WILMS TUMORS

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					WILMS TUMORS
Table of Contents
UPDATED 10/02/2008

Purpose of This PDQ summary
General Information
Cellular Classification

     Wilms Tumor
     Clear Cell Sarcoma
     Rhabdoid Tumors of the Kidney
     Mesoblastic Nephroma
     Renal Cell Carcinoma
     Nephroblastomatosis
     Neuroepithelial Tumors of the Kidney
     Desmoplastic Small Round Cell Tumor of the Kidney
     Cystic Partially Differentiated Nephroblastoma
     Multilocular Cystic Nephroma
     Primary Renal Synovial Sarcoma

Stage Information

     Wilms Tumor
     Stage I (43% of patients)
     Stage II (20% of patients)
     Stage III (21% of patients)
     Stage IV (11% of patients)
     Stage V (5% of patients)
     Anaplastic Histology

Treatment Option Overview

     Wilms Tumor

Standard Treatment Options for Wilms Tumor

     Additional Treatment Considerations
          Stage I Wilms tumor
          Stage IV Wilms tumor
          Stage V Wilms tumor
          Inoperable Wilms Tumors

Treatment Options Under Clinical Evaluation for Wilms Tumor

     Stage I
     Stage II
     Stage III
     Stage IV
     Current Clinical Trials

Clear Cell Sarcoma of the Kidney

     Standard Treatment Options
     Treatment Options Under Clinical Evaluation
     Current Clinical Trials
Rhabdoid Tumor of the Kidney

     Standard Treatment Options
     Treatment Options Under Clinical Evaluation
     Current Clinical Trials

Neuroepithelial Tumor of the Kidney

     Current Clinical Trials

Mesoblastic Nephroma

     Current Clinical Trials

Renal Cell Carcinoma

     Standard Treatment Options
     Current Clinical Trials

Recurrent Wilms Tumor and Other Childhood Kidney Tumors

     Current Clinical Trials

Get More Information From NCI
Changes to This Summary (10/02/2008)
More Information


Purpose of This PDQ summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed,
evidence-based information about the treatment of Wilms tumor and other childhood kidney tumors. This
summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

        Cellular classification.
        Stage information.
        Treatment options for Wilms tumor and other childhood kidney tumors.

This summary is intended as a resource to inform and assist clinicians and other health professionals who
care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making
health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These
designations are intended to help readers assess the strength of the evidence supporting the use of specific
interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence
ranking system in developing their level-of-evidence designations. Based on the strength of the available
evidence, treatment options are described as either “standard” or “under clinical evaluation.” These
classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in
Spanish.

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General Information
The National Cancer Institute (NCI) 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.

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 has 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 (COG-Q9401). 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 (COG-Q9401).[2-4] 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.[5-7]

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),[8] 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).[9-13] Klippel-Trénaunay syndrome, a unilateral
limb overgrowth syndrome, is not associated with Wilms tumor.[14] Examples of nonovergrowth syndromes
associated with Wilms tumor are isolated aniridia; trisomy 18; Wilms tumor, aniridia, genitourinary
anomalies, and mental retardation (WAGR) syndrome; Blooms syndrome, and Denys-Drash syndrome
(characterized by intersexual disorders, nephropathy, and Wilms tumor).[15] The constellation of WAGR
syndrome occurs in association with an interstitial deletion on chromosome 11 (del [11p13]).[16,17] 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),[18] both of which are associated with
mutations in the Wilms tumor 1 (WT1) gene at chromosome 11p13.[19] Specifically, germline missense
mutations in the WT1 gene are responsible for most Wilms tumors that occur as part of the Denys-Drash
syndrome.[20] 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.[9-13,21-23]

Wilms tumor (hereditary or sporadic) appears to result from changes in one or more of at least ten genes.
The WT1 gene 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.[24] Germline mutations in
WT1, however, have also been found in about 2% of phenotypically normal children with Wilms tumor.[25]
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.[17]

        Patients with aniridia or hemihypertrophy should be screened with ultrasound every 3 months until
      they reach age 8 years.[9] For patients with WAGR syndrome, the risk of developing Wilms tumor is
      as high as 45%.[26] 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. (Refer to the
      Cellular Classification section of this summary for more information). The incidence of bilateral Wilms
      tumor in children with WAGR syndrome is high (about 15%).[27] Treatment outcome at 4 years is
      similar to that of non-WAGR patients.[27] Children with WAGR syndrome are at increased risk of
      eventually developing renal failure and should be monitored.[28] Patients with Wilms tumor and
      aniridia without genitourinary abnormalities are at lesser risk but should be monitored for nephropathy
      or renal failure.[29] Children with Wilms tumor and any genitourinary anomalies are also at increased
      risk for late renal failure and should be monitored.[28] The incidence of Wilms tumor in children with
      sporadic aniridia is estimated to be about 5%.[27]

        A second Wilms tumor locus, Wilms tumor-2 (WT2) gene, maps to an imprinted region of
      chromosome 11p15.5 in association with Beckwith-Wiedemann syndrome. There are several
      candidate genes at the WT2 locus, comprising the two independent imprinted domains IGF2/H19 and
      KIP2/LIT1.[30] 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.[31] Loss of imprinting or gene methylation are
      rarely found at other loci supporting the specificity of loss of imprinting at IGF-2.[32] Wilms tumors in
      Asian children are not associated with either nephrogenic rests or IFG2 loss of imprinting.[33]

Observations suggest genetic heterogeneity in the etiology of Beckwith-Wiedemann syndrome with differing
levels of association with risk of tumor formation.[34] Approximately one-fifth of patients with Beckwith-
Wiedemann syndrome who develop Wilms tumor present with bilateral disease, though metachronous
bilateral disease is also observed.[9-11] 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.[35]

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. 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.[36] Overexpression and amplification of the gene CACNA1E
located at 1q25.3, which encodes the ion-conducting alpha-1 subunit of R-type voltage-dependent calcium
channels, is associated with relapse in favorable histology Wilms tumor.[37]

Despite the number of genes that appear to be involved in the development of Wilms tumor, hereditary
Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms
tumor. Siblings of children with Wilms tumor have a low likelihood of developing Wilms tumor.[38] Two
familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[39] The risk of
Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is quite low (<2%).[40]
About 4% to 5% of patients have bilateral Wilms tumors, but these are not usually hereditary.[41] 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.[42,43]

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.)

References

    1.   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]

    2.   Ritchey ML, Haase GM, Shochat S: Current management of Wilms' tumor. Semin Surg Oncol 9 (6):
         502-9, 1993 Nov-Dec. [PUBMED Abstract]

    3.   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]

    4.   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]

    5.   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]

    6.   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]

    7.   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]

    8.   Greenberg F, Stein F, Gresik MV, et al.: The Perlman familial nephroblastomatosis syndrome. Am
         J Med Genet 24 (1): 101-10, 1986. [PUBMED Abstract]

    9.   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]

    10. 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]

    11. 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]

    12. 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]
13. 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]

14. 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]

15. 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]

16. Clericuzio CL: Clinical phenotypes and Wilms tumor. Med Pediatr Oncol 21 (3): 182-7, 1993.
    [PUBMED Abstract]

17. Fischbach BV, Trout KL, Lewis J, et al.: WAGR syndrome: a clinical review of 54 cases. Pediatrics
    116 (4): 984-8, 2005. [PUBMED Abstract]

18. 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]

19. 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]

20. Royer-Pokora B, Beier M, Henzler M, et al.: Twenty-four new cases of WT1 germline mutations and
    review of the literature: genotype/phenotype correlations for Wilms tumor development. Am J Med
    Genet A 127 (3): 249-57, 2004. [PUBMED Abstract]

21. 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]

22. 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]

