Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®) 2/2 —Health Professional Version - National Cancer Institute

Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)—Health Professional Version - National Cancer Institute

Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version

Renal Cell Carcinoma (RCC)

In This Section

• Incidence of RCC
• Conditions Associated With RCC
• Genetic Testing for Children and Adolescents With RCC
• Genomics of RCC
• Histology of RCC
• Prognosis and Prognostic Factors for RCC
• Clinical Features and Diagnostic Evaluation of RCC
• Treatment of RCC
  • Radical nephrectomy with lymph node dissection
  • Renal-sparing surgery with lymph node dissection
  • Other approaches
• Treatment Options Under Clinical Evaluation for RCC
• Current Clinical Trials

Incidence of RCC

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 clear cell sarcoma of the kidney or rhabdoid tumors of the kidney. The annual incidence rate is approximately 4 cases per 1 million children, compared with an incidence of Wilms tumor of the kidney that is at least 29-fold higher.[1]

RCC, the most common primary malignancy of the kidney in adults, is rare 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.[2] Children and adolescents with RCC (n = 515) present with more advanced disease than do those aged 21 to 30 years.[1]

Conditions Associated With RCC

Conditions associated with RCC include the following:

• von Hippel-Lindau (VHL) disease. VHL disease is an autosomal dominant condition in which blood vessels in the retina and cerebellum grow excessively.[3] The gene for VHL disease is located on chromosome 3p26 and is a tumor-suppressor gene, which is either mutated or deleted in patients with the syndrome.
  Screening for the VHL gene is available.[4] To detect clear cell renal carcinoma in these individuals when the lesions are smaller than 3 cm and renal-sparing surgery can be performed, annual screening with abdominal ultrasound or magnetic resonance imaging (MRI) is recommended, beginning at age 8 to 11 years.[5]
  (Refer to the Von Hippel-Lindau Syndrome section in the PDQ summary on Genetics of Kidney Cancer (Renal Cell Cancer) for more information.)
• Tuberous sclerosis. 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.[6,7]
• Familial RCC. Familial RCC has been associated with an inherited chromosome translocation involving chromosome 3.[8] A high incidence of chromosome 3 abnormalities has also been demonstrated in nonfamilial renal tumors.
  Succinate dehydrogenase (SDHB, SDHC, and SDHD) is a Krebs cycle enzyme gene that has been associated with the development of familial RCC occurring with pheochromocytoma/paraganglioma. Germline mutations in a subunit of the gene have been reported in individuals with renal cancer and no history of pheochromocytoma.[9,10]
• Renal medullary carcinoma. A rare subtype of RCC, renal medullary carcinoma may be associated with sickle cell hemoglobinopathy.[11] 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.[12,13][ Level of evidence: 3iiA] Survival is poor and ranges from 2 weeks to 15 months, with a mean survival of 4 months.[11,13-16]
• Hereditary leiomyomatosis. Hereditary leiomyomatosis (of skin and uterus) and RCC is a distinct phenotype caused by dominant inheritance of a mutation in the FH gene. Screening for RCC starting as early as age 5 years has been recommended.[17,18]
• Previous treatment for childhood cancer. Survivors of childhood cancer who were treated with radiation and/or chemotherapy are at more risk of developing renal cancers than are the general population. Highest risk has been observed among neuroblastoma survivors, with renal-directed radiation therapy of 5 Gy or more, and with platinum-based chemotherapy.[19] Renal cancers have also been reported after treatment for rhabdomyosarcoma, leiomyosarcoma, acute lymphoblastic leukemia, primitive neuroectodermal tumors (PNET), and Wilms tumor.[20-25] (Refer to the Subsequent Neoplasms section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Genetic Testing for Children and Adolescents With RCC

Indications for germline genetic testing of children and adolescents with RCC to check for a related syndrome are described in Table 7.

Table 7. Indications for Germline Genetic Analysis (Screening) of Children and Adolescents with Renal Cell Carcinoma (RCC)a

ENLARGE

Indication for Testing	Tumor Histology	Gene Test	Related Syndrome
VHL = von Hippel-Lindau.
aAdapted from Linehan et al.[26]
Multifocal RCC or VHL lesions	Clear cell	VHL gene	von Hippel-Lindau syndrome
Family history of clear cell RCC or multifocal RCC with absent VHL mutation	Clear cell	Chromosome 3 gene translocations	Hereditary non-VHL clear cell RCC syndrome
Multifocal papillary RCC or family history of papillary RCC	Papillary	MET gene	Hereditary papillary RCC syndrome
Multifocal RCC or cutaneous fibrofolliculoma or pulmonary cysts or spontaneous pneumothorax	Chromophobe or oncocytic or clear cell	Germline sequence BHDgene	Birt-Hogg-Dubé syndrome
Personal or family history of early-onset uterine leiomyomata or cutaneous leiomyomata	Type 2 papillary or collecting duct carcinoma	FH gene	Hereditary leiomyomata/RCC syndrome
Multifocal RCC or early-onset RCC or presence of paraganglioma/pheochromocytoma or family history of paraganglioma/pheochromocytoma	Clear cell or chromophobe	SDHB gene, SDHC gene, SDHD gene	Hereditary paraganglioma/pheochromocytoma syndrome

Genomics of RCC

Translocation-positive carcinomas of the kidney are recognized as a distinct form of renal cell carcinoma (RCC) and may be the most common form of RCC in children, accounting for 40% to 50% of pediatric RCC.[27] In a Children's Oncology Group (COG) prospective clinical trial of 120 childhood and adolescent patients with RCC, nearly one-half of patients had translocation-positive RCC.[28] These carcinomas are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:

• ASPSCR in t(X;17)(p11.2;q25).
• PRCC in t(X;1)(p11.2;q21).
• SFPQ in t(X;1)(p11.2;p34).
• NONO in inv(X;p11.2;q12).
• Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).

Another less-common translocation subtype, t(6;11)(p21;q12), involving an Alpha–transcription factor EB (TFEB) gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[29]

Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. In one study, the postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[30,31]

Controversy exists as to the biological behavior of translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a more advanced stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[32-34] The outcomes for these patients are being studied in the ongoing COG AREN03B2 (NCT00898365) biology and classification study. Vascular endothelial growth factor receptor–targeted therapies and mammalian target of rapamycin (mTOR) inhibitors seem to be active in Xp11 translocation metastatic RCC.[35] Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.[22]

Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using TFE3 immunohistochemistry alone, because reported cases have lacked the translocation. There is a rare subset of RCC cases that is positive for TFE3and lack a TFE3 translocation, showing an ALK translocation instead. This subset of cases represents a newly recognized subgroup within RCC that is estimated to involve 15% to 20% of unclassified pediatric RCC. In the eight reported cases in children aged 6 to 16 years, the following was observed:[36-39]

• ALK was fused to VCL (vinculin) in a t(2;10)(p23;q22) translocation (n = 3). The VCLtranslocation cases all occurred in children with sickle cell trait, whereas none of the TMP3 translocation cases did.
• ALK was fused to TPM3 (tropomyosin 3) (n = 3).
• ALK was fused to HOOK-1 on 1p32 (n = 1).
• t(1;2) translocation fusing ALK and TMP3 (n = 1).

