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%.
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.
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.
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.