23. 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]

24. 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]

25. 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]

26. 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]

27. 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]

28. 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]

29. 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]
    30. 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]

    31. 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]

    32. Bjornsson HT, Brown LJ, Fallin MD, et al.: Epigenetic specificity of loss of imprinting of the IGF2
        gene in Wilms tumors. J Natl Cancer Inst 99 (16): 1270-3, 2007. [PUBMED Abstract]

    33. 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]

    34. 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]

    35. 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]

    36. 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]

    37. 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]

    38. 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]

    39. Ruteshouser EC, Huff V: Familial Wilms tumor. Am J Med Genet C Semin Med Genet 129 (1): 29-
        34, 2004. [PUBMED Abstract]

    40. Li FP, Williams WR, Gimbrere K, et al.: Heritable fraction of unilateral Wilms tumor. Pediatrics 81
        (1): 147-9, 1988. [PUBMED Abstract]

    41. 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]

    42. 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]

    43. 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]


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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. While associations between histologic
      features and prognosis or responsiveness to therapy have been suggested, with the exception of
      anaplasia, none of these features have reached statistical significance and therefore do not direct the
      initial therapy.[1]

        Anaplastic histology: Anaplastic histology is the single most important histologic predictor of
      response and survival in patients with Wilms tumor. There are two histologic criteria for anaplasia,
      both of which must be present for the diagnosis. They are the presence of multipolar polyploid mitotic
      figures with marked nuclear enlargement and hyperchromasia. Anaplasia correlates best with
      responsiveness to therapy rather than to aggressiveness. It is most consistently associated with poor
      prognosis when it is diffusely distributed and when identified at advanced stages. This is the reason
      why focal anaplasia and diffuse anaplasia are differentiated, both pathologically and therapeutically.
      Focal anaplasia is defined as the presence of one or a few sharply localized regions of anaplasia
      within a primary tumor. Focal anaplasia does not confer a poor prognosis, while diffuse anaplasia
      does.[2-4]

        Nephrogenic rests: Many Wilms tumors appear to arise from abnormally retained embryonic
      kidney precursor cells arranged in clusters termed nephrogenic rests. The term nephroblastomatosis
      is defined as the presence of diffuse or multifocal nephrogenic rests. There are two types: intralobar
      nephrogenic rests and perilobar nephrogenic rests. Diffuse hyperplastic perilobar nephroblastomatosis
      is defined as nephroblastomatosis forming a thick rind around one or both kidneys and is considered a
      preneoplastic condition.[1] Patients with any type of nephrogenic rest in a kidney removed for
      nephroblastoma should be considered at increased risk for tumor formation in the remaining kidney.
      This risk decreases with patient age.[5]

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 fibrovascular
septa.[6] Dysregulation of the epidermal growth factor receptor pathway has been demonstrated in CCSK.[7]
Previously, relapses have occurred in long intervals after the completion of chemotherapy (up to 10 years),
however with current therapy relapses after 3 years are uncommon.[8] The brain has emerged as a frequent
site of recurrent disease.[9,10]

Rhabdoid Tumors of the Kidney

Rhabdoid tumors (RT) are extremely aggressive malignancies that generally occur in infants and young
children. The most common locations are the kidney and central nervous system (atypical teratoid/rhabdoid
tumor), although RTs can also arise in most soft-tissue sites. Initially they were thought to be a
rhabdomyosarcomatoid variant of Wilms tumor when they occurred in the kidney.

Histologically, the most distinctive features of rhabdoid tumors of the kidney (RTK) are rather large cells with
large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic
cytoplasmic inclusions. A distinct clinical presentation with fever, hematuria, young age (mean 11 months),
and high tumor stage at presentation suggests a diagnosis of RTK.[11] RTK tends to metastasize to the
lungs and the brain. As many as 10% to 15% of patients with RTK also have central nervous system
lesions.[12]

RT in all anatomical locations have a similar molecular origin. Mutation or deletion of both copies of the
hSNF5/INI1 gene that maps to chromosome band 22q11.2 is observed in approximately 70% of primary
tumors. An additional 20% to 25% of tumors have reduced expression at the RNA or protein level, indicative
of a loss-of-function event. The INI1 protein is a component of the SWI/SNF chromatin remodeling complex
(a group of genes involved in cell signaling, growth, and differentiation). Identical mutations may give rise to
a brain or kidney tumor. Germline mutations of INI1 have been documented for patients with one or more
primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of
rhabdoid tumors.[13,14] In most cases, the mutations are de novo, and not inherited from a parent. Germline
mosaicism has been suggested for several families with multiple affected siblings. It does appear that those
patients with germline mutations have the worst prognosis.[15]

Mesoblastic Nephroma

Mesoblastic nephroma (MN) comprises about 5% of childhood kidney tumors. The median age of diagnosis
is 2 months and over 90% of cases appear within the first year of life. Twice as many males are diagnosed
as females. The diagnosis should be questioned when applied to individualsolder than 2 years. When
diagnosed in the first 7 months of life, the 5 year event-free survival (EFS) and overall survival rates are 94%
and 96%, respectively.[16]

Grossly, MN appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically,
they consist of spindled mesenchymal cells. They can be divided into two major types: classic and cellular.
Classic MN are often diagnosed by prenatal ultrasound or within 3 months after birth and closely resemble
infantile fibromatosis.[17] Infantile fibrosarcoma and cellular MN contain the same t(12;15)(p13;q25)
chromosomal translocation suggestive of a potential linkage.[18] The risk for recurrence within MN is closely
associated with the presence of a cellular component and with stage.[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 younger than 15 years. In the
older age group of adolescents (aged 15—19 years), approximately two-thirds of renal malignancies are
RCC.[19] 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.[20-23] RCC may be associated with von Hippel-Lindau
(VHL) disease, a hereditary condition in which blood vessels within the retina and cerebellum grow
excessively.[20] The gene for VHL is located on chromosome 3p25-26 and is a tumor-suppressor gene
whose function is lost in patients with the syndrome. Screening for the VHL gene is available.[24] RCC has
also been associated with tuberous sclerosis, a hereditary disease characterized by benign fatty cysts in the
kidney.[25,26] In tuberous sclerosis, the renal lesions may actually be epithelioid angiomyolipoma (also
called perivascular epithelioid cell tumor or PEComa), which is associated with aggressive or malignant
behavior and expresses melanocyte and smooth muscle markers.[27,28] Familial RCC has been associated
with an inherited chromosome translocation involving chromosome 3.[26] 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,[23,29] and there is a subset that appears to be genetically related to
alveolar soft part sarcoma.[30] RCC have been described in patients several years after diagnosis and
therapy for neuroblastoma.[31] A rare subtype of RCC, renal medullary carcinoma, may be associated with
sickle cell hemoglobinopathy.[32] Renal medullary carcinomas are highly aggressive malignancies
characterized clinically by a high stage at the time of detection, with widespread metastases and lack of
response to chemotherapy and radiation therapy. Survival is poor and ranges from 2 weeks to 15 months,
with a mean survival of 4 months.[32-34]

Pediatric RCC differs histologically from the adult counterparts. Although the two main morphological
subgroups of papillary and clear-cell can be identified, about 25% of RCCs show heterogeneous features
that do not fit into either one of these categories. Childhood RCCs are more frequently of the papillary
subtype (20% to 50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor,
metanephric adenoma and metanephric adenofibroma. More recently, the genetic translocations can be
used as the basis for subgrouping with many involving Xp11.2 resulting in the overexpressed transcription
factor genes TFE3 or TFEB. These Xp11.2-translocation carcinomas are recognized as a distinct entity but
resemble clear cell RCCs. One of these fusion variants of RCC is identical to the genetic change in alveolar
soft-part sarcoma, however, the genetic pathways to pathogenesis are not the same in these two disease
(with genetic features similar to those in adults with gains of chromosome 7 and 17) and of the Xp11
translocation type or the related t(6;11) translocation type.[20,23,35,36]
RCC may present with an abdominal mass, abdominal pain, or hematuria. 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. EFS and overall survival (OS) were each about 55% at 20 years
post treatment. 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.[25] 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.[37] In another series of 49 patients from a population-based
cancer registry, the findings were essentially confirmed. 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.[38]

