Wilms Tumor and Other Childhood Kidney Tumors Treatment

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Table of Contents

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, staging, and treatment of Wilms tumor and other childhood kidney tumors (clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, cystic partially-differentiated nephroblastoma, mesoblastic nephroma, and renal cell carcinoma).

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others in order to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers have been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Wilms tumor is a curable disease in the majority of affected children. Approximately 500 cases are diagnosed in the United States annually. More than 90% of patients survive 4 years after diagnosis, which is an improvement over the 80% survival observed from 1975 to 1984.[2] The prognosis is related not only to the stage of disease at diagnosis, the histopathologic features of the tumor, patient age, and tumor size, but also to the team approach to each patient by the pediatric surgeon, radiation oncologist, and pediatric oncologist.[2-5] Previous clinical trials have, in part, evaluated with some success whether reduced therapy is sufficient to control disease in patients with early-stage, favorable-histology Wilms tumor.[6-8]

Wilms tumor normally develops in otherwise healthy children; however, 10% of cases occur in individuals with recognized malformations. Children with Wilms tumor may have associated anomalies, including hemihypertrophy, cryptorchidism, and hypospadias. Approximately 10% of patients with Wilms tumor have a recognizable phenotypic syndrome (including overgrowth disease, aniridia, genetic malformations, and others). These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes have been divided into overgrowth and nonovergrowth categories. Overgrowth syndromes are the result of excessive prenatal and postnatal somatic growth, and result in macroglossia, nephromegaly, and hemihypertrophy. Examples of overgrowth syndromes are Beckwith-Wiedemann syndrome (10% to 20% of Wilms tumor incidence), isolated hemihypertrophy (3% to 5% of Wilms tumor incidence), Perlman syndrome (characterized by fetal gigantism, renal dysplasia, Wilms tumor, islet cell hypertrophy, multiple congenital anomalies, and mental retardation),[9] Sotos' syndrome (characterized by cerebral gigantism), and Simpson-Golabi-Behemel syndrome (characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers).[10-14] Klippel-Trénaunay syndrome, a unilateral limb overgrowth syndrome, is not associated with Wilms tumor.[15] Examples of nonovergrowth syndromes associated with Wilms tumor (42% of Wilms tumor incidence) are isolated aniridia; trisomy 18; Wilms tumor, aniridia, ambiguous genitalia, and mental retardation (WAGR) syndrome; Bloom's syndrome, and Denys-Drash syndrome (characterized by intersexual disorders, nephropathy, and Wilms tumor).[16] The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del [11p13]).[17,18] Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have the Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities),[19] both of which are associated with mutations in the WT1 gene at chromosome 11p13.[20,21] Children with a predisposition to develop Wilms tumor (e.g., Beckwith-Wiedemann syndrome, WAGR, hemihypertrophy, or aniridia) should be screened with ultrasound every 3 months until they reach age 8 years.[10-14,22-24]

Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of several genes. The Wilms tumor gene-1 (WT1) is located on the short arm of chromosome 11 (11p13). The normal function of WT1 is required for normal genitourinary development and is important for differentiation of the renal blastema. Germline WT1 mutations are associated with cryptorchidism and hypospadias.[25] Germline mutations in WT1, however, have also been found in about 2% of phenotypically normal children with Wilms tumor.[26] The offspring of such patients may also be at increased risk of developing Wilms tumor. A gene that causes aniridia (PAX-6) is located near the WT1 gene on chromosome 11p13, and deletions encompassing the WT1 and aniridia genes explain the association between aniridia and Wilms tumor. PAX-6 also affects brain development, and children with WAGR syndrome have a variety of central nervous system development disorders.[18] Patients with aniridia or hemihypertrophy should be screened with ultrasound every 3 months until they reach age 8 years.[10] For patients with WAGR syndrome, the risk of developing Wilms tumor is as high as 45%.[27] Children with WAGR syndrome are found to have small, favorable-histology tumors with low stage at diagnosis and a high incidence of intralobar nephrogenic rests. The incidence of bilateral Wilms tumor in WAGR children is high (about 15%).[28] Treatment outcome at 4 years is similar to that of non-WAGR patients.[28] Children with WAGR syndrome are at increased risk of eventually developing renal failure and should be monitored.[29] Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy or renal failure.[30] Children with Wilms tumor and any genitourinary anomalies are also at increased risk for late renal failure and should be monitored.[29] The incidence of Wilms tumor in children with sporadic aniridia is estimated to be about 5%.[28] A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5 in association with Beckwith-Wiedemann syndrome. There are several candidates for WT2, including insulin-like growth factors (IGF-2), H19, and LIT1, some of which are paternally imprinted (maternally active) and some maternally imprinted.[31] Loss of heterozygosity (LOH), which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes in this region has also been frequently observed and results in the same functional aberrations. A study of 35 sporadic primary Wilms tumors suggests that more than 80% have either LOH or loss of imprinting at 11p15.5.[32] Recent observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing levels of association with risk of tumor formation.[33] Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous bilateral disease is also observed.[10-12] A third gene, WTX, has been identified on the X chromosome and plays a role in normal kidney development. This gene is inactivated in approximately one third of Wilms tumors.[34]

Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p as evidenced by LOH for these regions in 17% and 11% of Wilms tumors, respectively. Patients classified by tumor-specific loss of these loci had significantly worse relapse-free and overall survival rates.[35,36] Combined loss of 1p and 16q are used to select favorable-histology Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group study.[37] Overexpression and gene amplification of CACNA1E, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium channels, is associated with favorable histology in Wilms tumor relapse.[38] Many Wilms tumors appear to arise from abnormally retained embryonic kidney precursor cells arranged in clusters termed nephrogenic rests. The different genetic lesions are associated with different subtypes of nephrogenic rests.[39] Wilms tumors that develop from intralobar nephrogenic rests generally contain heterologous elements such as smooth muscle, cartilage, and fat cells, and are associated with loss of DNA on the short arm of chromosome 11p and occasionally with WT1 gene mutation. In contrast, Wilms tumors that develop from perilobar nephrogenic rests, which appear to reflect a slightly later stage in renal embryonic development and are generally found in older children, are associated with loss of imprinting of the IGF2 gene, which stimulates cell proliferation.[40] Perilobar rests are also associated with Wilms tumors in children with Beckwith-Wiedemann syndrome.[41] Diffuse hyperplastic perilobar nephroblastomatosis is discussed in the Cellular Classification section of this summary. Remarkably, Wilms tumor in Asian children is not associated with either nephrogenic rests or IGF2 loss of imprinting.[42]

Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary Wilms tumor is uncommon, with 1% to 2% of patients having a positive family history for Wilms tumor.[43,44] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is quite low (<2%).[45] Siblings of children with Wilms tumor have a low likelihood of developing Wilms tumor.[43] About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary.[43,44] Many bilateral tumors are present at the time Wilms tumor is first diagnosed (i.e., synchronous), but a second Wilms tumor may also develop later in the remaining kidney of 1% to 3% of children treated successfully for Wilms tumor. The incidence of such metachronous bilateral Wilms tumors is much higher in children whose original Wilms tumor was diagnosed before age 12 months and/or whose resected kidney contains nephrogenic rests. Periodic abdominal ultrasound is recommended for early detection of metachronous bilateral Wilms tumor as follows: children with nephrogenic rests in the resected kidney (if younger than 48 months at initial diagnosis)—every 3 months for 6 years; children with nephrogenic rests in the resected kidney (if older than 48 months at initial diagnosis)—every 3 months for 4 years; other patients—every 6 months for 2 years, then yearly for an additional 1 to 3 years.[46,47]