Histology of RCC

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 of these categories.[3] Childhood RCCs are more frequently of the papillary subtype (20%–50% of pediatric RCCs) and can sometimes occur in the setting of Wilms tumor, metanephric adenoma, and metanephric adenofibroma.[40]

RCC in children and young adults has a different genetic and morphologic spectrum than that seen in older adults.[3,31,40,41]

Prognosis and Prognostic Factors for RCC

Prognostic factors for RCC include the following:

• Stage of disease.
• Lymph node involvement.

The primary prognostic factor for RCC is stage of disease. In 304 children and adolescents with RCC identified in the National Cancer Data Base, the median age was 13 years; 39% of patients presented with localized stage I disease, 16% with stage II disease, 33% with stage III disease, and 12% with stage IV disease. Five-year overall survival (OS) was 100% for patients with stage I and stage II disease, 71% for stage III disease, and 8% for stage IV disease.[42] Age and sex had no significant impact on survival. Survival was negatively impacted by increasing tumor size (P < .001), positive nodal status (P = .001), and higher pathologic stage (P < .001).[42] The data attained in this article from the National Cancer Data Base are limited, as some patient details are not available and follow up is incomplete. Tumor size of 4 cm or smaller may or may not impact survival and local lymph node involvement may not be as significant in children.

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.[27] In another series of 49 patients from a population-based cancer registry, the findings were similar. In this series, 33% of the patients had papillary subtype, 22% had translocation type, 6% had clear-cell subtype, and 16% were unclassified. 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.[43]

Clinical Features and Diagnostic Evaluation of RCC

RCC may present with the following:

• Abdominal mass.
• Abdominal pain.
• Hematuria.

Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors. In a COG prospective clinical trial of 40 patients with small (7 cm) primary tumors whose lymph nodes were adequately sampled, 19 had positive nodes.[28] Outcome results of this trial are pending. (Refer to the Stage Information for Renal Cell Cancer section in the PDQ summary on adult Renal Cell Cancer Treatment summary for more information about the staging evaluation.)

Treatment of RCC

Survival of patients with RCC is affected by stage of disease at presentation and the completeness of resection at radical nephrectomy. OS rates for all patients with RCC range from 64% to 87%. The 5-year survival rates for pediatric RCC are 90% or higher for stage I, higher than 80% for stage II, 70% for stage III, and lower than 15% for stage IV.[27] Retrospective analyses and the small number of patients involved place limitations on the level of evidence in the area of treatment.

Standard treatment options for RCC include the following:

1. Radical nephrectomy with lymph node dissection.
2. Renal-sparing surgery with lymph node dissection.

Radical nephrectomy with lymph node dissection

The primary treatment for RCC includes total surgical removal of the kidney and associated lymph nodes.[27]

Renal-sparing surgery with lymph node dissection

Renal-sparing surgery may be considered for carefully selected patients with low-volume localized disease. In two small series, patients who had partial nephrectomies seemed to have outcomes equivalent to those who had radical nephrectomies.[31,44]

Other approaches

As with adult RCC, there is no standard treatment for unresectable metastatic disease in children. The response to radiation is poor, and chemotherapy is not effective. Immunotherapy with such agents as interferon-alpha and interleukin-2 may have some effect on cancer control.[45,46] Spontaneous regression of pulmonary metastasis rarely occurs with resection of the primary tumor.

Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, and everolimus) have been approved for use in adults with RCC; however, these agents have not been tested in pediatric patients with RCC. Case reports of pediatric and adolescent patients with TFE3 RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[47,48] Disease regression and improvement in symptoms have been reported with the use of cabozantinib in pediatric patients with translocation-positive RCC expressing MET.[49] Any RCC that is positive for TFE3 and lacks a translocation should be tested for ALK expression and translocation. Recognition of this subtype may lead to consideration of ALK inhibitor therapy.[36]

(Refer to the PDQ summary on adult Renal Cell Cancer Treatment for more information about the use of targeted therapies.)