Nephroblastomatosis

Some nephrogenic rests may become hyperplastic which may produce a thick rind of blastemal or tubular
cells that enlarge the kidney. 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 these
hyperplastic nephrogenic rests. If left untreated, they may regress. Differentiation may occur following the
administration of chemotherapy. Current recommendations are for treatment with vincristine and
dactinomycin until nearly complete resolution as determined by imaging. Even with treatment with vincristine
and dactinomycin, about half of children will develop Wilms tumor, within an average of 36 months after
diagnosis. In a series of 52 patients, three patients died of recurrent Wilms tumor.[39] In treated 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 bilaterality and the subsequent Wilms tumors,
renal-sparing surgery is indicated.[39] These patients will be eligible for treatment on AREN0534 with
vincristine and dactinomycin.

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.[40,41] Primary NETK consist of primitive
neuroectodermal tumors characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion
transcripts . Within NETK, focal, atypical histologic features have been seen including clear cell sarcoma,
rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[40,42] (Refer to the PDQ
summary on Ewings Family of Tumors for more information about neuroepithelial tumors.)

Desmoplastic Small Round Cell Tumor of the Kidney

Desmoplastic small round cell tumor of the kidney is a rare, small, round blue tumor of the kidney. It is
diagnosed by its characteristic EWS-WT1 translocation.[43] For more information about desmoplastic small
round cell tumor of the kidney, please refer to the PDQ Childhood Soft Tissue Sarcoma Treatment
summary.

Cystic Partially Differentiated Nephroblastoma

Cystic partially differentiated nephroblastoma is a rare cystic variant of Wilms tumor (1%) with unique
pathologic and clinical characteristics. It is composed entirely of cysts and their thin septa are the only solid
portion of the tumor. The septa contain blastemal cells in any amount with or without embryonal stromal or
epithelial cell type. 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.[5]
Multilocular Cystic Nephroma

Multilocular cystic nephromas (MCN) are benign lesions consisting of cysts lined by renal epithelium. These
lesions can occur bilaterally and a familial pattern has been reported. MCN has been associated with
pleuropulmonary blastomas, so radiographic imaging studies of the chest should be followed in patients with
MCN.[44]

Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma (PRSS) is a subset of embryonal sarcoma of the kidney and is
characterized by the t(x;18)(p11;q11) SYT-SSX translocation. It is similar in histology to the monophasic
spindle cell synovial sarcoma. PRSS contains cystic structures derived from dilated, trapped renal tubules.
PRSS occurs more often in young adults and this type of renal tumor should be treated with different
chemotherapy regimens than traditional Wilms tumor.[45]

References

    1.   Perlman EJ: Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol 8 (3):
         320-38, 2005 May-Jun. [PUBMED Abstract]

    2.   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]

    3.   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]

    4.   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]

    5.   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]

    6.   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]

    7.   Little SE, Bax DA, Rodriguez-Pinilla M, et al.: Multifaceted dysregulation of the epidermal growth
         factor receptor pathway in clear cell sarcoma of the kidney. Clin Cancer Res 13 (15 Pt 1): 4360-4,
         2007. [PUBMED Abstract]

    8.   Seibel NL, Li S, Breslow NE, et al.: Effect of duration of treatment on treatment outcome for
         patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study
         Group. J Clin Oncol 22 (3): 468-73, 2004. [PUBMED Abstract]

    9.   Seibel NL, Sun J, Anderson JR, et al.: Outcome of clear cell sarcoma of the kidney (CCSK) treated
         on the National Wilms Tumor Study-5 (NWTS). [Abstract] J Clin Oncol 24 (Suppl 18): A-9000,
         502s, 2006.

    10. Radulescu VC, Gerrard M, Moertel C, et al.: Treatment of recurrent clear cell sarcoma of the kidney
        with brain metastasis. Pediatr Blood Cancer 50 (2): 246-9, 2008. [PUBMED Abstract]

    11. 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]
12. Tomlinson GE, Breslow NE, Dome J, et al.: Rhabdoid tumor of the kidney in the National Wilms'
    Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 23 (30): 7641-5, 2005. [PUBMED
    Abstract]

13. 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]

14. Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20 (1): E11,
    2006. [PUBMED Abstract]

15. Janson K, Nedzi LA, David O, et al.: Predisposition to atypical teratoid/rhabdoid tumor due to an
    inherited INI1 mutation. Pediatr Blood Cancer 47 (3): 279-84, 2006. [PUBMED Abstract]

16. van den Heuvel-Eibrink MM, Grundy P, Graf N, et al.: Characteristics and survival of 750 children
    diagnosed with a renal tumor in the first seven months of life: A collaborative study by the
    SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 50
    (6): 1130-4, 2008. [PUBMED Abstract]

17. 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]

18. 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]

19. 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.

20. 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]

21. Estrada CR, Suthar AM, Eaton SH, et al.: Renal cell carcinoma: Children's Hospital Boston
    experience. Urology 66 (6): 1296-300, 2005. [PUBMED Abstract]

22. 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]

23. 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]

24. Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J
    Paediatr Child Health 43 (4): 219-29, 2007. [PUBMED Abstract]

25. 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]

26. 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]

27. Park HK, Zhang S, Wong MK, et al.: Clinical presentation of epithelioid angiomyolipoma. Int J Urol
    14 (1): 21-5, 2007. [PUBMED Abstract]

28. Pea M, Bonetti F, Martignoni G, et al.: Apparent renal cell carcinomas in tuberous sclerosis are
    heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22
    (2): 180-7, 1998. [PUBMED Abstract]
29. 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]

30. 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]

31. Medeiros LJ, Palmedo G, Krigman HR, et al.: Oncocytoid renal cell carcinoma after neuroblastoma:
    a report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 23 (7): 772-80, 1999.
    [PUBMED Abstract]

32. Swartz MA, Karth J, Schneider DT, et al.: Renal medullary carcinoma: clinical, pathologic,
    immunohistochemical, and genetic analysis with pathogenetic implications. Urology 60 (6): 1083-9,
    2002. [PUBMED Abstract]

33. 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]

34. Watanabe IC, Billis A, Guimarães MS, et al.: Renal medullary carcinoma: report of seven cases
    from Brazil. Mod Pathol 20 (9): 914-20, 2007. [PUBMED Abstract]

35. Argani P, Antonescu CR, Couturier J, et al.: PRCC-TFE3 renal carcinomas: morphologic,
    immunohistochemical, ultrastructural, and molecular analysis of an entity associated with the
    t(X;1)(p11.2;q21). Am J Surg Pathol 26 (12): 1553-66, 2002. [PUBMED Abstract]

36. Argani P, Laé M, Ballard ET, et al.: Translocation carcinomas of the kidney after chemotherapy in
    childhood. J Clin Oncol 24 (10): 1529-34, 2006. [PUBMED Abstract]

37. 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]

38. 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]

39. 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]

40. 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]

41. 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]

42. Ellison DA, Parham DM, Bridge J, et al.: Immunohistochemistry of primary malignant
    neuroepithelial tumors of the kidney: a potential source of confusion? A study of 30 cases from the
    National Wilms Tumor Study Pathology Center. Hum Pathol 38 (2): 205-11, 2007. [PUBMED Abstract]

43. Wang LL, Perlman EJ, Vujanic GM, et al.: Desmoplastic small round cell tumor of the kidney in
    childhood. Am J Surg Pathol 31 (4): 576-84, 2007. [PUBMED Abstract]

44. Ashley RA, Reinberg YE: Familial multilocular cystic nephroma: a variant of a unique renal
    neoplasm. Urology 70 (1): 179.e9-10, 2007. [PUBMED Abstract]

45. Argani P, Faria PA, Epstein JI, et al.: Primary renal synovial sarcoma: molecular and morphologic
    delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg
    Pathol 24 (8): 1087-96, 2000. [PUBMED Abstract]
  Back to Top


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 (originally developed by the National Wilms Tumor Study Group and still used by the
Children's Oncology group) and incidence by stageare 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 (20% 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 (21% 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 is treated with preoperative chemotherapy and 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). Extension of the primary tumor within vena cava into thoracic vena cava and heart is
      considered stage III, rather than stage IV even though outside the abdomen.

