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Key Points
Incidence
Renal tumors are the fifth most common cancer in children younger than 15 years of age. It is estimated that 7.1 per million children are affected, and 500 new cases are reported each year in the United States. The median age at presentation is 3.5 years.
Histology of Pediatric Renal Tumors
Favorable histology Wilms tumor: 80% to 85%. Anaplastic Wilms tumor: 5% to 8%. Renal cell carcinoma: 5% to 8%. Clear-cell sarcoma of the kidney: 2% to 3%. Rhabdoid tumor of the kidney: 1% to 2%. Mesoblastic nephroma: 1% to 2%.
Biological Characteristics
The genes that are most frequently somatically altered in Wilms tumor are WT1 , AMER1 (WTX) , CTNNB1 (β-catenin), DROSHA , DGCR8 , DICER1 , SIX1, SIX2, and MLLT1 . TP53 mutations are observed in the vast majority of anaplastic Wilms tumors. IGF2 , which is normally expressed preferentially from the paternal allele, is frequently overexpressed through loss of imprinting or gene duplication of the paternal allele. Loss of heterozygosity (LOH) at 1p and 16q and gain of chromosome 1q are associated with higher relapse rates and are incorporated in the Children's Oncology Group (COG) risk stratification schema.
Staging Evaluation
Staging requires a patient's history, physical examination, complete blood cell count, hepatic and renal serum chemistries, urinalysis, chest computed tomography (CT), abdominal and pelvic CT or magnetic resonance imaging (MRI), and abdominal ultrasonography if the renal vein and inferior vena cava are not well visualized by cross-sectional imaging.
Primary Therapy
Surgical resection (nephrectomy, tumor resection, and staging) is the primary therapy for this tumor in the United States. Preoperative chemotherapy is routinely used in Europe.
Adjuvant Therapy
National Wilms Tumor Study Group (NWTS) investigations show that vincristine and dactinomycin result in excellent cure rates for patients with localized (stages I and II) Wilms tumor of favorable histology. Radiotherapy (RT) and doxorubicin are added for advanced local or metastatic disease (stages III and IV). The recently completed COG protocol augmented chemotherapy for patients with LOH at 1p and 16q. Chemotherapy is also intensified for focal and diffuse anaplastic Wilms tumor, clear-cell sarcoma of the kidney (CCSK), and rhabdoid tumor of the kidney (RTK). The flank or abdominal radiation dose is 10.8 Gy. Higher doses are recommended in patients with gross residual tissue or for stage III anaplastic tumors and RTK (19.8 Gy).
Retrieval Therapy
Retrieval therapy is based on original stage, prior treatment, and sites of relapse. It includes surgery, RT, and intensive multiple-agent chemotherapy with or without stem-cell transplantation.
Introduction
Wilms tumor, or nephroblastoma, is the most common childhood renal tumor, accounting for about 6% of pediatric malignant diseases. The grim outlook at the beginning of the 20th century (90% mortality rate) has effectively inversed to a survival rate of 90% in the early 21st century. Clinical trials in North America under the aegis of the National Wilms Tumor Study (NWTS) and, subsequently, the Children's Oncology Group (COG) and those in Europe, largely by the International Society of Pediatric Oncology (SIOP), have resulted in Wilms tumor therapy becoming a paradigm for successful multidisciplinary integration in the treatment of cancer. Successive NWTS and COG clinical trials have been based on postoperative therapies, whereas preoperative strategies have been the focus of SIOP investigators.
Clinical risk factors such as tumor stage and histology were identified so that treatment could be modulated in intensity according to risk groups, the objective being to achieve cure with minimum complications. As a result, children with low-risk tumors now receive minimal therapy whereas those at high risk benefit from more intensive therapy. The modern survivors of Wilms tumor enjoy a better quality of life owing to sequential reductions in the intensity of therapy.
Etiology and Epidemiology
The cause of Wilms tumor is unknown. The peak incidence is between 3 and 4 years of age. Wilms tumor may arise as sporadic or hereditary tumors or in the setting of specific genetic disorders. The overall annual incidence of Wilms tumor is 7.1 per million children, and approximately 500 new cases can be expected each year in North America. Wilms tumor is found more often in black than in white children, with a ratio of 1.25 : 1.00. Girls are affected more than boys in the same ratio.
Prevention and Early Detection
Prevention awaits an identified cause. Uncommon congenital anomalies (aniridia, genitourinary malformations, hemihypertrophy, or signs of overgrowth) may be seen in 13% to 28% of children with unilateral or bilateral disease, respectively. Syndromes associated with a higher risk for developing Wilms tumor include the “WAGR” syndrome (aniridia, genitourinary malformation, mental retardation), the Beckwith-Wiedemann syndrome, and the Denys-Drash syndrome (see section entitled “Biological Characteristics and Molecular Biology ”). Children with such syndromes should be screened for the development of Wilms tumor using ultrasonographic examinations of both kidneys every 3 months until age 5 years (WAGR) or 8 years (Beckwith-Wiedemann syndrome).