Treatment Options Under Clinical Evaluation for RCC

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• AREN1721 (NCT03595124) (Axitinib and Nivolumab in Treating Participants With Unresectable or Metastatic TFE/Translocation RCC [tRCC]): TFE/tRCC is a distinct, typically translocation-associated RCC with characteristic morphology and immunohistochemical expression of TFE3 or TFEB. Nearly 50% of pediatric RCCs are tRCC, and it accounts for 1% to 5% of RCCs overall, typically in the adolescent and young adult population. This is the first prospective therapeutic study of patients with tRCC. Patients aged 12 months and older who have histologically confirmed unresectable TFE/tRCC or metastatic TFE/tRCC diagnosed using WHO-defined criteria are eligible. Patients may be newly diagnosed or have received previous cancer therapy and must have measurable disease. Patients will be randomly assigned at the time of enrollment to one of three therapeutic arms: axitinib, nivolumab, or a combination of axitinib and nivolumab.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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18. Bayley JP, Launonen V, Tomlinson IP: The FH mutation database: an online database of fumarate hydratase mutations involved in the MCUL (HLRCC) tumor syndrome and congenital fumarase deficiency. BMC Med Genet 9: 20, 2008. [PUBMED Abstract]
19. Wilson CL, Ness KK, Neglia JP, et al.: Renal carcinoma after childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 105 (7): 504-8, 2013. [PUBMED Abstract]
20. Dhall D, Al-Ahmadie HA, Dhall G, et al.: Pediatric renal cell carcinoma with oncocytoid features occurring in a child after chemotherapy for cardiac leiomyosarcoma. Urology 70 (1): 178.e13-5, 2007. [PUBMED Abstract]
21. Schafernak KT, Yang XJ, Hsueh W, et al.: Pediatric renal cell carcinoma as second malignancy: reports of two cases and a review of the literature. Can J Urol 14 (6): 3739-44, 2007. [PUBMED Abstract]
22. Rais-Bahrami S, Drabick JJ, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma: delayed but massive and lethal metastases of a chemotherapy-associated secondary malignancy. Urology 70 (1): 178.e3-6, 2007. [PUBMED Abstract]
23. Brassesco MS, Valera ET, Bonilha TA, et al.: Secondary PSF/TFE3-associated renal cell carcinoma in a child treated for genitourinary rhabdomyosarcoma. Cancer Genet 204 (2): 108-10, 2011. [PUBMED Abstract]
24. Breslow NE, Lange JM, Friedman DL, et al.: Secondary malignant neoplasms after Wilms tumor: an international collaborative study. Int J Cancer 127 (3): 657-66, 2010. [PUBMED Abstract]
25. Falzarano SM, McKenney JK, Montironi R, et al.: Renal Cell Carcinoma Occurring in Patients With Prior Neuroblastoma: A Heterogenous Group of Neoplasms. Am J Surg Pathol 40 (7): 989-97, 2016. [PUBMED Abstract]
26. Linehan WM, Pinto PA, Bratslavsky G, et al.: Hereditary kidney cancer: unique opportunity for disease-based therapy. Cancer 115 (10 Suppl): 2252-61, 2009. [PUBMED Abstract]
27. 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]
28. Geller JI, Ehrlich PF, Cost NG, et al.: Characterization of adolescent and pediatric renal cell carcinoma: A report from the Children's Oncology Group study AREN03B2. Cancer 121 (14): 2457-64, 2015. [PUBMED Abstract]
29. Argani P, Hicks J, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol 34 (9): 1295-303, 2010. [PUBMED Abstract]
30. 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]
31. 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]
32. Geller JI, Argani P, Adeniran A, et al.: Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 112 (7): 1607-16, 2008. [PUBMED Abstract]
33. Camparo P, Vasiliu V, Molinie V, et al.: Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 32 (5): 656-70, 2008. [PUBMED Abstract]
34. Qiu Rao, Bing Guan, Zhou XJ: Xp11.2 Translocation renal cell carcinomas have a poorer prognosis than non-Xp11.2 translocation carcinomas in children and young adults: a meta-analysis. Int J Surg Pathol 18 (6): 458-64, 2010. [PUBMED Abstract]
35. Malouf GG, Camparo P, Oudard S, et al.: Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol 21 (9): 1834-8, 2010. [PUBMED Abstract]
36. Thorner PS, Shago M, Marrano P, et al.: TFE3-positive renal cell carcinomas are not always Xp11 translocation carcinomas: Report of a case with a TPM3-ALK translocation. Pathol Res Pract 212 (10): 937-942, 2016. [PUBMED Abstract]
37. Cajaiba MM, Jennings LJ, Rohan SM, et al.: ALK-rearranged renal cell carcinomas in children. Genes Chromosomes Cancer 55 (5): 442-51, 2016. [PUBMED Abstract]
38. Smith NE, Deyrup AT, Mariño-Enriquez A, et al.: VCL-ALK renal cell carcinoma in children with sickle-cell trait: the eighth sickle-cell nephropathy? Am J Surg Pathol 38 (6): 858-63, 2014. [PUBMED Abstract]
39. Cajaiba MM, Jennings LJ, George D, et al.: Expanding the spectrum of ALK-rearranged renal cell carcinomas in children: Identification of a novel HOOK1-ALK fusion transcript. Genes Chromosomes Cancer 55 (10): 814-7, 2016. [PUBMED Abstract]
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Rhabdoid Tumors of the Kidney

In This Section

• General Information About Rhabdoid Tumors of the Kidney
• Genomics of Rhabdoid Tumors of the Kidney
• Rhabdoid Predisposition Syndrome
• Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney
• Prognosis and Prognostic Factors for Rhabdoid Tumors of the Kidney
• Treatment of Rhabdoid Tumor of the Kidney
• Treatment Options Under Clinical Evaluation for Rhabdoid Tumors of the Kidney
• Current Clinical Trials

General Information About Rhabdoid Tumors of the Kidney

Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney (termed malignant rhabdoid tumors) and the central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for information about the treatment of CNS disease.) Relapses occur early (median time from diagnosis, 8 months).[1,2]

A distinct clinical presentation that suggests a diagnosis of rhabdoid tumor of the kidney includes the following:[3]

• Fever.
• Hematuria.
• Young age (mean age, 11 months).
• Advanced tumor stage at presentation.

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported.[1] Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions.[4] The staging system used for rhabdoid tumor of the kidney is the same system used for Wilms tumor. (Refer to the Stage Information for Wilms Tumorsection of this summary for more information.)

Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions.

Genomics of Rhabdoid Tumors of the Kidney

Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1/INI1/SNF5/BAF47 gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1encodes a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[5,6] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by mutations that are commonly frameshift or nonsense mutations that lead to premature truncation of the SMARCB1 protein.[6,7] A small percentage of rhabdoid tumors are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[8,9] Exome sequencing of 35 cases of rhabdoid tumor identified a very low mutation rate, with no genes having recurring mutations other than SMARCB1, which appeared to contribute to tumorigenesis.[10]

Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[11,12] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 alterations.[6,13] In most cases, the mutations are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline mutation or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months).[14] Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis.[15,16] Germline mutations in SMARCA4have also been reported in patients with rhabdoid tumors.[8,17]

Rhabdoid Predisposition Syndrome

Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid predisposition syndrome. This has been confirmed by the presence of germline mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. These cases have been labeled as rhabdoid tumor predisposition syndrome, type 1. Thirty-five patients (N = 100) with rhabdoid tumors of the brain, kidney, or soft tissues were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma; and two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.[6]

Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[8,9] In these cases, SMARCA4 behaves as a classical tumor suppressor, with one deleterious mutation inherited in the germline and the other acquired in the tumor. Another report describes an autosomal dominant pattern of inheritance discovered through an exome sequencing project.[18]

Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney

Germline analysis is suggested for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations in which a specific SMARCB1 mutation or deletion has been documented in the family.[6]

Recommendations for surveillance in patients with germline SMARCB1 mutations have been developed on the basis of epidemiology and clinical course of rhabdoid tumors. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 mutations. The aggressive natural history of the disease, apparently high penetrance, and well-defined age of onset for CNS atypical teratoid/rhabdoid tumor suggest that surveillance could prove beneficial. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[19]

Surveillance for patients with germline SMARCB1 mutations includes the following:

• Children younger than 1 year: It is suggested that infants have thorough physical and neurologic examinations and monthly head ultrasounds to assess for the development of a CNS tumor. It is also suggested that infants undergo abdominal ultrasounds that focus on the kidneys every 2 to 3 months to assess for renal lesions.[19]
• Children aged 1 to 4 years: From age 1 year to approximately age 4 years, after which the risk of developing a new rhabdoid tumor rapidly declines, it is suggested that brain and spine magnetic resonance imaging (MRI) and abdominal ultrasound be performed every 3 months.[19]

Prognosis and Prognostic Factors for Rhabdoid Tumors of the Kidney

Patients with rhabdoid tumors of the kidney continue to have a poor prognosis. In a review of 142 patients from the National Wilms Tumor Studies (NWTS) (NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 [COG-Q9401/NCT00002611]), age and stage were identified as important prognostic factors:[4]

• Age at diagnosis. 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% (highly significant).
• Stage of disease. Patients with stage I and stage II disease had an OS rate of 42%; higher stage was associated with a 16% OS rate.
• Presence of a CNS lesion. All but one patient with a CNS lesion (n = 32) died.

Treatment of 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 optimal treatment.