Clear cell sarcoma of the kidney, rhabdoid tumor of the kidney, neuroepithelial tumor of the kidney, and cystic partially-differentiated nephroblastoma are childhood renal tumors unrelated to Wilms tumor. (Refer to the Cellular Classification section of this summary for more information.) Because of their renal location, they have been treated on clinical trials developed by the National Wilms Tumor Study Group. The approach to their treatment, however, is distinctive from that of Wilms tumor, and requires timely and accurate diagnosis by a pathologist with experience with these types of renal tumors.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with Wilms tumor and other childhood kidney tumors. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997. [PUBMED Abstract]
Green DM, Children's Oncology Group: Phase III Multimodality Therapy Based on Histology, Stage, Age, and Tumor Size in Children With Wilms' Tumor, Clear Cell Sarcoma of the Kidney, or Rhabdoid Tumors of the Kidney, COG-Q9401, Clinical trial, Completed. [PDQ Clinical Trial]
Ritchey ML, Haase GM, Shochat S: Current management of Wilms' tumor. Semin Surg Oncol 9 (6): 502-9, 1993 Nov-Dec. [PUBMED Abstract]
Breslow N, Sharples K, Beckwith JB, et al.: Prognostic factors in nonmetastatic, favorable histology Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 68 (11): 2345-53, 1991. [PUBMED Abstract]
Ritchey ML, Shamberger RC, Haase G, et al.: Surgical complications after primary nephrectomy for Wilms' tumor: report from the National Wilms' Tumor Study Group. J Am Coll Surg 192 (1): 63-8; quiz 146, 2001. [PUBMED Abstract]
D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 64 (2): 349-60, 1989. [PUBMED Abstract]
Mitchell C, Jones PM, Kelsey A, et al.: The treatment of Wilms' tumour: results of the United Kingdom Children's cancer study group (UKCCSG) second Wilms' tumour study. Br J Cancer 83 (5): 602-8, 2000. [PUBMED Abstract]
Green DM, Breslow NE, Beckwith JB, et al.: Treatment with nephrectomy only for small, stage I/favorable histology Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 19 (17): 3719-24, 2001. [PUBMED Abstract]
Greenberg F, Stein F, Gresik MV, et al.: The Perlman familial nephroblastomatosis syndrome. Am J Med Genet 24 (1): 101-10, 1986. [PUBMED Abstract]
Green DM, Breslow NE, Beckwith JB, et al.: Screening of children with hemihypertrophy, aniridia, and Beckwith-Wiedemann syndrome in patients with Wilms tumor: a report from the National Wilms Tumor Study. Med Pediatr Oncol 21 (3): 188-92, 1993. [PUBMED Abstract]
DeBaun MR, Siegel MJ, Choyke PL: Nephromegaly in infancy and early childhood: a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome. J Pediatr 132 (3 Pt 1): 401-4, 1998. [PUBMED Abstract]
DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998. [PUBMED Abstract]
Porteus MH, Narkool P, Neuberg D, et al.: Characteristics and outcome of children with Beckwith-Wiedemann syndrome and Wilms' tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 18 (10): 2026-31, 2000. [PUBMED Abstract]
Hoyme HE, Seaver LH, Jones KL, et al.: Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79 (4): 274-8, 1998. [PUBMED Abstract]
Greene AK, Kieran M, Burrows PE, et al.: Wilms tumor screening is unnecessary in Klippel-Trenaunay syndrome. Pediatrics 113 (4): e326-9, 2004. [PUBMED Abstract]
Pelletier J, Bruening W, Kashtan CE, et al.: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67 (2): 437-47, 1991. [PUBMED Abstract]
Clericuzio CL: Clinical phenotypes and Wilms tumor. Med Pediatr Oncol 21 (3): 182-7, 1993. [PUBMED Abstract]
Fischbach BV, Trout KL, Lewis J, et al.: WAGR syndrome: a clinical review of 54 cases. Pediatrics 116 (4): 984-8, 2005. [PUBMED Abstract]
Barbosa AS, Hadjiathanasiou CG, Theodoridis C, et al.: The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor. Hum Mutat 13 (2): 146-53, 1999. [PUBMED Abstract]
Coppes MJ, Huff V, Pelletier J: Denys-Drash syndrome: relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr 123 (5): 673-8, 1993. [PUBMED Abstract]
Koziell AB, Grundy R, Barratt TM, et al.: Evidence for the genetic heterogeneity of nephropathic phenotypes associated with Denys-Drash and Frasier syndromes. Am J Hum Genet 64 (6): 1778-81, 1999. [PUBMED Abstract]
Gracia Bouthelier R, Lapunzina P: Follow-up and risk of tumors in overgrowth syndromes. J Pediatr Endocrinol Metab 18 (Suppl 1): 1227-35, 2005. [PUBMED Abstract]
Lapunzina P: Risk of tumorigenesis in overgrowth syndromes: a comprehensive review. Am J Med Genet C Semin Med Genet 137 (1): 53-71, 2005. [PUBMED Abstract]
Scott RH, Walker L, Olsen ØE, et al.: Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child 91 (12): 995-9, 2006. [PUBMED Abstract]
Diller L, Ghahremani M, Morgan J, et al.: Constitutional WT1 mutations in Wilms' tumor patients. J Clin Oncol 16 (11): 3634-40, 1998. [PUBMED Abstract]
Little SE, Hanks SP, King-Underwood L, et al.: Frequency and heritability of WT1 mutations in nonsyndromic Wilms' tumor patients: a UK Children's Cancer Study Group Study. J Clin Oncol 22 (20): 4140-6, 2004. [PUBMED Abstract]
Muto R, Yamamori S, Ohashi H, et al.: Prediction by FISH analysis of the occurrence of Wilms tumor in aniridia patients. Am J Med Genet 108 (4): 285-9, 2002. [PUBMED Abstract]
Breslow NE, Norris R, Norkool PA, et al.: Characteristics and outcomes of children with the Wilms tumor-Aniridia syndrome: a report from the National Wilms Tumor Study Group. J Clin Oncol 21 (24): 4579-85, 2003. [PUBMED Abstract]
Breslow NE, Collins AJ, Ritchey ML, et al.: End stage renal disease in patients with Wilms tumor: results from the National Wilms Tumor Study Group and the United States Renal Data System. J Urol 174 (5): 1972-5, 2005. [PUBMED Abstract]
Breslow NE, Takashima JR, Ritchey ML, et al.: Renal failure in the Denys-Drash and Wilms' tumor-aniridia syndromes. Cancer Res 60 (15): 4030-2, 2000. [PUBMED Abstract]
Algar EM, St Heaps L, Darmanian A, et al.: Paternally inherited submicroscopic duplication at 11p15.5 implicates insulin-like growth factor II in overgrowth and Wilms' tumorigenesis. Cancer Res 67 (5): 2360-5, 2007. [PUBMED Abstract]
Satoh Y, Nakadate H, Nakagawachi T, et al.: Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms' tumours. Br J Cancer 95 (4): 541-7, 2006. [PUBMED Abstract]
Bliek J, Gicquel C, Maas S, et al.: Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS). J Pediatr 145 (6): 796-9, 2004. [PUBMED Abstract]
Rivera MN, Kim WJ, Wells J, et al.: An X chromosome gene, WTX, is commonly inactivated in Wilms tumor. Science 315 (5812): 642-5, 2007. [PUBMED Abstract]
Coppes MJ, Haber DA, Grundy PE: Genetic events in the development of Wilms' tumor. N Engl J Med 331 (9): 586-90, 1994. [PUBMED Abstract]
Grundy PE, Telzerow PE, Breslow N, et al.: Loss of heterozygosity for chromosomes 16q and 1p in Wilms' tumors predicts an adverse outcome. Cancer Res 54 (9): 2331-3, 1994. [PUBMED Abstract]
Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 23 (29): 7312-21, 2005. [PUBMED Abstract]
Natrajan R, Little SE, Reis-Filho JS, et al.: Amplification and overexpression of CACNA1E correlates with relapse in favorable histology Wilms' tumors. Clin Cancer Res 12 (24): 7284-93, 2006. [PUBMED Abstract]
Beckwith JB: Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet 79 (4): 268-73, 1998. [PUBMED Abstract]
Breslow NE, Beckwith JB, Perlman EJ, et al.: Age distributions, birth weights, nephrogenic rests, and heterogeneity in the pathogenesis of Wilms tumor. Pediatr Blood Cancer 47 (3): 260-7, 2006. [PUBMED Abstract]
Ravenel JD, Broman KW, Perlman EJ, et al.: Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J Natl Cancer Inst 93 (22): 1698-703, 2001. [PUBMED Abstract]
Fukuzawa R, Breslow NE, Morison IM, et al.: Epigenetic differences between Wilms' tumours in white and east-Asian children. Lancet 363 (9407): 446-51, 2004. [PUBMED Abstract]
Bonaïti-Pellié C, Chompret A, Tournade MF, et al.: Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study. Med Pediatr Oncol 20 (4): 284-91, 1992. [PUBMED Abstract]
Breslow NE, Beckwith JB: Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study. J Natl Cancer Inst 68 (3): 429-36, 1982. [PUBMED Abstract]
Li FP, Williams WR, Gimbrere K, et al.: Heritable fraction of unilateral Wilms tumor. Pediatrics 81 (1): 147-9, 1988. [PUBMED Abstract]
Paulino AC, Thakkar B, Henderson WG: Metachronous bilateral Wilms' tumor: the importance of time interval to the development of a second tumor. Cancer 82 (2): 415-20, 1998. [PUBMED Abstract]
Coppes MJ, Arnold M, Beckwith JB, et al.: Factors affecting the risk of contralateral Wilms tumor development: a report from the National Wilms Tumor Study Group. Cancer 85 (7): 1616-25, 1999. [PUBMED Abstract]

Cellular Classification

Wilms Tumor

Although most patients with a histologic diagnosis of Wilms tumor fare well with current treatment, approximately 10% of patients have histopathologic features that are associated with a poorer prognosis, and, in some types, with a high incidence of relapse and death. Wilms tumor can be separated into two prognostic groups on the basis of histopathology:

Favorable histology: Histologically, Wilms tumor mimics development of a normal kidney consisting of three cell types: blastemal, epithelial (tubules), and stromal. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties. There is no anaplasia in the tumor.