Stage IV (11% of patients)

In stage IV Wilms tumor, hematogenous metastases (lung, liver, bone, brain), 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]

Anaplastic Histology

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]

References

     1.   Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 9
          (5): 877-87, 1991. [PUBMED Abstract]

     2.   Perlman EJ: Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol 8 (3):
          320-38, 2005 May-Jun. [PUBMED Abstract]

     3.   Ritchey ML, Coppes MJ: The management of synchronous bilateral Wilms tumor. Hematol Oncol
          Clin North Am 9 (6): 1303-15, 1995. [PUBMED Abstract]

     4.   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]

  Back to Top
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— 5) are as follows:

    1.   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.

    2.   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.

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

    4.   Single-dose of dactinomycin per course (stages I–II FH, stage I anaplastic), (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]

    5.   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]

    6.   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 except for bilateral tumors. Also, some rare,
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 through a flank approach.[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. Patients who develop renal failure while on therapy can continue
receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be
given at full doses, however, dactinomycin was associated with severe neutropenia. Reductions in dosing
these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed
while the patient is receiving the therapy.[31,32]

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.[33] 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 are at increased risk).[34] 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.)

As mentioned previously, 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. 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 and pediatric oncologist with
experience with these types of renal tumors.[35]

References

    1.   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]

    2.   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]

    3.   Green DM: The treatment of stages I-IV favorable histology Wilms' tumor. J Clin Oncol 22 (8):
         1366-72, 2004. [PUBMED Abstract]

    4.   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]

    5.   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]

    6.   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]

    7.   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]
8.   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]

9.   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]

10. 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]

11. 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]

12. Ritchey ML: Renal sparing surgery for Wilms tumor. J Urol 174 (4 Pt 1): 1172-3, 2005. [PUBMED
     Abstract]

13. 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]

14. 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]

15. Ritchey ML: Primary nephrectomy for Wilms' tumor: approach of the National Wilms' Tumor Study
    Group. Urology 47 (6): 787-91, 1996. [PUBMED Abstract]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. 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]

22. 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]

23. Shamberger RC, Ritchey ML, Haase GM, et al.: Intravascular extension of Wilms tumor. Ann Surg
    234 (1): 116-21, 2001. [PUBMED Abstract]

24. 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]
     25. 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]

     26. 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]

     27. 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]

     28. 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]

     29. 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]

     30. 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]

     31. Feusner JH, Ritchey ML, Norkool PA, et al.: Renal failure does not preclude cure in children
         receiving chemotherapy for Wilms tumor: a report from the National Wilms Tumor Study Group.
         Pediatr Blood Cancer 50 (2): 242-5, 2008. [PUBMED Abstract]

     32. Veal GJ, English MW, Grundy RG, et al.: Pharmacokinetically guided dosing of carboplatin in
         paediatric cancer patients with bilateral nephrectomy. Cancer Chemother Pharmacol 54 (4): 295-
         300, 2004. [PUBMED Abstract]

     33. 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]

     34. 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]

     35. Ahmed HU, Arya M, Levitt G, et al.: Part I: Primary malignant non-Wilms' renal tumours in children.
         Lancet Oncol 8 (8): 730-7, 2007. [PUBMED Abstract]

   Back to Top


Standard Treatment Options for Wilms Tumor
Table 1 describes the standard chemotherapy regimens used to treat Wilms tumor.


Table 1. Standard Chemotherapy Regimens for
Wilms Tumor                                                                       Regimen Description
                                                         Enlarge
                          Regimen Name

Regimen EE4A [1]                                                   vincristine, dactinomycin x 18 weeks post-
                                                                   nephrectomy

Regimen DD4A [1]                                                   vincristine, dactinomycin, doxorubicin x 24 weeks
                                                                   post nephrectomy

Regimen I [2]                                                      vincristine, doxorubicin, cyclophosphamide,
Table 1. Standard Chemotherapy Regimens for
Wilms Tumor                                                                             Regimen Description
                                                              Enlarge
                               Regimen Name

                                                                         etoposide x 24 weeks




Table 2 provides an overview of the standard treatment based on published results for all stages of Wilms
tumor as well as survival information.


Table 2. Overview
of Wilms Tumor
                                                 RFS
Standard Treatment                   Histology    or    OS
                                                                    Treatment (see Table 1 for chemotherapy regimen
                                                                                      definitions)
                                                 EFS
by Stage
                          Enlarge
                  Stage

Stage I [1-3]                       FH           92%   98%     Nephrectomy + lymph node sampling followed by regimen
                                                 RFS           EE4A

                                    FA or DA     69%   83%     Nephrectomy + lymph node sampling followed by regimen
                                                 EFS           EE4A and XRT

Stage II [1,2,4]                    FH           85%   96%     Nephrectomy + lymph node sampling followed by regimen
                                                 RFS           EE4A

                                    FA (very     80%   80%     Nephrectomy + lymph node sampling followed by abdominal
                                    small        EFS           XRT and regimen DD4A
                                    numbers)

                                    DA           83%   82%     Nephrectomy + lymph node sampling followed by abdominal
                                                 EFS           XRT and regimen I

Stage III [1,2]                     FH           90%   95%     Nephrectomy + lymph node sampling followed by abdominal
                                                 RFS           XRT and regimen DD4A

                                    FA           88%   100%    Nephrectomy + lymph node sampling followed by abdominal
                                                 RFS           XRT and regimen DD4A

                                    FA           71%   71%     Preoperative treatment with regimen DD4A followed by
                                                 RFS           nephrectomy + lymph node sampling and abdominal XRT

                                    DA           46%   53%     Preoperative treatment with regimen I followed by nephrectomy
                                                 EFS           + lymph node sampling and abdominal XRT

                                    DA           65%   67%     Immediate nephrectomy + lymph node sampling followed by
                                                 EFS           abdominal XRT and regimen I

Stage IV [1,2,4]                    FH           80%   90%     Nephrectomy + lymph node sampling, followed by abdominal
                                                 RFS           XRT,a bilateral pulmonary XRT,b and regimen DD4A

                                    FA           61%   72%     Nephrectomy + lymph node sampling, followed by abdominal
                                                 EFS           XRT, a bilateral pulmonary XRT,b and regimen DD4A

                                    DA           33%   33%     Immediate nephrectomy + lymph node sampling followed by
                                                 EFS           abdominal XRT,a whole-lung XRT,a and regimen I

                                    DA           31%   44%     Preoperative treatment with regimen I followed by nephrectomy
                                                 EFS           + lymph node sampling, followed by abdominal XRT,a and
                                                               whole-lung XRTb

Stage V [1,5-13]                    FH           65%   78%     Bilateral renal biopsies and staging of each kidney followed by
                                                       (10     preoperative treatment with regimen EE4A (if disease in both
                                                       year    kidneys ≤ stage II) or regimen DD4A (if disease in both kidneys
                                                       OS)     > stage II), followed by second look surgery and possibly more
                                                               chemotherapy and/ or XRT
Table 2. Overview
of Wilms Tumor
                                                        RFS
Standard Treatment                      Histology        or        OS
                                                                                 Treatment (see Table 1 for chemotherapy regimen
                                                                                                   definitions)
                                                        EFS
by Stage
                         Enlarge
              Stage

                                       AH              44%       55%        Bilateral renal biopsies and staging of each kidney followed by
                                                                            preoperative treatment with regimen I, followed by second look
                                                                            surgery and possibly more chemotherapy and/ or XRT

AH = anaplastic histology; DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall
survival; RFS = relapse-free survival; XRT = flank radiation therapy
a
Abdominal XRT is planned according to local stage of renal tumor.
b
Pulmonary XRT is reserved for patients with chest x-ray evidence of pulmonary metastases.