There is no standard treatment option for rhabdoid tumor of the kidney.[20]

The following results have been observed in studies of rhabdoid tumor of the kidney:

1. On the basis of a retrospective comparison of tumor response to preoperative treatment with vincristine/dactinomycin versus vincristine/dactinomycin/doxorubicin, doxorubicin is considered an active drug in malignant rhabdoid tumor of the kidney.[21][Level of evidence: 3iiiDiv]
2. The NWTS-5 trial closed the arm for rhabdoid tumor treatment with cyclophosphamide, etoposide, and carboplatin because poor outcome was observed. Combinations of etoposide and cisplatin; etoposide and ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used.[22,23]
3. Treatment with high-dose alkylator therapy followed by consolidation with high-dose chemotherapy and, in some cases, autologous stem cell transplant after achieving a radiographic remission has resulted in some long-term survival (5 of 13 patients). None of the patients with unresectable primary tumors survived in this small series (N = 21).[24]
4. A retrospective analysis of 58 patients with malignant rhabdoid tumor of the kidney from the International Society of Pediatric Oncology (SIOP), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), and European Rhabdoid Tumor Registry was performed.[25]
   • For the entire group, the 2-year event-free survival (EFS) was 37%, and the OS was 38%.
   • Patients with multifocal involvement (n = 12) had significantly inferior survival than did patients with pulmonary or mediastinal metastases or local disease.
   • Patients who underwent upfront chemotherapy had a lower, but not statistically significant, 2-year EFS than did patients who underwent immediate surgical resection.
   • Younger age (<12 months) and local stage III disease were associated with significantly inferior survival than were stage I and stage II disease.
   • No difference was seen in 2-year EFS for patients without progression within 90 days consolidated by high-dose stem cell transplantation (SCT) (n = 10) compared with patients without consolidation by SCT (n = 21).

Treatment Options Under Clinical Evaluation for Rhabdoid Tumors of the Kidney

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
• NCT02601937 (A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. van den Heuvel-Eibrink MM, van Tinteren H, Rehorst H, et al.: Malignant rhabdoid tumours of the kidney (MRTKs), registered on recent SIOP protocols from 1993 to 2005: a report of the SIOP renal tumour study group. Pediatr Blood Cancer 56 (5): 733-7, 2011. [PUBMED Abstract]
2. Reinhard H, Reinert J, Beier R, et al.: Rhabdoid tumors in children: prognostic factors in 70 patients diagnosed in Germany. Oncol Rep 19 (3): 819-23, 2008. [PUBMED Abstract]
3. 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]
4. 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]
5. Imbalzano AN, Jones SN: Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability. Cancer Cell 7 (4): 294-5, 2005. [PUBMED Abstract]
6. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011. [PUBMED Abstract]
7. Versteege I, Sévenet N, Lange J, et al.: Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394 (6689): 203-6, 1998. [PUBMED Abstract]
8. Schneppenheim R, Frühwald MC, Gesk S, et al.: Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet 86 (2): 279-84, 2010. [PUBMED Abstract]
9. Hasselblatt M, Gesk S, Oyen F, et al.: Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. Am J Surg Pathol 35 (6): 933-5, 2011. [PUBMED Abstract]
10. Lee RS, Stewart C, Carter SL, et al.: A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest 122 (8): 2983-8, 2012. [PUBMED Abstract]
11. 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]
12. Biegel JA: Molecular genetics of atypical teratoid/rhabdoid tumor. Neurosurg Focus 20 (1): E11, 2006. [PUBMED Abstract]
13. Bourdeaut F, Lequin D, Brugières L, et al.: Frequent hSNF5/INI1 germline mutations in patients with rhabdoid tumor. Clin Cancer Res 17 (1): 31-8, 2011. [PUBMED Abstract]
14. Geller JI, Roth JJ, Biegel JA: Biology and Treatment of Rhabdoid Tumor. Crit Rev Oncog 20 (3-4): 199-216, 2015. [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. Sévenet N, Sheridan E, Amram D, et al.: Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet 65 (5): 1342-8, 1999. [PUBMED Abstract]
17. Hasselblatt M, Nagel I, Oyen F, et al.: SMARCA4-mutated atypical teratoid/rhabdoid tumors are associated with inherited germline alterations and poor prognosis. Acta Neuropathol 128 (3): 453-6, 2014. [PUBMED Abstract]
18. Witkowski L, Lalonde E, Zhang J, et al.: Familial rhabdoid tumour 'avant la lettre'--from pathology review to exome sequencing and back again. J Pathol 231 (1): 35-43, 2013. [PUBMED Abstract]
19. Teplick A, Kowalski M, Biegel JA, et al.: Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician. Eur J Pediatr 170 (3): 285-94, 2011. [PUBMED Abstract]
20. Ahmed HU, Arya M, Levitt G, et al.: Part II: Treatment of primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (9): 842-8, 2007. [PUBMED Abstract]
21. Furtwängler R, Nourkami-Tutdibi N, Leuschner I, et al.: Malignant rhabdoid tumor of the kidney: significantly improved response to pre-operative treatment intensified with doxorubicin. Cancer Genet 207 (9): 434-6, 2014. [PUBMED Abstract]
22. 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]
23. 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]
24. Venkatramani R, Shoureshi P, Malvar J, et al.: High dose alkylator therapy for extracranial malignant rhabdoid tumors in children. Pediatr Blood Cancer 61 (8): 1357-61, 2014. [PUBMED Abstract]
25. Furtwängler R, Kager L, Melchior P, et al.: High-dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival-The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]

Clear Cell Sarcoma of the Kidney

In This Section

• General Information About Clear Cell Sarcoma of the Kidney
• Genomics of Clear Cell Sarcoma of the Kidney
• Treatment of Clear Cell Sarcoma of the Kidney
  • Surgery, chemotherapy, and radiation therapy
• Current Clinical Trials

General Information About Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is not a Wilms tumor variant, but it is an important primary renal tumor associated with a higher rate of relapse and death than is favorable-histology (FH) Wilms tumor.[1] The classic pattern of clear cell sarcoma of the kidney is defined by nests or cords of cells separated by regularly spaced fibrovascular septa. In addition to pulmonary metastases, clear cell sarcoma also spreads to bone, brain, and soft tissue.[1] (Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Younger age and stage IV disease have been identified as adverse prognostic factors for event-free survival (EFS).[2]

Historically, relapses have occurred in long intervals after the completion of chemotherapy (up to 14 years); however, with current therapy, relapses after 3 years are uncommon.[3] The brain is a frequent site of recurrent disease, suggesting that it is a sanctuary site for cells that are protected from the intensive chemotherapy that patients currently receive.[2-5] An awareness of the clinical signs of recurrent disease in the brain is important during regular follow-up. There are no standard recommendations for the frequency of brain imaging during follow-up.