Anaplastic histology: Wilms tumor may be focal or diffuse (extreme cellular pleomorphism and atypia).[1] Focal anaplasia does not confer a poor prognosis, while diffuse anaplasia does. Anaplasia is associated with resistance to chemotherapy and may still be detected after preoperative chemotherapy.[2-4]

Clear Cell Sarcoma

Clear cell sarcoma of the kidney (CCSK) is not a Wilms tumor variant, but it is an important primary renal tumor associated with a significantly higher rate of relapse and death than favorable histology Wilms tumor. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue. The classic pattern of CCSK is defined by nests or cords of cells separated by regularly spaced arborizing fibrovascular septa.[5]

Rhabdoid Tumors of the Kidney

Initially thought to be a rhabdomyosarcomatoid variant of Wilms tumor, rhabdoid tumors of the kidney (RTK) are a distinctive and highly malignant tumor type. The most distinctive features of RTK are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions. The cell of origin is unknown. A distinct clinical presentation with fever, hematuria, young age (mean 11 months), and high tumor stage at presentation suggests a diagnosis of RTK.[6] RTK tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with RTK also have central nervous system lesions.[7,8]

The characteristic molecular lesion found in RTK is loss-of-function mutations of the hSNF5/INI1 gene, which is located at chromosome band 22q11.2.[9,10] This same molecular abnormality is found in tumors of the central nervous system termed atypical teratoid and rhabdoid tumors without the kidney involvement.[9,10] Some patients with rhabdoid tumors have constitutional mutations of the hSNF5/INI1 gene,[9,11] and these children are at increased risk for second primary brain tumors.[12]

Neuroepithelial Tumors of the Kidney

Neuroepithelial tumors of the kidney (NETK) are extremely rare and demonstrate a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with penetration of the renal capsule, extension into the renal vein, and metastases.[13,14] Primary NETK consist of primitive neuroectodermal tumors characterized by CD99 (MIC-2) immunostaining and the EWS/FLI-1 or closely related gene fusion products and small cell carcinomas characterized by chromogranin positivity. The two subtypes may be difficult to distinguish. Within both types of NETK, focal, atypical histologic features have been seen including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[13] (Refer to the PDQ summary on Ewings Family of Tumors for more information about neuroepithelial tumors.)

Cystic Partially Differentiated Nephroblastoma

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%) with unique pathologic and clinical characteristics. Several pathologic features distinguish this neoplasm from standard Wilms tumor. Patients with stage I disease have a 100% survival rate with surgery alone. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[15]

Mesoblastic Nephroma

Mesoblastic nephroma comprises about 5% of childhood kidney tumors, with twice as many males diagnosed as females. About half of all mesoblastic nephromas are of the classic histologic subtype and are often diagnosed by prenatal ultrasound or within 3 months after birth.[16] The cellular subtype is commonly found in older infants and often has a t(12;15) (p13;q25) translocation and/or chromosome 11 trisomy, cytogenetic abnormalities shared with congenital fibrosarcoma.[17]

Renal Cell Carcinoma

Malignant epithelial tumors arising in the kidneys of children account for more than 5% of new pediatric renal tumors; therefore, they are more common than CCSK or RTK. Renal cell carcinoma (RCC), the most common primary malignancy of the kidney in adults, occurs rarely in children, representing fewer than 3% of renal cancers in children younger than 15 years.[18] Renal cancers occur much less frequently in the 15- to 19-year-old age group than in younger children; however, among this older age group, approximately two-thirds of renal malignancies are RCC.[18] The annual incidence rate is approximately 4 per 1 million children compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher. RCC in young patients has a different genetic and morphologic spectrum than that seen in older adults.[19-22] RCC may be associated with von Hippel-Lindau disease, a hereditary condition in which blood vessels within the retina and cerebellum grow excessively.[19] The gene for von Hippel-Lindau is located on chromosome 3p25-26 and is a tumor-suppressor gene whose function is lost in patients with the syndrome. RCC has also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the kidney.[23-25] Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[24] A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors. A significant number of RCC tumors in children have Xp11.2 translocations,[22] and there is a subset that appears to be genetically related to alveolar soft part sarcoma. RCC may be associated with sickle cell disease and/or neuroblastoma.[26,27]

Pediatric RCC differs histologically from the adult counterparts. RCC tumors can be divided into two subgroups consisting of the clear cell lesions and papillary RCC. The clear cell lesions are the true conventional adult-type RCC, complete with abnormalities of chromosome 3p25. The second subgroup of pediatric RCCs are the classic papillary type, which are common in children and show the same genetic features as those found in adults (gains of chromosome 7 and 17). About half of patients with the papillary subtype have genetic alterations in Xp11.2 involving TFE3.[22,28] RCC may present with an abdominal mass, abdominal pain, or hematuria.[29] In a series of 41 children with RCC, the median age was 124 months with 46% presenting with localized stage I and stage II, 29% with stage III, and 22% with stage IV disease using the Robson classification system. The sites of metastases were the lungs, liver, and lymph nodes. Event-free survival and overall survival (OS) were each about 55% at 20 years posttreatment. Patients with stage I and stage II disease had an 89% OS rate, while those with stage III and stage IV disease had a 23% OS rate at 20 years posttreatment. An important difference between the outcomes in children and adults with RCC is the prognostic significance of local lymph node involvement. Adults presenting with RCC and involved lymph nodes have a 5-year OS of approximately 20%, but the literature suggests that 72% of children with RCC and local lymph node involvement at diagnosis (without distant metastases) survive their disease.[30] In another series of 49 patients from a population-based cancer registry, the findings were essentially confirmed.[31] In this series, 33% of the patients had papillary subtype, 22% had translocation type, 16% were unclassified, and 6% had clear cell subtype. Survival at 5 years was 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.[31]