Additional Treatment Considerations
Stage I Wilms tumor

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 addressing this question in a large study. In the National
Wilms Tumor Study-5 (NWTS-5 trial), for children older than 2 years at diagnosis with stage I FH Wilms
tumors that weigh more than 550 g, results suggested the costs of the therapy may outweigh the
benefits.[14] In NWTS-5 these patients did not receive any postoperative chemotherapy or radiation. The
study was designed conservatively based on the assumption that only 50% of the patients with recurrence
could be successfully salvaged. The 3-year interim analysis showed a 2-year event–free survival (EFS) of
86.5% which indicated,according to the statistical design,that there was 95% probability that “no treatment”
had failed. This part of the study was closed to further accrual and children with recent nephrectomy were
advised to receive treatment as per regimen EE4A (see Table 1). Of the 75 children treated with
nephrectomy only prior to closure of the protocol, 11 patients relapsed or developed metachronous disease
in the contralateral kidney 0.3 to 2.3 years after diagnosis (median: 4 months, mean: 0.64 years). The sites
of relapse were lung (five patients) and operative bed (three patients). Three patients developed disease in
the contralateral kidney. The OS of these 11 relapsed patients is 91%. The salvage rate in this cohort of
patients from NWTS-5 was much higher (91%) than the postulated rate of 50%, a finding that supports a
less conservative approach.[14]

Stage IV Wilms tumor

For patients with stage IV (FH) Wilms tumor, the role of pulmonary irradiation has been examined
retrospectively (based on chest x-ray results) and is being examined prospectively (based on computerized
tomography (CT) scan results) to identify clinical and radiological features in patients that suggest that
radiation can be omitted in certain subsets. Investigators in the United Kingdom reviewed outcomes in
children with stage IV Wilms tumor with pulmonary metastases at diagnosis and the factors that contributed
to the decision to withhold pulmonary radiation. Patients who underwent pulmonary irradiation had a 9 year
EFS of 79% versus 53% in patients who did not, although there was no difference in OS. Pulmonary
radiation decreased the chance of lung relapse (8% vs 23%). No consistent features could be identified to
aid in the selection of patients who could safely avoid pulmonary irradiation.[15]

Stage V Wilms tumor

The treatment of children with bilateral Wilms tumor must be individualized. The goals of therapy are to
eradicate all tumor and to preserve as much normal renal tissue as possible with the hope of decreasing the
risk of chronic renal failure among these children.[5,6] Studies demonstrate no difference in survival for
children who undergo initial bilateral biopsy followed by chemotherapy and then surgical resection compared
with patients who have initial resection followed by chemotherapy. Initially, patients should undergo bilateral
renal biopsies with staging of each kidney. Primary tumor excision should not be attempted, but patients
should be given preoperative chemotherapy. Initial treatment is with regimen EE-4A (see Table 1) if the
renal tumors are of FH and not more extensive than stage II. Those with higher stage and FH disease
should receive regimen DD-4A (see Table 1), and those with AH should receive regimen I (see Table 1).
Following 6 weeks of chemotherapy, the patient should be reassessed. If serial imaging studies show no
further reduction in tumor, a second-look surgical procedure should be performed (partial nephrectomy or
wedge excision) if negative margins can be obtained; otherwise, sequential biopsies should be done to
establish the reason for failure to respond. This approach will identify patients with anaplasia or
differentiation, select them for early surgery, and define the intensity of chemotherapy to be
administered.[7,8] Chemotherapy and/or radiation therapy following the second-look operation is dependent
on the response to initial therapy, with more aggressive therapy required for patients with inadequate
response to initial therapy observed at the second procedure.[7,9-13]

Renal transplantation for children with Wilms tumor is usually delayed until 1 to 2 years have passed without
evidence of malignancy.[16] Similarly, renal transplantation for children with Denys-Drash syndrome and
Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of
treatment for the tumor.[16]

Approximately 10% of patients with bilateral tumors have AH and may benefit from more aggressive
chemotherapy and radiation therapy, and an aggressive surgical approach at the second-look operation.[2]

Inoperable Wilms Tumors

Patients who have tumors with caval extension above the hepatic veins or that are so massive that their
surgeons consider the risk of initial surgical removal too great should be biopsied and treated with
preoperative chemotherapy.[12,17] If surgery is performed on a patient with caval or atrial extension, care
should be taken to ensure that appropriate resources are available for pediatric cardiopulmonary
bypass.[18,19] On the NWTS-5, these patients were treated after biopsy by initial chemotherapy with
vincristine and dactinomycin with or without doxorubicin. If no reduction in tumor size occurred after using
three drugs, then radiation therapy was used.[20] Surgery was performed as soon as sufficient tumor
shrinkage had occurred, generally at week 6 of therapy. If resection of the tumor could not occur at that time,
the patient had a second-look procedure to confirm a persistent tumor. Failure of the tumor to shrink could
be a result of a predominance of skeletal or benign elements. Patients were subsequently treated as for
stage III tumors, which includes postoperative radiation therapy.[21] Because of the 5% to 10% error rate in
preoperative diagnosis of renal masses after radiographic assessment, confirmation of the diagnosis by
biopsy (which may be performed percutaneously) should be obtained prior to chemotherapy.[12]

References

    1.   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]

    2.   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]

    3.   Green DM, Beckwith JB, Breslow NE, et al.: Treatment of children with stages II to IV anaplastic
         Wilms' tumor: a report from the National Wilms' Tumor Study Group. J Clin Oncol 12 (10): 2126-31,
         1994. [PUBMED Abstract]

    4.   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]

    5.   Montgomery BT, Kelalis PP, Blute ML, et al.: Extended followup of bilateral Wilms tumor: results of
         the National Wilms Tumor Study. J Urol 146 (2 ( Pt 2)): 514-8, 1991. [PUBMED Abstract]

    6.   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]
   7.   Fuchs J, Wünsch L, Flemming P, et al.: Nephron-sparing surgery in synchronous bilateral Wilms'
        tumors. J Pediatr Surg 34 (10): 1505-9, 1999. [PUBMED Abstract]

   8.   Shamberger RC, Haase GM, Argani P, et al.: Bilateral Wilms' tumors with progressive or
        nonresponsive disease. J Pediatr Surg 41 (4): 652-7; discussion 652-7, 2006. [PUBMED Abstract]

   9.   Ritchey ML, Green DM, Thomas PR, et al.: Renal failure in Wilms' tumor patients: a report from the
        National Wilms' Tumor Study Group. Med Pediatr Oncol 26 (2): 75-80, 1996. [PUBMED Abstract]

   10. Horwitz JR, Ritchey ML, Moksness J, et al.: Renal salvage procedures in patients with synchronous
       bilateral Wilms' tumors: a report from the National Wilms' Tumor Study Group. J Pediatr Surg 31
       (8): 1020-5, 1996. [PUBMED Abstract]