Genomics of Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is an uncommon renal tumor that comprises approximately 5% of all primary renal malignancies in children, and it is observed most often before age 3 years. The molecular background of clear cell sarcoma of the kidney is poorly understood because of its rarity and lack of experimental models.

Several biological features of clear cell sarcoma of the kidney have been described, including the following:

• Internal tandem duplications in exon 15 of the BCOR gene (BCL6 corepressor) were reported in 100% (20 of 20 cases) of clear cell sarcoma of the kidney cases but in none of the other pediatric renal tumors evaluated.[6] Other reports have confirmed the finding of BCOR internal tandem duplications in clear cell sarcoma of the kidney.[7-10] Hence, BCOR internal tandem duplications appear to play a key role in the tumorigenesis of clear cell sarcoma of the kidney, and their identification should aid in the differential diagnosis of renal tumors.[6]
• The YWHAE-NUTM2 fusion (involving either NUTM2B or NUTM2E) resulting from t(10;17) was reported in 12% of cases of clear cell sarcoma of the kidney.[11] The presence of the YWHAE-NUTM2 fusion appears to be mutually exclusive with the presence of BCORinternal tandem duplications; this observation is based on a study of 22 cases of clear cell sarcoma of the kidney that included two cases with the YWHAE-NUTM2 fusion and 20 cases with BCOR internal tandem duplications.[7] The gene expression profiles for cases with the YWHAE-NUTM2 fusion were distinctive from those with BCOR internal tandem duplications.
• Evaluation of 13 clear cell sarcoma of the kidney tumors for changes in chromosome copy number, mutations, and rearrangements found a single case with the YWHAE-NUTM2 fusion and 12 cases with BCOR internal tandem duplications.[9,12] No other recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified, providing further support for the role of BCOR internal tandem duplication as the primary oncogenic driver for clear cell sarcoma of the kidney.[12]

Treatment of Clear Cell Sarcoma of the Kidney

Because of the relative rarity of this tumor, all patients with clear cell sarcoma 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 optimal treatment.

The approach for treating clear cell sarcoma of the kidney is different from the approach for treating Wilms tumor because the overall survival (OS) of children with clear cell sarcoma of the kidney remains lower than that for patients with FH Wilms tumor. All patients undergo postoperative radiation to the tumor bed and receive doxorubicin as part of their chemotherapy regimen.

The standard treatment option for clear cell sarcoma of the kidney is the following:

1. Surgery, chemotherapy, and radiation therapy.

Surgery, chemotherapy, and radiation therapy

Evidence (surgery, chemotherapy, and radiation therapy):

1. In the National Wilms Tumor Study (NWTS)-3 trial (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 clear cell sarcoma of the kidney.[1]
2. The NWTS-4 trial used regimen DD-4A, which consisted of vincristine, dactinomycin, and doxorubicin for 15 months and radiation therapy.[13]
   • NWTS-4 reported that patients who were treated with vincristine, doxorubicin, and dactinomycin for 15 months had an improved relapse-free survival compared with patients who were treated for 6 months (88% vs. 61% at 8 years).
3. In the NWTS-5 (COG-Q9401/NCT00002611) trial, children with stages I to IV clear cell sarcoma of the kidney 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.[3]
   • With this treatment, the 5-year EFS was 79%, and the OS was 90%.
   • Stage I patients had 5-year EFS and OS rates of 100%.
   • Stage II patients had a 5-year EFS of 88% and a 5-year OS of 98%.
   • Stage III patients had a 5-year EFS of 73% and a 5-year OS of 89%.
   • Stage IV patients had a 5-year EFS of 29% and a 5-year OS of 36%.
4. A review of patients with stage I clear cell sarcoma of the kidney treated on the NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 trials showed an excellent 100% OS with a wide variety of chemotherapy and radiation therapy regimens.[14]

(Refer to the Treatment of Recurrent Clear Cell Sarcoma of the Kidney section of this summary for information about recurrent disease.)

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. 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]
2. Furtwängler R, Gooskens SL, van Tinteren H, et al.: Clear cell sarcomas of the kidney registered on International Society of Pediatric Oncology (SIOP) 93-01 and SIOP 2001 protocols: a report of the SIOP Renal Tumour Study Group. Eur J Cancer 49 (16): 3497-506, 2013. [PUBMED Abstract]
3. Seibel NL, Chi YY, Perlman EJ, et al.: Impact of cyclophosphamide and etoposide on outcome of clear cell sarcoma of the kidney treated on the National Wilms Tumor Study-5 (NWTS-5). Pediatr Blood Cancer : e27450, 2018. [PUBMED Abstract]
4. 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]
5. Gooskens SL, Furtwängler R, Spreafico F, et al.: Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study. Br J Cancer 111 (2): 227-33, 2014. [PUBMED Abstract]
6. Ueno-Yokohata H, Okita H, Nakasato K, et al.: Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney. Nat Genet 47 (8): 861-3, 2015. [PUBMED Abstract]
7. Karlsson J, Valind A, Gisselsson D: BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer 55 (2): 120-3, 2016. [PUBMED Abstract]
8. Astolfi A, Melchionda F, Perotti D, et al.: Whole transcriptome sequencing identifies BCOR internal tandem duplication as a common feature of clear cell sarcoma of the kidney. Oncotarget 6 (38): 40934-9, 2015. [PUBMED Abstract]
9. Roy A, Kumar V, Zorman B, et al.: Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney. Nat Commun 6: 8891, 2015. [PUBMED Abstract]
10. Wong MK, Ng CCY, Kuick CH, et al.: Clear cell sarcomas of the kidney are characterised by BCOR gene abnormalities, including exon 15 internal tandem duplications and BCOR-CCNB3 gene fusion. Histopathology 72 (2): 320-329, 2018. [PUBMED Abstract]
11. O'Meara E, Stack D, Lee CH, et al.: Characterization of the chromosomal translocation t(10;17)(q22;p13) in clear cell sarcoma of kidney. J Pathol 227 (1): 72-80, 2012. [PUBMED Abstract]
12. Gooskens SL, Gadd S, Guidry Auvil JM, et al.: TCF21 hypermethylation in genetically quiescent clear cell sarcoma of the kidney. Oncotarget 6 (18): 15828-41, 2015. [PUBMED Abstract]
13. 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]
14. Kalapurakal JA, Perlman EJ, Seibel NL, et al.: Outcomes of patients with revised stage I clear cell sarcoma of kidney treated in National Wilms Tumor Studies 1-5. Int J Radiat Oncol Biol Phys 85 (2): 428-31, 2013. [PUBMED Abstract]

Congenital Mesoblastic Nephroma

In This Section

• General Information About Congenital Mesoblastic Nephroma
• Treatment of Congenital Mesoblastic Nephroma
  • Nephrectomy
  • Adjuvant chemotherapy
• Current Clinical Trials