Biological Characteristics and Molecular Biology
The biological characterization of Wilms tumor has provided the foundation for our understanding of key concepts in cancer genetics, including the roles of tumor suppressor genes and loss of genomic imprinting in tumorigenesis. Although Wilms tumor was one of the original examples in Knudson's two-hit model of cancer development, subsequent research has shown that multiple genes and several genetic events contribute to the formation of this malignant disorder. The molecular changes that have been described in Wilms tumor can be classified as primary events predisposing to the development of tumor or secondary events associated with tumor progression.
WT1
Initial insights into the molecular biology of Wilms tumor were derived from the observation that in patients with WAGR syndrome, the risk for developing the tumor is about 50%. Cytogenetic analysis of individuals with this syndrome showed deletions at chromosome 11p13, which was later found to be the locus of a contiguous set of genes, including PAX6, the gene causing aniridia, and WT1, one of the Wilms tumor genes. The WT1 gene encodes a transcription factor that is crucial to normal kidney and gonadal development. The Denys-Drash syndrome—which is characterized by pseudohermaphroditism, glomerulopathy, renal failure, and a 75% chance of Wilms tumor development—is caused by point mutations in the zinc-finger DNA-binding region of the WT1 gene. Although WT1 has a clear role in tumorigenesis of Wilms tumor in patients with the WAGR and Denys-Drash syndromes, only a minority of patients with sporadic Wilms tumor carries WT1 mutations in the germline (< 5%) or in tumor tissue (6%-18%).
IGF2/H19
The Beckwith-Wiedemann syndrome is an overgrowth disorder manifested by large birth weight, macroglossia, organomegaly, hemihypertrophy, neonatal hypoglycemia, abdominal wall defects, ear abnormalities, and predisposition to Wilms tumor and other malignant disorders. Approximately 5% of individuals with this syndrome develop Wilms tumor. Beckwith-Wiedemann syndrome maps to chromosome 11p15, a locus sometimes called “WT2” because it was the second locus shown to be associated with Wilms tumor.
The 11p15 locus consists of several genetically imprinted genes that are in two clusters or imprinting centers. Several combinations of genetic and epigenetic alterations can give rise to Beckwith-Wiedemann syndrome, with increasing recognition of genotype-phenotype relationships. Imprinting Center 1, which contains the IGF2 and H19 genes, has been most implicated in Wilms tumor predisposition. Alterations in Imprinting Center 2, which contains the genes CDKN1C , KCNQ1 , and KCNQ1OT1 , are not strongly linked to Wilms tumor development. Approximately 70% of Wilms tumors have LOH or loss of imprinting (LOI) at the 11p15 locus.
Wnt Signaling Pathway Genes ( WTX and β-Catenin)
Alterations of the Wnt signaling pathway have been implicated in several human malignancies. Central to the pathway is the activator, β-catenin, which is degraded in the absence of Wnt signaling. Activating mutations in the gene encoding β-catenin (CTNNB1) occur in approximately 15% of Wilms tumors. Interestingly, mutations in CTNNB1 occur mostly in tumors in which WT1 is also mutated, suggesting that these two events cooperate in the formation of Wilms tumor. AMER1 (also known as WTX), a Wilms tumor suppressor gene on the X chromosome, is inactivated in one-third of sporadic Wilms tumor cases. In contrast to the two-hit model of inactivation of WT1 , WTX is inactivated by a monoallelic “single-hit” event that targets the X chromosome in tumors in males and the active X chromosome in tumors in females. WTX has been shown to be a negative regulator of Wnt/β-catenin signaling.
MicroRNA Processing Genes
Somatic mutations in DROSHA , DGCR8 , XPO5 , and DICER1 , genes involved in processing microRNA (miRNA), were discovered in approximately 15% of Wilms tumors. These gene mutations inhibit the formation of miRNAs that suppress tumor growth, including the miR-200 family and Let-7, which are involved in the mesenchymal to epithelial transition (MET) in renal development. Mutations in the SIX1 and SIX2 transcription factor genes, also involved in renal development, have been observed in 7% to 10% of Wilms tumors.
TP53 Mutation
Approximately 50% of anaplastic Wilms tumors have detectable TP53 mutations, whereas TP53 mutations are uncommon in favorable histology tumors. However, if the TP53 mutation status is assessed in a comprehensive manner to include gene sequencing, copy number analysis, and immunohistochemistry on sections of tumor demonstrated to contain anaplastic changes, nearly all anaplastic Wilms tumors have evidence of TP53 mutation. TP53 mutation has been associated with unfavorable prognosis in advanced-stage anaplastic Wilms tumor. However, it is likely that the detection of a TP53 mutation in an arbitrarily selected tumor sample reflects the burden of anaplasia, which, in turn, correlates with prognosis.
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