develop from abnormally
persistent nephrogenic rests, which represent undifferentiated metanephric
mesenchyme (see Plate 2-1). These rests may be either perilobar, meaning they
are confined to the periphery of the kidney and sharply defined, or intralobar,
meaning they occur anywhere within the kidney and have indistinct borders.
Although nephrogenic rests are seen in up to 1% of newborns, they normally
remain dormant, involute, or differentiate. A small minority, however, are
believed to give rise to Wilms tumors, as inferred from the fact that 40% of
those with unilateral Wilms tumors, and nearly 100% of those with bilateral
tumors, have persistent nephrogenic rests.
Abnormalities in several genes have been associated
with Wilms tumors. WT1, for example, is located on chromosome 11p13 and
encodes a zinc finger tumor suppressor important for normal renal and gonadal
development. This gene is mutated in about 5% to 15% of Wilms tumors. A subset
of patients with WT1 abnormalities have broader genetic syndromes that
feature Wilms tumors as a single component. Denys-Drash syndrome, for example,
results from a missense mutation of WT1 and is associated with Wilms
tumors, pseudohermaphroditism, and diffuse renal mesangial sclerosis.
Meanwhile, WAGR syndrome results from deletion of WT1 and is associated
with Wilms tumor, aniridia, genitourinary malformations, and mental
retardation. The association between Wilms tumor and aniridia reflects the fact
that the PAX6 gene is located adjacent to WT1 and causes aniridia
when mutated.
A second gene, known as WT2, is believed to
reside within a locus located at chromosome 11p15. This locus contains several
genes that are imprinted, meaning that the allele from either the father or the
mother is expressed, but not both. Mutations at this locus underpin the
Beckwith-Wiedemann syndrome, which features overgrowth (large birth weight,
macroglossia, macrosomia, hemihypertrophy, organomegaly), omphalocele, ear
pits/creases, and Wilms tumor. Of note, it appears that multiple genes at this
locus, rather than a single gene, may be involved in the pathogenesis of Wilms
tumor.
In addition to abnormalities in WT1 and WT2,
Wilms tumors have also been associated with loss of heterozygosity at 16q and
1p, as well as with mutations in p53 (encoded on 17p13).
Most of the mutations underlying Wilms tumors are
believed to arise either in the germ line or in the tumor tissue alone. Thus
despite these numerous genetic associations, only a very small minority of
patients who develop Wilms tumors have a positive family history. In such patients, abnormalities are not at 11p but rather
at 17q12-21 (FWT1) and 19q13.3-13.4 (FWT2).
PRESENTATION AND DIAGNOSIS
In a vast majority of children with Wilms tumor, the
presenting symptom is a palpable abdominal mass, which may be associated with
abdominal pain, hematuria (from extension into the collecting system or
ureter), and/or hypertension (from
increased renin secretion). Other nonspecific symptoms, which may occur in some
cases, include fever, malaise, and weight loss.
Ultrasound should be the initial study to assess for
the presence of a renal mass and, if one is seen, to determine with color
Doppler imaging if there is extension into the inferior vena cava. If a renal
tumor is seen, or if the kidney cannot be a equately visualized, CT or MRI should be performed.
Other pediatric intraabdominal malignancies or benign
lesions that should be considered include other renal tumors, neuroblastoma,
teratoma, lipoma, hamartoma, and lymphoma. In most cases, complete surgical
excision and histopathologic examination of the tumor is necessary to establish
the definitive diagnosis.
GROSS APPEARANCE AND HISTOPATHOLOGIC FINDINGS OF WILMS TUMOR
TREATMENT
According to the most common protocols, patients are
treated with primary surgical excision of the tumor. If there is a unilateral
tumor, nephrectomy is performed along with sampling of hilar and ipsilateral
paraaortic or caval lymph nodes. If there are bilateral tumors, as in 5% of
cases, a biopsy should be performed first to confirm the diagnosis, then
neoadjuvant chemotherapy should be administered to reduce the tumor burden.
Once neoadjuvant therapy is complete, renal-sparing surgery (such as partial
nephrectomy) should be performed to preserve as much renal function as
possible. After surgery, subsequent treatment is based on the stage and
histopathologic tumor subtype. According to the National Wilms Tumor Study
guidelines, stage I tumors are confined to the kidney and can be completely
removed with surgery. Stage II tumors penetrate the capsule and may invade
adjacent vessels but can nonetheless be completely removed with surgery. Stage
III tumors have positive margins or nonhematogenous intraabdominal spread
(i.e., lymph node involvement, tumor spillage, peritoneal involvement) that
remains after surgery. Stage IV tumors have hematogenous metastases to distant
sites, such as the lung, liver, bone, or brain. Stage V tumors are bilateral.
All of these stages receive an “A” suffix if surgical histopathology reveals anaplastic features.
For patients with stage I or II tumors, treatment
consists of nephrectomy and adjuvant chemotherapy. A subgroup of patients (<2 years of age and less
than 550 g of body weight) with stage I tumors may only require observation
after surgery because their prognosis seems extremely favorable. For patients
with stage III or IV tumors, treatment consists of nephrectomy followed by
adjuvant chemotherapy and radiotherapy. For patients with stage V tumors,
neoadjuvant treatment is offered, as described previously, followed by a
reassessment of the tumor burden of each kidney and nephron-sparing surgery
whenever possible.
The recommended chemotherapy regimens include various
combinations of vincristine, dactinomycin, doxorubicin, and cyclophosphamide,
with the specific regimens varying based on tumor stage, histopathologic
findings, and mutation profile (e.g., presence or absence of loss of
heterozygosity at 1p and 16q).
The histopathologic findings are important predictors
of the response to chemotherapy. Wilms tumors classically contain blastemal,
epithelial, and stromal components. The blastemal cells are dense,
undifferentiated, and haphazardly arranged in sheets. The epithelial cells are
columnar or cuboidal and line tubules. The stromal cells have a variable
appearance, ranging from nondescript spindle cells to more differentiated
cells, such as those characteristic of muscle, fat, or bone. All three
components may be present, or one or more may be absent. Tumors with
predominantly epithelial and stromal components are generally less aggressive.
Tumors with predominantly blastemal features are more aggressive but still respond to chemotherapy in most cases. Tumors
with poorly differentiated, anaplastic cells (which contain multipolar mitotic
figures and enlarged, hyperchromatic nuclei) respond poorly to chemotherapy and
radiotherapy.
FOLLOW-UP
The recommended schedule for follow-up examinations
and testing after treatment depends on the initial stage of the cancer and treatment type. Follow-up
visits should consist of physical examinations and imaging tests (chest
radiograph, abdominal ultrasound) to rule out tumor recurrence and to assess
for possible side effects of chemotherapy or radiotherapy. Blood and urine
tests should also be performed during every follow-up visit to evaluate
remaining renal function. The frequency of follow-up visits can decrease over
time if no
abnormal or concerning findings are noted.