Diffuse Hyperplastic Perilobar Nephroblastomatosis

In diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), the cortical surface of one or both kidneys is composed of hyperplastic nephroblastic tissue in whole or in part. The diagnosis may be made radiographically, most readily by magnetic resonance imaging, in which the homogeneity of the hypointense rind-like lesion on contrast-enhanced imaging differentiates it from Wilms tumor. Biopsy often cannot discriminate Wilms tumor from DHPLN unless the interface between DHPLN and normal renal tissue is included. Wilms tumor has a characteristic fibrous pseudocapsule, while DHPLN does not. If left untreated, most children with DHPLN will develop Wilms tumor. Current recommendations are for treatment with vincristine and actinomycin-D until nearly complete resolution of DHPLN as determined by imaging. Even with treatment with vincristine and actinomycin-D, about half of children will develop Wilms tumor, within an average of 36 months after diagnosis of DHPLN. Despite this, the overall survival rate for these children is approximately 50%. In a series of 52 patients, three patients died of recurrent Wilms tumor.[32] In treated DHPLN children, as many as one-third of Wilms tumors are anaplastic, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical. Patients are followed by imaging at a maximum interval of 3 months for a minimum of 7 years. Given the high incidence of bilateral DHPLN and the subsequent Wilms tumors, renal-sparing surgery is indicated.[32]

Current Clinical Trials

General information about clinical trials is also available from the NCI Web site.

References

Zuppan CW, Beckwith JB, Luckey DW: Anaplasia in unilateral Wilms' tumor: a report from the National Wilms' Tumor Study Pathology Center. Hum Pathol 19 (10): 1199-209, 1988. [PUBMED Abstract]
Vujanić GM, Harms D, Sandstedt B, et al.: New definitions of focal and diffuse anaplasia in Wilms tumor: the International Society of Paediatric Oncology (SIOP) experience. Med Pediatr Oncol 32 (5): 317-23, 1999. [PUBMED Abstract]
Faria P, Beckwith JB, Mishra K, et al.: Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognostic significance: a report from the National Wilms Tumor Study Group. Am J Surg Pathol 20 (8): 909-20, 1996. [PUBMED Abstract]
Dome JS, Cotton CA, Perlman EJ, et al.: Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol 24 (15): 2352-8, 2006. [PUBMED Abstract]
Argani P, Perlman EJ, Breslow NE, et al.: Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms Tumor Study Group Pathology Center. Am J Surg Pathol 24 (1): 4-18, 2000. [PUBMED Abstract]
Amar AM, Tomlinson G, Green DM, et al.: Clinical presentation of rhabdoid tumors of the kidney. J Pediatr Hematol Oncol 23 (2): 105-8, 2001. [PUBMED Abstract]
Weeks DA, Beckwith JB, Mierau GW, et al.: Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol 13 (6): 439-58, 1989. [PUBMED Abstract]
Rorke LB, Packer R, Biegel J: Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neurooncol 24 (1): 21-8, 1995. [PUBMED Abstract]
Biegel JA, Zhou JY, Rorke LB, et al.: Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res 59 (1): 74-9, 1999. [PUBMED Abstract]
Versteege I, Sévenet N, Lange J, et al.: Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394 (6689): 203-6, 1998. [PUBMED Abstract]
Sévenet N, Sheridan E, Amram D, et al.: Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65 (5): 1342-8, 1999. [PUBMED Abstract]
Savla J, Chen TT, Schneider NR, et al.: Mutations of the hSNF5/INI1 gene in renal rhabdoid tumors with second primary brain tumors. J Natl Cancer Inst 92 (8): 648-50, 2000. [PUBMED Abstract]
Parham DM, Roloson GJ, Feely M, et al.: Primary malignant neuroepithelial tumors of the kidney: a clinicopathologic analysis of 146 adult and pediatric cases from the National Wilms' Tumor Study Group Pathology Center. Am J Surg Pathol 25 (2): 133-46, 2001. [PUBMED Abstract]
Jimenez RE, Folpe AL, Lapham RL, et al.: Primary Ewing's sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol 26 (3): 320-7, 2002. [PUBMED Abstract]
Blakely ML, Shamberger RC, Norkool P, et al.: Outcome of children with cystic partially differentiated nephroblastoma treated with or without chemotherapy. J Pediatr Surg 38 (6): 897-900, 2003. [PUBMED Abstract]
Furtwaengler R, Reinhard H, Leuschner I, et al.: Mesoblastic nephroma--a report from the Gesellschaft fur Pädiatrische Onkologie und Hämatologie (GPOH). Cancer 106 (10): 2275-83, 2006. [PUBMED Abstract]
Vujanić GM, Sandstedt B, Harms D, et al.: Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 38 (2): 79-82, 2002. [PUBMED Abstract]
Bernstein L, Linet M, Smith MA, et al.: Renal Tumors. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 79-90. Also available online. Last accessed April 19, 2007.
Bruder E, Passera O, Harms D, et al.: Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 28 (9): 1117-32, 2004. [PUBMED Abstract]
Estrada CR, Suthar AM, Eaton SH, et al.: Renal cell carcinoma: Children's Hospital Boston experience. Urology 66 (6): 1296-300, 2005. [PUBMED Abstract]
Carcao MD, Taylor GP, Greenberg ML, et al.: Renal-cell carcinoma in children: a different disorder from its adult counterpart? Med Pediatr Oncol 31 (3): 153-8, 1998. [PUBMED Abstract]
Ramphal R, Pappo A, Zielenska M, et al.: Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family. Am J Clin Pathol 126 (3): 349-64, 2006. [PUBMED Abstract]
Indolfi P, Terenziani M, Casale F, et al.: Renal cell carcinoma in children: a clinicopathologic study. J Clin Oncol 21 (3): 530-5, 2003. [PUBMED Abstract]
Wang N, Perkins KL: Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet 11 (4): 479-81, 1984. [PUBMED Abstract]
Eble JN: Angiomyolipoma of kidney. Semin Diagn Pathol 15 (1): 21-40, 1998. [PUBMED Abstract]
Argani P, Antonescu CR, Illei PB, et al.: Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 159 (1): 179-92, 2001. [PUBMED Abstract]
Altinok G, Kattar MM, Mohamed A, et al.: Pediatric renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions and clinicopathologic associations. Pediatr Dev Pathol 8 (2): 168-80, 2005 Mar-Apr. [PUBMED Abstract]
Perlman EJ: Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol 8 (3): 320-38, 2005 May-Jun. [PUBMED Abstract]
Strouse JJ, Spevak M, Mack AK, et al.: Significant responses to platinum-based chemotherapy in renal medullary carcinoma. Pediatr Blood Cancer 44 (4): 407-11, 2005. [PUBMED Abstract]
Geller JI, Dome JS: Local lymph node involvement does not predict poor outcome in pediatric renal cell carcinoma. Cancer 101 (7): 1575-83, 2004. [PUBMED Abstract]
Selle B, Furtwängler R, Graf N, et al.: Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts. Cancer 107 (12): 2906-14, 2006. [PUBMED Abstract]
Perlman EJ, Faria P, Soares A, et al.: Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients. Pediatr Blood Cancer 46 (2): 203-21, 2006. [PUBMED Abstract]