   11. Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee. J Clin Oncol 9
       (5): 877-87, 1991. [PUBMED Abstract]

   12. Ritchey ML: The role of preoperative chemotherapy for Wilms' tumor: the NWTSG perspective.
       National Wilms' Tumor Study Group. Semin Urol Oncol 17 (1): 21-7, 1999. [PUBMED Abstract]

   13. Zuppan CW, Beckwith JB, Weeks DA, et al.: The effect of preoperative therapy on the histologic
       features of Wilms' tumor. An analysis of cases from the Third National Wilms' Tumor Study. Cancer
       68 (2): 385-94, 1991. [PUBMED Abstract]

   14. 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]

   15. Nicolin G, Taylor R, Baughan C, et al.: Outcome after pulmonary radiotherapy in Wilms' tumor
       patients with pulmonary metastases at diagnosis: a UK Children's Cancer Study Group, Wilms'
       Tumour Working Group Study. Int J Radiat Oncol Biol Phys 70 (1): 175-80, 2008. [PUBMED Abstract]

   16. Kist-van Holthe JE, Ho PL, Stablein D, et al.: Outcome of renal transplantation for Wilms' tumor and
       Denys-Drash syndrome: a report of the North American Pediatric Renal Transplant Cooperative
       Study. Pediatr Transplant 9 (3): 305-10, 2005. [PUBMED Abstract]

   17. Shamberger RC, Ritchey ML, Haase GM, et al.: Intravascular extension of Wilms tumor. Ann Surg
       234 (1): 116-21, 2001. [PUBMED Abstract]

   18. 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]

   19. Ritchey ML, Kelalis PP, Haase GM, et al.: Preoperative therapy for intracaval and atrial extension
       of Wilms tumor. Cancer 71 (12): 4104-10, 1993. [PUBMED Abstract]

   20. Green DM, Breslow NE, Evans I, et al.: The effect of chemotherapy dose intensity on the
       hematological toxicity of the treatment for Wilms' tumor. A report from the National Wilms' Tumor
       Study. Am J Pediatr Hematol Oncol 16 (3): 207-12, 1994. [PUBMED Abstract]

   21. 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]

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Treatment Options Under Clinical Evaluation for Wilms Tumor
Stage I

The following treatment options are currently under investigation in Children's Oncology Group (COG)
clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Favorable Histology

        COG-AREN0532: 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 regimen DD-4A (dactinomycin, doxorubicin, and
      vincristine for 24 weeks). Patients who are younger than 2 years and have Wilms tumors that weigh
      less than 550 g and who have a negative microscopic evaluation of lymph nodes are eligible for
      observation only. Other stage I patients will be treated with the standard therapy regimen EE-4A
      (dactinomycin and vincristine for 18 weeks) postnephrectomy.

Anaplastic (Focal or Diffuse) Histology

       COG-AREN0321: In this study patients with stage I will be treated with standard regimen DD-4A
      and radiation therapy.

Stage II

The following treatment options are currently under investigation in COG clinical trials. Information about
ongoing clinical trials is available from the NCI Web site.

Favorable Histology

        COG-AREN0532: In this study, all tumors will be stratified based on central pathology review and
      molecular analysis (LOH at chromosomes 1p and 16q). Patients with LOH at 1p and 16q will be
      upstaged to receive treatment with regimen DD-4A . Stage II patients without LOH will be treated with
      standard therapy regimen EE-4A postnephrectomy.

Focal Anaplastic

         Patients with stage II will be treated with standard regimen DD-4A and radiation therapy.

Diffuse Anaplastic

        COG-AREN0321: In this study, patients will be treated with the UH-1 regimen (cyclophosphamide,
      carboplatin, and etoposide alternating with vincristine, doxorubicin, and cyclophosphamide for 30
      weeks) and radiation therapy.

Stage III

The following treatment options are currently under investigation in COG clinical trials. Information about
ongoing clinical trials is available from the NCI Web site.

Favorable Histology

        COG-AREN0532: Patients in this study will be treated with standard therapy regimen DD-4A and
      radiation therapy. Patients who have loss of heterozygosity at chromosomes 1p and 16q will be
      moved to AREN0533 with regimen M (consisting of vincristine, dactinomycin, and doxorubicin
      alternating with cyclophosphamide and etoposide) for a total of 24 weeks and radiation therapy.
Focal Anaplastic

       COG-AREN0321: In this trial, patients with stage III will be treated with standard regimen DD-4A
      and radiation therapy.

Diffuse Anaplastic

        COG-AREN0321: In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Stage IV

The following treatment options are currently under investigation in COG clinical trials. Information about
ongoing clinical trials is available from the NCI Web site.

Favorable Histology

        COG-AREN0533: In this trial, patients with pulmonary metastases only (detected by chest
      computerized tomography [CT] scans) will start treatment with standard chemotherapy regimen DD-
      4A and undergo abdominal irradiation if local stage III. Pulmonary metastases will be re-evaluated at 6
      weeks with chest CT scan. Patients with complete resolution of pulmonary metastases will be
      considered rapid complete responders and will continue therapy with regimen DD-4A without any
      pulmonary radiation therapy. Patients who do not have a complete response (slow incomplete
      responders) will be switched to regimen M ( for a total of 24 weeks) and undergo radiation therapy to
      their lungs. It is recommended that biopsies on residual pulmonary lesions be performed before
      radiation therapy is delivered.

      Patients with an LOH at chromosomes 1p and 16q will be treated with regimen M with radiation
      therapy to all sites of disease. Patients with metastases outside or in addition to lung metastases will
      be treated with regimen M and radiation therapy.

Focal Anaplastic

        COG-AREN0321: In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Diffuse Anaplastic (No Measurable Disease)

        COG-AREN0321: In this trial, patients will be treated with the UH-1 regimen and radiation therapy.

Diffuse Anaplastic (Measurable Disease)

        COG-AREN0321: In this trial, patients will be treated with window therapy consisting of vincristine
      and irinotecan for 12 weeks. If they respond to the window therapy, they will receive therapy
      consisting of UH-2 (cyclophosphamide, carboplatin, and etoposide; vincristine, doxorubicin, and
      cyclophosphamide; vincristine, irinotecan, and radiation therapy) for 30 weeks. Patients not
      responding to the window therapy would then be treated on UH-1 and radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with stage I Wilms tumor, stage II Wilms tumor, stage III Wilms tumor, stage IV Wilms tumor and recurrent
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.
  Back to Top


Clear Cell Sarcoma of the Kidney
Because of the relative rarity of this tumor, all patients with clear cell sarcoma of the kidney (CCSK) 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 renal tumors is required to determine and implement optimum treatment.