General Information About Congenital Mesoblastic Nephroma

Mesoblastic nephroma comprises about 5% of childhood kidney tumors, and more than 90% of cases appear within the first year of life. More than 15% of the cases are detected prenatally.[1] It is the most common kidney tumor found in infants younger than 6 months.[2] The median age of diagnosis is 1 to 2 months. Twice as many males as females are diagnosed. The diagnosis should be questioned when applied to individuals older than 2 years.[1]

When patients are diagnosed in the first 7 months of life, the 5-year event-free survival rate is 94%, and the overall survival (OS) rate is 96%.[3] In a report from the United Kingdom of 50 children with mesoblastic nephroma studied on clinical trials and 80 cases from the national registry in the same time period, there were no deaths.[1] However, in a comprehensive review of the literature, 12 deaths were reported; of these 12 deaths, 7 were from surgical complications in infants.[4][Level of evidence: 3iiiDii]

Grossly, mesoblastic nephromas appear as solitary, unilateral masses indistinguishable from nephroblastoma. Microscopically, they consist of spindled mesenchymal cells. Mesoblastic nephroma can be divided into three histologic subtypes:

• Classic.[5]
• Cellular. The cellular subtype is identical to infantile fibrosarcoma.[6]
• Mixed. The mixed subtype (<10%) is a mixture of classic and cellular patterns.[7]

Two major genetic variants have been described in congenital mesoblastic nephroma: t(12;15)(q13;q25), resulting in a fusion of ETV6 and NTRK3, and trisomy 11.[8] These genetic aberrations were only identified in the cellular and (less commonly in) mixed subtypes of congenital mesoblastic nephroma and never in the classic form.[4,6]

The risk of recurrence for patients with mesoblastic nephroma is closely associated with the presence of a cellular subtype and with stage III disease.[5]

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Treatment of Congenital Mesoblastic Nephroma

OS of congenital mesoblastic nephroma patients is excellent; however, reported causes of death in about half of the cases are treatment-related and most of these patients were very young (median age, <1 year).[4] This underscores the special attention that infants with renal tumors require, with respect to timing and type of treatment and the importance of a dedicated expert pediatric oncology setting.

Standard treatment options for stages I and II (80% of patients) and stage III (classic and mixed subtypes) congenital mesoblastic nephroma include the following:

1. Nephrectomy only.

Treatment options for stage III (cellular subtype) congenital mesoblastic nephroma include the following:

1. Nephrectomy.
2. Chemotherapy.

Nephrectomy

Evidence (nephrectomy):

1. A prospective clinical trial enrolled 50 patients with congenital mesoblastic nephroma.[5]
   • The results confirmed that complete surgical resection, which includes the entire capsule, is adequate therapy for most patients with mesoblastic nephroma.
   • Two of 50 patients died.
   • Patients were at increased risk of local and eventually metastatic recurrence when there was stage III disease (incomplete resection and/or histologically positive resection margin), cellular subtype, and age 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 discerned.
2. Study numbers are small for patients with stage III congenital mesoblastic nephroma.[1,5,9] Of 12 well-documented classic and mixed type stage III patients undergoing surgery only, one patient experienced a relapse but survived after treatment for the relapse.

Adjuvant chemotherapy

Adjuvant chemotherapy has been recommended for patients with stage III cellular subtype who are aged 3 months or older at diagnosis.[5] In a study of stage III cellular type congenital mesoblastic nephroma, 7 of 12 patients who were treated with surgery only suffered from a relapse, while 4 of 14 patients who were treated with adjuvant chemotherapy (primarily dactinomycin/vincristine and sometimes doxorubicin) developed a relapse.[1,5,9] Cyclophosphamide and ifosfamide have been combined with these agents and have shown activity.[10]

Infants younger than 2 months with incompletely resected, stage III disease may not need chemotherapy.[1]

(Refer to the Treatment of Recurrent Congenital Mesoblastic Nephroma section of this summary for information about recurrent disease.)

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. England RJ, Haider N, Vujanic GM, et al.: Mesoblastic nephroma: a report of the United Kingdom Children's Cancer and Leukaemia Group (CCLG). Pediatr Blood Cancer 56 (5): 744-8, 2011. [PUBMED Abstract]
2. Jehangir S, Kurian JJ, Selvarajah D, et al.: Recurrent and metastatic congenital mesoblastic nephroma: where does the evidence stand? Pediatr Surg Int 33 (11): 1183-1188, 2017. [PUBMED Abstract]
3. 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]
4. Gooskens SL, Houwing ME, Vujanic GM, et al.: Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
5. 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]
6. El Demellawy D, Cundiff CA, Nasr A, et al.: Congenital mesoblastic nephroma: a study of 19 cases using immunohistochemistry and ETV6-NTRK3 fusion gene rearrangement. Pathology 48 (1): 47-50, 2016. [PUBMED Abstract]
7. Argani P, Ladanyi M: Recent advances in pediatric renal neoplasia. Adv Anat Pathol 10 (5): 243-60, 2003. [PUBMED Abstract]
8. 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]
9. Bayindir P, Guillerman RP, Hicks MJ, et al.: Cellular mesoblastic nephroma (infantile renal fibrosarcoma): institutional review of the clinical, diagnostic imaging, and pathologic features of a distinctive neoplasm of infancy. Pediatr Radiol 39 (10): 1066-74, 2009. [PUBMED Abstract]
10. McCahon E, Sorensen PH, Davis JH, et al.: Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy. Med Pediatr Oncol 40 (5): 288-92, 2003. [PUBMED Abstract]

Ewing Sarcoma of the Kidney

In This Section

• General Information About Ewing Sarcoma of the Kidney
• Treatment of Ewing Sarcoma of the Kidney
• Current Clinical Trials

General Information About Ewing Sarcoma of the Kidney

Ewing sarcoma (previously known as neuroepithelial tumor) of the kidney is extremely rare and demonstrates a unique proclivity for young adults. It is a highly aggressive neoplasm, more often presenting with large tumors and penetration of the renal capsule, extension into the renal vein, and in 40% of cases, evidence of metastases.[1-3]

Ewing sarcoma of the kidney is characterized by CD99 (MIC-2) positivity and the detection of EWS/FLI-1 fusion transcripts. In Ewing sarcoma of the kidney, focal, atypical histologic features have been seen, including clear cell sarcoma, rhabdoid tumor, malignant peripheral nerve sheath tumors, and paraganglioma.[1,4] (Refer to the PDQ summary on Ewing Sarcoma Treatment for more information.)