Stage Information

Wilms Tumor

The stage is determined by the results of the imaging studies and both the surgical and pathologic findings at nephrectomy and is the same for tumors with favorable or anaplastic histology. Thus, patients should be characterized by a statement of both criteria (for example, stage II, favorable histology or stage II, anaplastic histology).[1,2]

The staging system employed by the National Wilms Tumor Study Group and incidence by stage is outlined below.[2]

Stage I (43% of patients)

In stage I Wilms tumor, all of the following criteria must be met:

Tumor is limited to the kidney and is completely resected.

The renal capsule is intact.

The tumor is not ruptured or biopsied prior to removal.

No involvement of renal sinus vessels.

No evidence of the tumor at or beyond the margins of resection.

[Note: For a tumor to qualify for certain therapeutic protocols as stage I, regional lymph nodes must be examined microscopically.]

Stage II (23% of patients)

In stage II Wilms tumor, the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:

There is regional extension of the tumor (i.e., penetration of the renal sinus capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below).

Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor.

[Note: Rupture or spillage confined to the flank, including biopsy of the tumor, is no longer included in stage II and is now included in stage III.]

Stage III (23% of patients)

In stage III Wilms tumor, there is residual nonhematogenous tumor present following surgery that is confined to the abdomen. Any one of the following may occur:

Lymph nodes within the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for stage IV.)

The tumor has penetrated through the peritoneal surface.

Tumor implants are found on the peritoneal surface.

Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination).

The tumor is not completely resectable because of local infiltration into vital structures.

Tumor spillage occurs either before or during surgery.

The tumor was biopsied (using tru-cut biopsy, open biopsy, or fine-needle aspiration) before removal.

The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen).

Stage IV (10% of patients)

In stage IV Wilms tumor, hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdominopelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present.)

Stage V (5% of patients)

In stage V Wilms tumor, bilateral involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease. The 4-year survival is 94% for those patients whose most advanced lesion is stage I or stage II, and 76% for those whose most advanced lesion is stage III.[3]

Stage I-IV Anaplasia

Anaplastic histology accounts for about 10% of Wilms tumors. Children with anaplastic tumors have a worse prognosis than children with favorable histology when compared stage to stage. These tumors are more resistant to the chemotherapy traditionally used in children with Wilms tumor (favorable histology).[4]

Current Clinical Trials

General information about clinical trials is also available from the NCI Web site.

References

Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 9 (5): 877-87, 1991. [PUBMED Abstract]
D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 64 (2): 349-60, 1989. [PUBMED Abstract]
Ritchey ML, Coppes MJ: The management of synchronous bilateral Wilms tumor. Hematol Oncol Clin North Am 9 (6): 1303-15, 1995. [PUBMED Abstract]
Dome JS, Cotton CA, Perlman EJ, et al.: Treatment of anaplastic histology Wilms' tumor: results from the fifth National Wilms' Tumor Study. J Clin Oncol 24 (15): 2352-8, 2006. [PUBMED Abstract]

Treatment Option Overview

Wilms Tumor

Because of the relative rarity of this tumor, all patients with Wilms tumor should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating Wilms tumor is required to determine and implement optimum treatment.

The National Wilms Tumor Study Group, which is now part of the Children’s Oncology Group, has established standard treatment for Wilms tumor in North America which consists of surgery followed by chemotherapy and, in some patients, radiation therapy.[1-3] The major treatment conclusions of the National Wilms Tumor Studies (NWTS 1-4) are:

Routine, postoperative radiation therapy of the flank is not necessary for children with stage I tumors or stage II tumors with favorable histology (FH) when postnephrectomy combination chemotherapy consisting of vincristine and dactinomycin is administered.

The prognosis for patients with stage III/FH is best when treatment includes: (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank.

The addition of cyclophosphamide to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV/FH tumors.