For CCSK, 5-year event-free survival (EFS) and overall survival (OS) for stage I is 100%; stage II is
87% and 97% respectively; stage III is 74% and 87% respectively; and stage IV is 36% and 45%
respectively (regimen I [see description below]).[1]

Standard Treatment Options

The approach for treating CCSK is different from Wilms tumor since the OS of children with CCSK remains
considerably lower than for patients with favorable histology Wilms tumor. In the National Wilms Tumor
Study-3 (NWTS-3), the addition of doxorubicin to the combination of vincristine, dactinomycin, and radiation
therapy resulted in an improvement in disease-free survival for patients with CCSK.[2] NWTS-4 showed that
patients treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free
survival compared with patients treated for 6 months (88% vs. 61% at 8 years).[3] In the NWTS-5 study,
children with stages I to IV CCSK were treated with a new chemotherapeutic regimen combining vincristine,
doxorubicin, cyclophosphamide, and etoposide in an attempt to further improve the survival of these high-
risk groups. All patients received radiation therapy to the tumor bed. With this treatment, the 5-year EFS was
approximately 89%, and OS was approximately 79%. Stage I patients had 100% 5-year EFS and OS. Stage
II patients had a 5-year EFS of approximately 87% and OS of approximately 97%. Stage III patients had an
approximately 74% 5-year EFS and an approximately 87% 5-year OS. Stage IV patients had a 5-year EFS
of approximately 36% and 5-year OS of 45%. CCSK has been characterized by late relapses; however, in
NWTS-5, most relapses occurred within 3 years. In NWTS-5, the most common site of recurrence was the
brain.[1]

        Regimen DD-4A (vincristine, dactinomycin, and doxorubicin) for 15 months and radiation
      therapy.[3]

        Regimen I (vincristine, doxorubicin, cyclophosphamide, and etoposide) and radiation therapy.[1]

Treatment Options Under Clinical Evaluation

The following treatment option is currently under investigation in a Children's Oncology Group clinical trial.
Information about ongoing clinical trials is available from the NCI Web site.

        COG-AREN0321: In this trial, the role of radiation therapy is being evaluated in stage I disease.
      Patients who have undergone lymph node dissection will be treated only with regimen I . Patients with
      stage II and III will be treated with regimen I and radiation therapy. Stage IV patients will be treated
      with UH-1 radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with clear cell sarcoma of the kidney. 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
     1.   Seibel NL, Sun J, Anderson JR, et al.: Outcome of clear cell sarcoma of the kidney (CCSK) treated
          on the National Wilms Tumor Study-5 (NWTS). [Abstract] J Clin Oncol 24 (Suppl 18): A-9000,
          502s, 2006.

     2.   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]

     3.   Seibel NL, Li S, Breslow NE, et al.: Effect of duration of treatment on treatment outcome for
          patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study
          Group. J Clin Oncol 22 (3): 468-73, 2004. [PUBMED Abstract]

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Rhabdoid Tumor of the Kidney
Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney 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 renal tumors is required to determine and implement optimum treatment.

Patients with rhabdoid tumor of the kidney continue to have a poor prognosis with 4-year overall survival
(OS) for stage I patients of 33%, stage II of 47%, stage III of 22%, and stage IV of 8%.[1]

Standard Treatment Options

        No satisfactory treatment has been developed for these children. The National Wilms Tumor Study-
      5 (NWTS-5) closed the treatment arm for rhabdoid tumor with cyclophosphamide, etoposide, and
      carboplatin because of poor outcome. Combinations of etoposide and cisplatin; etoposide and
      ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used (COG-
      Q9401).[2,3] In a review of 142 patients from NWTS 1-5, stage and age are significant prognostic
      factors. Patients with stage I and stage II disease had an OS rate of 42%; higher stage was
      associated with a 16% OS. Infants younger than 6 months at diagnosis demonstrated a 4-year OS of
      9%, whereas OS in patients aged 2 years and older was 41%. All except one patient with a CNS
      lesion died.[1]

Treatment Options Under Clinical Evaluation

The following treatment option is currently under investigation in a Children's Oncology Group (COG) clinical
trial. Information about ongoing clinical trials is available from the NCI Web site.

        COG-AREN0321: In this trial, patients with stages I, II, III, and IV (without measurable disease) will
      be treated with UH-1, which consists of cyclophosphamide, carboplatin, and etoposide alternating with
      vincristine, doxorubicin, and cyclophosphamide for 30 weeks, and radiation therapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with rhabdoid tumor of the kidney. 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
    1.   Tomlinson GE, Breslow NE, Dome J, et al.: Rhabdoid tumor of the kidney in the National Wilms'
         Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol 23 (30): 7641-5, 2005. [PUBMED
         Abstract]

    2.   Waldron PE, Rodgers BM, Kelly MD, et al.: Successful treatment of a patient with stage IV
         rhabdoid tumor of the kidney: case report and review. J Pediatr Hematol Oncol 21 (1): 53-7, 1999
         Jan-Feb. [PUBMED Abstract]

    3.   Wagner L, Hill DA, Fuller C, et al.: Treatment of metastatic rhabdoid tumor of the kidney. J Pediatr
         Hematol Oncol 24 (5): 385-8, 2002 Jun-Jul. [PUBMED Abstract]

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Neuroepithelial Tumor of the Kidney
Optimal treatment has not been established for these tumors. Treatment according to Ewings/ PNET
protocols should be considered.[1]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with peripheral primitive neuroectodermal tumor of the kidney. 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

    1.   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]

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Mesoblastic Nephroma
When diagnosed in the first 7 months of life, the 5 year event-free survival and overall survival rates are 94%
and 96%, respectively.[1]

A prospective clinical trial that enrolled 50 patients confirmed that complete surgical resection, which
includes the entire capsule, is adequate therapy for most patients with mesoblastic nephroma.[2] In this
study, only 2 of 50 patients died. Patients were at increased risk for local and eventually metastatic
recurrence if there was stage III (incomplete resection and/or histologically positive resection margin),
cellular subtype, and aged 3 months or older at diagnosis. Because of the small numbers of patients and the
overlapping incidence of these characteristics (5 of 50 patients), the significance of the individual
characteristics could not be discriminated. Adjuvant chemotherapy has been recommended for patients who
share these three characteristics, though the benefit of adjuvant therapy will remain unproven with such a
low incidence of disease.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with congenital mesoblastic nephroma. 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

    1.   van den Heuvel-Eibrink MM, Grundy P, Graf N, et al.: Characteristics and survival of 750 children
         diagnosed with a renal tumor in the first seven months of life: A collaborative study by the
         SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups. Pediatr Blood Cancer 50
         (6): 1130-4, 2008. [PUBMED Abstract]

    2.   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]

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Renal Cell Carcinoma


Standard Treatment Options

Survival is affected by stage of disease at presentation and the completeness of resection at radical
nephrectomy. Overall survival rates range from 64 – 87%. The 5 year survival for stage I is 90% or higher,
stages IIIII is 50% to 80%, and stage IV is 9%,which is similar to the stage-for-stage survival in renal cell
carcinoma (RCC) in adults. Retrospective analyses and the small number of patients involved place
limitations on the level of evidence in the area of treatment. The primary treatment for RCC includes total
surgical removal of the kidney and associated lymph nodes.[1] In two small series, patients who had partial
nephrectomies seem to have outcomes equivalent to those who have radical nephrectomies. Partial
nephrectomy may be considered in carefully selected patients with low–volume localized disease.[2,3] There
is no evidence that adjuvant therapy is beneficial in children with lymph-node positive, nonmetastatic
disease.[1] Treatment of unresectable metastatic disease is presently unsatisfactory, similar to adult RCC; it
is poorly responsive to radiation and there is no effective chemotherapy regimen. Immunotherapy, such as
interferon-alpha and interleukin-2, may have some effect on cancer control.[4] Rare spontaneous regression
of pulmonary metastasis may occur with resection of the primary tumor. (Refer to the PDQ summary on
adult Renal Cell Cancer Treatment for more information.)