Treatment of Ewing Sarcoma of the Kidney

There is no standard treatment option for Ewing sarcoma of the kidney. However, treatment with chemotherapy and radiation therapy and an aggressive surgical approach seem to be associated with a better outcome than previously reported.[2] Consideration should also be given to substituting cyclophosphamide for ifosfamide in patients after they have undergone a nephrectomy. [2,3]

Treatment according to Ewing sarcoma protocols should be considered.[1]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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]
2. Tagarelli A, Spreafico F, Ferrari A, et al.: Primary renal soft tissue sarcoma in children. Urology 80 (3): 698-702, 2012. [PUBMED Abstract]
3. Rowe RG, Thomas DG, Schuetze SM, et al.: Ewing sarcoma of the kidney: case series and literature review of an often overlooked entity in the diagnosis of primary renal tumors. Urology 81 (2): 347-53, 2013. [PUBMED Abstract]
4. 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]

Primary Renal Myoepithelial Carcinoma

In This Section

• General Information About Primary Renal Myoepithelial Carcinoma
• Treatment of Primary Renal Myoepithelial Carcinoma

General Information About Primary Renal Myoepithelial Carcinoma

Myoepithelial carcinomas are aggressive malignancies primarily affecting soft tissues with occasional visceral origin. Approximately 20% of all reported cases have been described in children and are associated with a particularly unfavorable outcome, frequent development of metastases, and short overall survival.[1]

Two cases of primary renal myoepithelial carcinoma have occurred in children, and both cases had a translocation involving EWSR1 and the novel fusion partner KLF15, a transcription factor uniquely functioning within the kidney. Helpful features to establish the diagnosis include coexpression of cytokeratins, S-100, and smooth muscle markers, and the documentation of EWSR1 rearrangements.[2]

Treatment of Primary Renal Myoepithelial Carcinoma

Although no standard therapy has been established, surgical resection of the primary tumor and pulmonary nodules (if present) has been used in addition to chemotherapy and radiation therapy.[2]

References

1. Gleason BC, Fletcher CD: Myoepithelial carcinoma of soft tissue in children: an aggressive neoplasm analyzed in a series of 29 cases. Am J Surg Pathol 31 (12): 1813-24, 2007. [PUBMED Abstract]
2. Cajaiba MM, Jennings LJ, Rohan SM, et al.: Expanding the Spectrum of Renal Tumors in Children: Primary Renal Myoepithelial Carcinomas With a Novel EWSR1-KLF15 Fusion. Am J Surg Pathol 40 (3): 386-94, 2016. [PUBMED Abstract]

Cystic Partially Differentiated Nephroblastoma

In This Section

• General Information About Cystic Partially Differentiated Nephroblastoma
• Treatment of Cystic Partially Differentiated Nephroblastoma

General Information About 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. DICER1 mutations have not been reported in cystic partially differentiated nephroblastoma, which supports a distinction between multilocular cystic nephromas and cystic partially differentiated nephroblastoma.[1]

Recurrence has been reported after tumor spillage during surgery.[2][Level of evidence: 3iiiA]

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Treatment of Cystic Partially Differentiated Nephroblastoma

Standard treatment options for cystic partially differentiated nephroblastoma include the following:

1. Surgery. Patients with stage I disease have a 100% survival rate with surgery alone.[3]
2. Surgery and adjuvant chemotherapy. Patients with stage II disease have an excellent outcome with tumor resection followed by postoperative vincristine and dactinomycin.[3]

References

1. Cajaiba MM, Khanna G, Smith EA, et al.: Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations. Hum Pathol 48: 81-7, 2016. [PUBMED Abstract]
2. Baker JM, Viero S, Kim PC, et al.: Stage III cystic partially differentiated nephroblastoma recurring after nephrectomy and chemotherapy. Pediatr Blood Cancer 50 (1): 129-31, 2008. [PUBMED Abstract]
3. 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]

Multilocular Cystic Nephroma

In This Section

• General Information About Multilocular Cystic Nephroma
• Treatment of Multilocular Cystic Nephroma

General Information About Multilocular Cystic Nephroma

Multilocular cystic nephromas are uncommon benign lesions consisting of cysts lined by renal epithelium. They are characterized by a bimodal age distribution, affecting either infants/young children or adult females. These lesions can occur bilaterally, and a familial pattern has been reported.

Multilocular cystic nephroma has been associated with pleuropulmonary blastoma and the DICER1 mutation. Anaplastic sarcoma of the kidney has also been associated with the DICER1 mutation.[1] This is in contrast to adult cystic nephromas, which lack DICER1mutations, and supports the difference between adult and pediatric cases. Genetic counseling, DICER1 mutation testing, and screening for lung lesions of a solid or cystic nature should be considered.[2-5]

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Treatment of Multilocular Cystic Nephroma

The standard treatment option for multilocular cystic nephroma is surgery.

References

1. Wu MK, Goudie C, Druker H, et al.: Evolution of Renal Cysts to Anaplastic Sarcoma of Kidney in a Child With DICER1 Syndrome. Pediatr Blood Cancer 63 (7): 1272-5, 2016. [PUBMED Abstract]
2. Dehner LP, Messinger YH, Schultz KA, et al.: Pleuropulmonary Blastoma: Evolution of an Entity as an Entry into a Familial Tumor Predisposition Syndrome. Pediatr Dev Pathol 18 (6): 504-11, 2015 Nov-Dec. [PUBMED Abstract]
3. Doros LA, Rossi CT, Yang J, et al.: DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod Pathol 27 (9): 1267-80, 2014. [PUBMED Abstract]
4. Cajaiba MM, Khanna G, Smith EA, et al.: Pediatric cystic nephromas: distinctive features and frequent DICER1 mutations. Hum Pathol 48: 81-7, 2016. [PUBMED Abstract]
5. Li Y, Pawel BR, Hill DA, et al.: Pediatric Cystic Nephroma Is Morphologically, Immunohistochemically, and Genetically Distinct From Adult Cystic Nephroma. Am J Surg Pathol 41 (4): 472-481, 2017. [PUBMED Abstract]

Primary Renal Synovial Sarcoma

In This Section

• General Information About Primary Renal Synovial Sarcoma
• Treatment of Primary Renal Synovial Sarcoma

General Information About Primary Renal Synovial Sarcoma

Primary renal synovial sarcoma 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 and is considered an aggressive tumor with adverse patient outcomes in more than 50% of cases (n = 16).[1] Primary renal synovial sarcoma contains cystic structures derived from dilated, trapped renal tubules. Primary renal synovial sarcoma occurs more often in young adults.

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Treatment of Primary Renal Synovial Sarcoma

The standard treatment option for primary renal synovial sarcoma is chemotherapy. Chemotherapy regimens that are different from those traditionally used for Wilms tumor are used.[2]

References

1. Schoolmeester JK, Cheville JC, Folpe AL: Synovial sarcoma of the kidney: a clinicopathologic, immunohistochemical, and molecular genetic study of 16 cases. Am J Surg Pathol 38 (1): 60-5, 2014. [PUBMED Abstract]
2. 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]

Anaplastic Sarcoma of the Kidney

In This Section

• General Information About Anaplastic Sarcoma of the Kidney
• Treatment of Anaplastic Sarcoma of the Kidney

General Information About Anaplastic Sarcoma of the Kidney

Anaplastic sarcoma of the kidney is a rare renal tumor that has been identified mainly in patients younger than 15 years.