Single-dose (pulse-intensive) treatment with dactinomycin (stages I–II/FH, stage I anaplastic), and doxorubicin (stage III/FH, stages III–IV, or stages I–IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, and results in the same event-free survival, greater dose intensity, and is associated with less toxicity and expense.[4]

Eighteen weeks of therapy is adequate for patients with stage I/FH whereas other patients can be treated with 6 months of therapy instead of 15 months.[1,4-7]

Tumor-specific loss of heterozygosity for combined 1p and 16q predicts recurrence of FH Wilms tumor and may be used to select patients for more aggressive treatment.[8]

Operative principles have evolved from NWTS trials. The most important role for the surgeon is to ensure complete tumor removal without rupture and perform an assessment of the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal incision is the procedure of choice.[9] For patients with resectable tumors, preoperative biopsy should not be performed.[9] Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies are suggestive of regional and contralateral kidney involvement, the contralateral kidney should be formally explored to rule out bilateral involvement. This should be done prior to nephrectomy since the diagnosis of bilateral disease would dramatically alter the approach.[10] Partial nephrectomy remains controversial and is not recommended. Rarely, very small tumors may be discovered by ultrasound screening, and these cases may be considered for partial nephrectomy.[11] In North America, renal-sparing partial nephrectomy of unilateral Wilms tumor following administration of chemotherapy to shrink the tumor mass is considered investigational.[12,13] Hilar, periaortic, iliac, and celiac lymph node sampling is mandatory.[9] Furthermore, any suspicious node basin should be sampled. Margins of resection, residual tumor, and any suspicious node basins should be marked with titanium clips. Liver wedge resection or partial duodenal or colonic resections are acceptable for complete en bloc excision. Wilms tumor arising in a horseshoe kidney is rare and accurate preoperative diagnosis is important in planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.[14]

Patients with massive, nonresectable unilateral tumors, bilateral tumors, or venacaval tumor thrombus above the hepatic veins are candidates for preoperative chemotherapy because of the risk of initial surgical resection.[9,15-17] Preoperative chemotherapy should follow a biopsy, which may be performed percutaneously.[18-23] Preoperative chemotherapy makes tumor removal easier and may reduce the frequency of surgical complications.[15,16,23-25] Although progressive tumor growth on chemotherapy is rare, such growth is associated with a poorer prognosis.[26] Current therapy in North America for patients diagnosed by needle biopsy alone is for a stage III tumor (in the absence of metastases) of favorable or anaplastic histology.

Newborns and all infants younger than 12 months require a reduction in chemotherapy doses to 50% of those given to older children.[27] This reduction diminishes toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.[28] Liver function tests in children with Wilms tumor should be monitored closely during the early course of therapy based on hepatic toxic effects (veno-occlusive disease) reported in those patients.[29,30] Dactinomycin should not be administered during radiation therapy. Children treated for Wilms tumor are at increased risk for developing second malignant neoplasms. This risk depends on the intensity of their therapy, including the use of radiation and doxorubicin, and on possible genetic factors.[31] Congestive heart failure has been shown to be a risk in children treated with doxorubicin with the degree of risk influenced by cumulative doxorubicin dose, radiation to the heart, and gender (females at increased risk).[32] Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

Current Clinical Trials

General information about clinical trials is also available from the NCI Web site.

