Wilms' tumor in children: an overview.

Wilms’ tumor is the most frequently occurring renal tumor in children and is one of the most treatment-responsive tumors. A tumor-suppressor gene and other genetic abnormalities have been implicated in its etiology. In addition, patients with several congenital anomalies, such as Beckwith-Wiedemann syndrome, WAGR syndrome, and DenysDrash syndrome, have an increased risk of Wilms’ tumor. Previously, a three-drug chemotherapy regimen with surgery and radiotherapy was used with patients in all stages. Now, patients with early-stage Wilms’ tumor are treated with a two-drug regimen without radiotherapy, whereas those in advanced stages still receive the three-drug regimen and radiotherapy. Two large collaborative groups – the National Wilms’ Tumor Study Group (NWTS) in the United States and the International Society of Pediatric Oncology (SIOP) in Europe – are involved in Wilms’ tumor management, which differs in some aspects. Multimodality treatment has been used successfully, and in Europe preoperative strategies are used as well. As the survival rate has now reached 90%, the primary objectives of the physician are to perform nephronsparing surgery in selected cases and to reduce the dosage and duration of chemotherapy and radiotherapy in appropriate cases. Other renal tumors occur rarely, but have also been treated successfully in the last decade. Copyright © 2008 S. Karger AG, Basel Published online: January 11, 2008 Ali Varan, MD Department of Pediatric Oncology, Hacettepe University Institute of Oncology, TR–06100 Ankara (Turkey) Tel. +90 312 305 2990, Fax +90 312 310 7018 E-Mail [email protected] © 2008 S. Karger AG, Basel 1660–2110/08/1082–0083$24.50/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /5 /2 01 7 9: 35 :0 9 A M Varan Nephron Clin Pract 2008;108:c83–c90 c84 and the creation of cooperative groups in North America and Europe, the survival rate improved from 30 to 90% between 1930 and 2000. Epidemiology Childhood cancers constitute between 0.5 and 1% of all cancers. In the USA, the incidence of Wilms’ tumor is 7.6 cases per million under 15 years of age [4] , and about 500 new cases occur annually. Wilms’ tumor represents 5.9% of all childhood malignant tumors [5] . There is a minor racial difference in the incidence of Wilms’ tumors. The Asian population has about half the incidence rate of Western countries, and its rate in the black population is 2.5 times higher [6, 7] . The incidence of Wilms’ tumor in other countries is similar to that in the USA. In Turkey, childhood renal tumors represent 7.1% of all childhood tumors [8] . The population-based incidence rate in a part of Italy was 4.5% for Wilms’ tumor [9] . Wilms’ tumor is seen mostly in children between the ages of 1 and 5 years, and the peak age is 3. Although adult patients with Wilms’ tumor have been reported, it is extremely rare in people older than 15 years of age [10] . The male-female ratio is near 1, ranging from 0.8 to 0.95 in various studies. Wilms’ Tumor Genetics Two frequent genetic abnormalities in Wilms’ tumor are the WT1 and WT2 gene deletions: WT1. The first identified gene in Wilms’ tumor, WT1, is responsible for genitourinary development. It is a tumor-suppressor gene located on 11p13 that is expressed in the kidney, gonads, spleen, and mesothelium. It encodes four zinc finger transcriptional factors that have regulatory functions on cell growth, differentiation, and apoptosis. Normal WT1 gene expression is necessary for the maturation of the blastemal cells, and reduced WT1 expression is associated with the stromal predominant Wilms’ tumor. Lee and Haber [11] report on the functions of the WT1 gene and its association with connective tissue growth factor and vitamin D receptors. Its deletion has been shown in WAGR and Denys-Drash syndrome [12, 13] . WT2. This gene is located on 11p15 and is found in Beckwith-Wiedemann syndrome [14] . Some functions of this gene are related to insulin-like growth factor 2 (IGF2), which encodes embryonal growth factor. Other Genetic Abnormalities. In addition to IGF-2, H19 and p57 Kip2 are overexpressed or mutated in some patients with Wilms’ tumor. p57 Kip2 encodes cyclin-dependent kinase inhibitors and is a putative tumor suppressor [15, 16] . The p53 tumor suppressor gene has been found in 75% of patients with anaplastic histology [17] . This gene regulates cell proliferation and induces apoptosis. -Catenin is a cellular adhesion molecule that promotes overexpression of the c-myc and cyclin D1. Catenin mutation has been detected in 15% of patients with Wilms’ tumor [18] . There is a strong correlation between reduced expression of the WT1 gene and  -catenin mutation. Familial Wilms’ tumor has been found in 1–2% of Wilms’ tumor cases [19] . Although this tumor does have the WT1 gene, some familial tumors have linkage in the 17q, and this locus has been named FWT1. Some such tumors have demonstrated a 19q anomaly, which has been described as FWT2 [15] . Other chromosomal abnormalities, such as loss of heterozygosity (LOH) of 16q, 1p, and 7p, have been identified [20] . This defect has been associated with poor prognosis, relapses, and death and has resulted in a poor outcome in patients with favorable histology Wilms’ tumor. In a recent report, a 9-year-old boy with trisomy 18 had Wilms’ tumor [21] . In this case, LOH was demonstrated at isochromosome 7q and heterozygosity of 16q was found in addition to trisomy 18. Associated Congenital Abnormalities Wilms’ tumor has been associated with several congenital abnormalities. Children with genitourinary anomalies, such as horseshoe kidney, renal dysplasia, bilateral cystic renal disease, cryptoorchidism, hypospadias, aniridia, and hemihypertrophy, have a higher incidence of Wilms’ tumor [22] . In addition, it is a component of the syndromes described below. Beckwith-Wiedemann Syndrome. This syndrome is associated with macroglossia, visceromegaly, omphalocele, and gigantism. About 4–5% of patients with this syndrome have Wilms’ tumor as well [23] . Although the incidence of bilateral disease has increased, the prognosis is still excellent [23] . The molecular defect is on chromosome 11p15.5 [14] . It is not clear if this defect is the same as is found on the WT2 gene. IGF-2 abnormalities are related to this gene and may be responsible for the development of Wilms’ tumor and the Beckwith-Wiedemann syndrome. WAGR Syndrome. The components of this syndrome are Wilms’ tumor, aniridia, genitourinary abnormalities, and mental retardation. Cardiopulmonary problems, head anomalies, neurobehavioral disorders, musculoD ow nl oa de d by : 54 .7 0. 40 .1 1 10 /5 /2 01 7 9: 35 :0 9 A M Wilms’ Tumor in Children Nephron Clin Pract 2008;108:c83–c90 c85 skeletal defects, and metabolic problems have also been reported [12] . The 11p13 chromosomal deletion has been identified. The Wilms’ tumor risk is 30% in this syndrome. In a review of 54 patients with WAGR syndrome, 31 had Wilms’ tumor and 53 had aniridia [12] . Denys-Drash Syndrome. Male pseudo hermaphroditism, glomerulonephritis, and Wilms’ tumor are part of this syndrome. There is also an association with a defect on the WT1 gene [13] . Perlman Syndrome. This syndrome can be associated with Wilms’ tumor and includes macrosomia, islet cell hyperplasia, renal hamartomas, and an atypical face shape [24] .