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with childhood renal cell carcinoma. 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

    1.   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]

    2.   Cook A, Lorenzo AJ, Salle JL, et al.: Pediatric renal cell carcinoma: single institution 25-year case
         series and initial experience with partial nephrectomy. J Urol 175 (4): 1456-60; discussion 1460,
         2006. [PUBMED Abstract]

    3.   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]
    4.   Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal
         cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13 (3): 688-
         96, 1995. [PUBMED Abstract]

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Recurrent Wilms Tumor and Other Childhood Kidney Tumors
Children with relapsed favorable-histology Wilms tumor have a variable prognosis, depending on the site of
relapse, the time from initial diagnosis to relapse, and their previous therapy. Favorable prognostic factors
include no prior treatment with doxorubicin, relapse more than 12 months after diagnosis, and intra-
abdominal relapse in a patient not previously treated with abdominal radiation.[1-3]

Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy
with vincristine and dactinomycin who relapse can be successfully retreated. Fifty–eight patients were
treated on the National Wilms Tumor Study-5 (NWTS-5) relapse protocol with surgical excision when
feasible, radiation therapy and alternating courses of vincristine, doxorubicin and cyclophosphamide and
etoposide and cyclophosphamide. Four–year event-free survival (EFS) after relapse was 71% and overall
survival (OS) was 82%. For those patients who relapsed only to their lungs the 4–year EFS after relapse
was 68% and OS was 81%.[4] Approximately 50% of unilateral Wilms tumor patients who relapse or
progress after initial treatment with vincristine, dactinomycin and doxorubicin and radiation can be
successfully retreated. Sixty patients were treated on the NWTS-5 relapse protocol with alternating courses
of cyclophosphamide/etoposide and carboplatin/etoposide, surgery and radiation therapy. EFS (4–year) and
OS were 42% and 48%, respectively, and 49% and 53% for patients who relapsed in the lungs only.[5]

Patients with stages II–IV anaplastic-histology tumors at diagnosis have a very poor prognosis upon
recurrence.[6] The combination of ifosfamide, etoposide, and carboplatin has demonstrated activity in this
group of patients, but significant hematologic toxic effects have been observed.[7,8] While high-dose
chemotherapy followed by autologous hematopoietic stem cell transplant has been utilized,[9-11] an
intergroup study of the former Pediatric Oncology Group and the former Children’s Cancer Group used a
salvage induction regimen of cyclophosphamide and etoposide (CE) alternating with carboplatin and
etoposide (PE) followed by delayed surgery. Disease-free patients were assigned to maintenance
chemotherapy with five cycles of alternating CE and PE, and the remainder of patients to ablative therapy
and autologous marrow transplant. All patients received local radiation therapy. The 3-year survival was
52% for all eligible patients, while the 3-year survival was 64% and 42% for the chemotherapy consolidation
and autologous marrow transplant subgroups, respectively.[3] The outcome of hematopoietic stem cell
rescue in selected patients may be superior, [11] however, patients with gross residual disease going into
transplant do not do as well.[9] Patients in whom such salvage attempts fail should be offered treatment on
available phase I or phase II studies.

Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy.
Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear
cell sarcoma of the kidney (CCSK) involving the brain have responded to treatment with ifosfamide,
carboplatin and etoposide (ICE) coupled with local control consisting of either surgical resection and /or
radiation.[12] Patients with recurrent rhabdoid tumor of the kidney, CCSK, neuroepithelial tumor of the
kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II
clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients
with recurrent 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
    1.   Grundy P, Breslow N, Green DM, et al.: Prognostic factors for children with recurrent Wilms' tumor:
         results from the Second and Third National Wilms' Tumor Study. J Clin Oncol 7 (5): 638-47, 1989.
         [PUBMED Abstract]

    2.   Malogolowkin M, Bergman T, Seibel N, et al.: Outcome and prognostic factors (PF) for patients with
         recurrent Wilms tumor (R-WT) National Wilms Tumor Study 3 and 4 (NWTS 3,4). [Abstract]
         Proceedings of the American Society of Clinical Oncology 20: A-3136, 2001.

    3.   Tannous R, Giller R, Holmes E, et al.: Intensive therapy for high risk (HR) relapsed Wilms' tumor
         (WT): a CCG-4921/POG-9445 study report. [Abstract] Proceedings of the American Society of
         Clinical Oncology 19: A2315, 2000.

    4.   Green DM, Cotton CA, Malogolowkin M, et al.: Treatment of Wilms tumor relapsing after initial
         treatment with vincristine and actinomycin D: a report from the National Wilms Tumor Study Group.
         Pediatr Blood Cancer 48 (5): 493-9, 2007. [PUBMED Abstract]

    5.   Malogolowkin M, Cotton CA, Green DM, et al.: Treatment of Wilms tumor relapsing after initial
         treatment with vincristine, actinomycin D, and doxorubicin. A report from the National Wilms Tumor
         Study Group. Pediatr Blood Cancer 50 (2): 236-41, 2008. [PUBMED Abstract]

    6.   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]

    7.   Abu-Ghosh AM, Krailo MD, Goldman SC, et al.: Ifosfamide, carboplatin and etoposide in children
         with poor-risk relapsed Wilms' tumor: a Children's Cancer Group report. Ann Oncol 13 (3): 460-9,
         2002. [PUBMED Abstract]

    8.   Kung FH, Bernstein ML, Camitta BM, et al.: Ifosfamide/carboplatin/etoposide (ICE) in the treatment
         of advanced, recurrent Wilms tumor. [Abstract] Proceedings of the American Society of Clinical
         Oncology 18: A-2156, 559a, 1999.

    9.   Garaventa A, Hartmann O, Bernard JL, et al.: Autologous bone marrow transplantation for pediatric
         Wilms' tumor: the experience of the European Bone Marrow Transplantation Solid Tumor Registry.
         Med Pediatr Oncol 22 (1): 11-4, 1994. [PUBMED Abstract]

    10. Pein F, Michon J, Valteau-Couanet D, et al.: High-dose melphalan, etoposide, and carboplatin
        followed by autologous stem-cell rescue in pediatric high-risk recurrent Wilms' tumor: a French
        Society of Pediatric Oncology study. J Clin Oncol 16 (10): 3295-301, 1998. [PUBMED Abstract]

    11. Campbell AD, Cohn SL, Reynolds M, et al.: Treatment of relapsed Wilms' tumor with high-dose
        therapy and autologous hematopoietic stem-cell rescue: the experience at Children's Memorial
        Hospital. J Clin Oncol 22 (14): 2885-90, 2004. [PUBMED Abstract]

    12. Radulescu VC, Gerrard M, Moertel C, et al.: Treatment of recurrent clear cell sarcoma of the kidney
        with brain metastasis. Pediatr Blood Cancer 50 (2): 246-9, 2008. [PUBMED Abstract]

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Get More Information From NCI
Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information
Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m.
Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a
trained Cancer Information Specialist is available to answer your questions.

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The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an
Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through
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questions about cancer.

Write to us

For more information from the NCI, please write to this address:

         NCI Public Inquiries Office
         Suite 3036A
         6116 Executive Boulevard, MSC8322
         Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and
organizations that offer support and resources for cancer patients and their families. For a quick search, use
our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most
closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services.
Hospitals in your area may have information about local and regional agencies that have information on
finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer
treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These
publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials.
Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics,
and NCI research activities. NCI materials on these and other topics may be ordered online or printed
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Changes to This Summary (10/02/2008)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes
available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

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More Information
About PDQ

        PDQ® - NCI's Comprehensive Cancer Database.

         Full description of the NCI PDQ database.
Additional PDQ Summaries

        PDQ® Cancer Information Summaries: Adult Treatment

         Treatment options for adult cancers.

        PDQ® Cancer Information Summaries: Pediatric Treatment

         Treatment options for childhood cancers.

        PDQ® Cancer Information Summaries: Supportive and Palliative Care

         Side effects of cancer treatment, management of cancer-related complications and pain, and
         psychosocial concerns.

        PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

         Tests or procedures that detect specific types of cancer.

        PDQ® Cancer Information Summaries: Prevention

         Risk factors and methods to increase chances of preventing specific types of cancer.

        PDQ® Cancer Information Summaries: Genetics

         Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social
         concerns.

        PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

         Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have
questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-
CANCER (1-800-422-6237).

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