References

D'Angio GJ, Breslow N, Beckwith JB, et al.: Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer 64 (2): 349-60, 1989. [PUBMED Abstract]
Jereb B, Burgers JM, Tournade MF, et al.: Radiotherapy in the SIOP (International Society of Pediatric Oncology) nephroblastoma studies: a review. Med Pediatr Oncol 22 (4): 221-7, 1994. [PUBMED Abstract]
Green DM: The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol 22 (8): 1366-72, 2004. [PUBMED Abstract]
Green DM, Breslow NE, Beckwith JB, et al.: Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 16 (1): 237-45, 1998. [PUBMED Abstract]
Green DM, Breslow NE, Beckwith JB, et al.: Effect of duration of treatment on treatment outcome and cost of treatment for Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 16 (12): 3744-51, 1998. [PUBMED Abstract]
D'Angio GJ, Evans AE, Breslow N, et al.: The treatment of Wilms' tumor: Results of the national Wilms' tumor study. Cancer 38 (2): 633-46, 1976. [PUBMED Abstract]
D'Angio GJ, Evans A, Breslow N, et al.: The treatment of Wilms' tumor: results of the Second National Wilms' Tumor Study. Cancer 47 (9): 2302-11, 1981. [PUBMED Abstract]
Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 23 (29): 7312-21, 2005. [PUBMED Abstract]
Ehrlich PF, Ritchey ML, Hamilton TE, et al.: Quality assessment for Wilms' tumor: a report from the National Wilms' Tumor Study-5. J Pediatr Surg 40 (1): 208-12; discussion 212-3, 2005. [PUBMED Abstract]
Ritchey ML, Shamberger RC, Hamilton T, et al.: Fate of bilateral renal lesions missed on preoperative imaging: a report from the National Wilms Tumor Study Group. J Urol 174 (4 Pt 2): 1519-21; discussion 1521, 2005. [PUBMED Abstract]
McNeil DE, Langer JC, Choyke P, et al.: Feasibility of partial nephrectomy for Wilms' tumor in children with Beckwith-Wiedemann syndrome who have been screened with abdominal ultrasonography. J Pediatr Surg 37 (1): 57-60, 2002. [PUBMED Abstract]
Ritchey ML: Renal sparing surgery for Wilms tumor. J Urol 174 (4 Pt 1): 1172-3, 2005. [PUBMED Abstract]
Cozzi DA, Zani A: Nephron-sparing surgery in children with primary renal tumor: indications and results. Semin Pediatr Surg 15 (1): 3-9, 2006. [PUBMED Abstract]
Neville H, Ritchey ML, Shamberger RC, et al.: The occurrence of Wilms tumor in horseshoe kidneys: a report from the National Wilms Tumor Study Group (NWTSG). J Pediatr Surg 37 (8): 1134-7, 2002. [PUBMED Abstract]
Ritchey ML: Primary nephrectomy for Wilms' tumor: approach of the National Wilms' Tumor Study Group. Urology 47 (6): 787-91, 1996. [PUBMED Abstract]
Ritchey ML, Kelalis PP, Breslow N, et al.: Surgical complications after nephrectomy for Wilms' tumor. Surg Gynecol Obstet 175 (6): 507-14, 1992. [PUBMED Abstract]
Lall A, Pritchard-Jones K, Walker J, et al.: Wilms' tumor with intracaval thrombus in the UK Children's Cancer Study Group UKW3 trial. J Pediatr Surg 41 (2): 382-7, 2006. [PUBMED Abstract]
Tournade MF, Com-Nougué C, Voûte PA, et al.: Results of the Sixth International Society of Pediatric Oncology Wilms' Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms' tumor. J Clin Oncol 11 (6): 1014-23, 1993. [PUBMED Abstract]
Oberholzer HF, Falkson G, De Jager LC: Successful management of inferior vena cava and right atrial nephroblastoma tumor thrombus with preoperative chemotherapy. Med Pediatr Oncol 20 (1): 61-3, 1992. [PUBMED Abstract]
Saarinen UM, Wikström S, Koskimies O, et al.: Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children. J Clin Oncol 9 (3): 406-15, 1991. [PUBMED Abstract]
Dykes EH, Marwaha RK, Dicks-Mireaux C, et al.: Risks and benefits of percutaneous biopsy and primary chemotherapy in advanced Wilms' tumour. J Pediatr Surg 26 (5): 610-2, 1991. [PUBMED Abstract]
Thompson WR, Newman K, Seibel N, et al.: A strategy for resection of Wilms' tumor with vena cava or atrial extension. J Pediatr Surg 27 (7): 912-5, 1992. [PUBMED Abstract]
Shamberger RC, Ritchey ML, Haase GM, et al.: Intravascular extension of Wilms tumor. Ann Surg 234 (1): 116-21, 2001. [PUBMED Abstract]
Shamberger RC, Guthrie KA, Ritchey ML, et al.: Surgery-related factors and local recurrence of Wilms tumor in National Wilms Tumor Study 4. Ann Surg 229 (2): 292-7, 1999. [PUBMED Abstract]
Szavay P, Luithle T, Semler O, et al.: Surgery of cavoatrial tumor thrombus in nephroblastoma: a report of the SIOP/GPOH study. Pediatr Blood Cancer 43 (1): 40-5, 2004. [PUBMED Abstract]
Ora I, van Tinteren H, Bergeron C, et al.: Progression of localised Wilms' tumour during preoperative chemotherapy is an independent prognostic factor: a report from the SIOP 93-01 nephroblastoma trial and study. Eur J Cancer 43 (1): 131-6, 2007. [PUBMED Abstract]
Corn BW, Goldwein JW, Evans I, et al.: Outcomes in low-risk babies treated with half-dose chemotherapy according to the Third National Wilms' Tumor Study. J Clin Oncol 10 (8): 1305-9, 1992. [PUBMED Abstract]
Morgan E, Baum E, Breslow N, et al.: Chemotherapy-related toxicity in infants treated according to the Second National Wilms' Tumor Study. J Clin Oncol 6 (1): 51-5, 1988. [PUBMED Abstract]
Green DM, Norkool P, Breslow NE, et al.: Severe hepatic toxicity after treatment with vincristine and dactinomycin using single-dose or divided-dose schedules: a report from the National Wilms' Tumor Study. J Clin Oncol 8 (9): 1525-30, 1990. [PUBMED Abstract]
Raine J, Bowman A, Wallendszus K, et al.: Hepatopathy-thrombocytopenia syndrome--a complication of dactinomycin therapy for Wilms' tumor: a report from the United Kingdom Childrens Cancer Study Group. J Clin Oncol 9 (2): 268-73, 1991. [PUBMED Abstract]
Breslow NE, Takashima JR, Whitton JA, et al.: Second malignant neoplasms following treatment for Wilm's tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 13 (8): 1851-9, 1995. [PUBMED Abstract]
Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001. [PUBMED Abstract]

Stage I Wilms Tumor

Regardless of histology, all stage I Wilms tumor patients have an excellent prognosis with the same treatment.[1]

For favorable-histology tumors (the 4-year relapse-free survival rate is 92%, and the 4-year overall survival [OS] rate is 98%):[2]

Nephrectomy with lymph node sampling and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin (NWTS Regimen EE-4A).

For focal or diffuse anaplastic tumors (the 4-year event-free survival rate is 69.5%, and the 4-year OS rate is 82.6%):[3] In the National Wilms Tumor Study Group-5 (NWTS-5) study, patients with stage I Wilms tumor with diffuse and focal anaplasia were managed with vincristine and dactinomycin based on the excellent outcomes for this patient group in previous studies.[4] The outcomes of these patient groups in the NWTS-5 study were not as favorable as in previous studies.[3]

Nephrectomy with lymph node sampling and 18 weeks of chemotherapy with vincristine and pulse-intensive dactinomycin.

It may be possible to treat a subset of stage I Wilms tumor patients with surgery alone without chemotherapy. The Children’s Oncology Group is planning a large study to address this question. In the NWTS-5, infants with stage I/FH Wilms tumor who were younger than 24 months and whose nephrectomy specimen weighed less than 550 g underwent surgery only.[5] The study was designed with a stringent stopping rule (interim analysis of RFS ≤90%), which was exceeded, mandating the closure of the study. Most patients could be successfully salvaged with chemotherapy, however, with a 2-year OS rate of 100%.

Treatment Options Under Clinical Evaluation

The following treatment options are currently under investigation in national and/or institutional clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Favorable Histology

AREN0532:[6] In this study, all tumors will be stratified based on central pathology review and molecular analysis (loss of heterozygosity [LOH] at chromosomes 1p and 16q). Patients with LOH at 1p and 16q will be upstaged to receive treatment with DD-4A (dactinomycin