Patients present with a renal mass, with the most common sites of metastases being the lungs, liver, and bones. (Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Cytogenetic abnormalities such as rearrangement between 10q21 and 18p11.2 have been reported.[1] These tumors show pathologic features similar to those of pleuropulmonary blastoma of childhood (refer to the Pleuropulmonary blastoma section in the PDQ summary on Unusual Cancers of Childhood for more information) and undifferentiated embryonal sarcoma of the liver (refer to the Treatment Options for Undifferentiated Embryonal Sarcoma of the Liver section in the PDQ summary on Childhood Liver Cancerfor more information). Because of the relationship between pleuropulmonary blastoma and renal sarcomas, genetic counseling and testing for a germline DICER1 mutation should be considered. Screening for lung lesions of a solid or cystic nature should also be considered on the basis of age and DICER1 mutation testing.[2]

Treatment of Anaplastic Sarcoma of the Kidney

There is no standard treatment option for anaplastic sarcoma of the kidney. In the past, these tumors have been identified as anaplastic Wilms tumor and treated accordingly.[3]

References

1. Gomi K, Hamanoue S, Tanaka M, et al.: Anaplastic sarcoma of the kidney with chromosomal abnormality: first report on cytogenetic findings. Hum Pathol 41 (10): 1495-9, 2010. [PUBMED Abstract]
2. Doros LA, Rossi CT, Yang J, et al.: DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma. Mod Pathol 27 (9): 1267-80, 2014. [PUBMED Abstract]
3. Vujanić GM, Kelsey A, Perlman EJ, et al.: Anaplastic sarcoma of the kidney: a clinicopathologic study of 20 cases of a new entity with polyphenotypic features. Am J Surg Pathol 31 (10): 1459-68, 2007. [PUBMED Abstract]

Nephroblastomatosis

In This Section

• General Information About Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)
• Treatment of Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)

General Information About Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)

Some multifocal nephrogenic rests may become hyperplastic, which may produce a thick rind of blastemal or tubular cells that enlarge the kidney. Radiological studies may be helpful in making the difficult distinction between diffuse hyperplastic perilobar nephroblastomatosis and Wilms tumor. On magnetic resonance imaging, nephrogenic rests appear homogeneous and hypointense with contrast, whereas Wilms tumor has mixed echogenicity and inhomogeneous appearance. Incisional biopsies are difficult to interpret, and it is essential that the biopsy includes the juncture between the lesion and surrounding renal parenchyma.[1] Differentiation may occur after chemotherapy is administered.

Treatment of Nephroblastomatosis (Diffuse Hyperplastic Perilobar Nephroblastomatosis)

Treatment options for diffuse hyperplastic perilobar nephroblastomatosis include the following:

1. Preoperative chemotherapy.
2. Renal-sparing surgery. Given the high incidence of bilaterality and subsequent Wilms tumors, renal-sparing surgery may be indicated.[1]

Evidence (preoperative chemotherapy and surgery):

1. In a series of 52 patients with diffuse hyperplastic perilobar nephroblastomatosis, 33 patients were treated with chemotherapy and/or radiation therapy initially, 16 patients underwent unilateral nephrectomy, and 3 patients were observed only.[1]
   • A total of 24 patients developed Wilms tumor (including the 3 patients who were observed only), at a median of 30 months.
   • Eighteen of the 33 patients who received adjuvant chemotherapy alone developed a Wilms tumor.
   • Of 16 patients who underwent a nephrectomy and adjuvant therapy, 3 developed Wilms tumor, despite the fact that 14 of 16 patients had bilateral disease.
   • Thirty-three percent of the patients who developed Wilms tumor had anaplastic Wilms tumor at some time during their course, probably as a result of selection of chemotherapy-resistant tumors, so early detection is critical.

On the basis of this report, it is recommended that patients with diffuse hyperplastic perilobar nephroblastomatosis are monitored by imaging at a maximum interval of 3 months, for a minimum of 7 years; complete resection of growing lesions should be strongly considered because of this high incidence of anaplasia after chemotherapy.[1]

References

1. 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]

Treatment of Recurrent Childhood Kidney Tumors

In This Section

• Prognosis, Prognostic Factors, and Risk Categories for Recurrent Wilms Tumor
• Treatment of Standard-Risk Relapsed Wilms Tumor
  • Surgery, radiation therapy, and chemotherapy
• Treatment of High-Risk and Very High-Risk Relapsed Wilms Tumor
  • Chemotherapy, surgery, and/or radiation therapy
  • HSCT
• Treatment Options Under Clinical Evaluation for Recurrent Wilms Tumor
• Treatment of Recurrent Clear Cell Sarcoma of the Kidney
  • Treatment options under clinical evaluation for recurrent clear cell sarcoma of the kidney
• Treatment of Recurrent Congenital Mesoblastic Nephroma
  • Treatment options under clinical evaluation for recurrent congenital mesoblastic nephroma
• Current Clinical Trials

Patients with recurrent rhabdoid tumor of the kidney, clear cell sarcoma of the kidney, neuroepithelial tumor of the kidney, and renal cell carcinoma should be considered for treatment on available phase I and phase II clinical trials.

Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.

Table 8 describes the treatment options for recurrent childhood kidney tumors.

Table 8. Treatment Options for Recurrent Childhood Kidney Tumors

Tumor Type	Treatment Options
Standard-risk relapsed Wilms tumor	Surgery, radiation therapy, and chemotherapy
High-risk and very high-risk relapsed Wilms tumor	Chemotherapy, surgery, and/or radiation therapy
	Hematopoietic stem cell transplantation
Recurrent clear cell sarcoma of the kidney	Chemotherapy, surgery, and/or radiation therapy
Recurrent congenital mesoblastic nephroma	Surgery, chemotherapy, and radiation therapy

Prognosis, Prognostic Factors, and Risk Categories for Recurrent Wilms Tumor

Approximately 15% of patients with favorable-histology (FH) Wilms tumor and 50% of patients with anaplastic-histology Wilms tumor experience recurrence.[1] The most common site of relapse is lung, followed by abdomen/flank and liver. Recurrence in the brain (0.5%) or bone is rare in children with Wilms tumor.[2,3] Historically, the salvage rate for patients with recurrent FH Wilms tumor was 25% to 40%. As a result of modern treatment combinations, the outcome after recurrence has improved up to 60%.[4,5]

A number of potential prognostic features influencing postrecurrence outcome have been analyzed, but it is difficult to determine whether these factors are independent of each other. Also, the following prognostic factors appear to be changing as therapy for primary and recurrent Wilms tumor evolves:

• Anaplastic histology.[6]
• Advanced tumor stage.[6]
• Sex. Sex was predictive of outcome, with males faring worse than females.[4,7]

The National Wilms Tumor Study (NWTS)-5 trial (NWTS-5 [COG-Q9401/NCT00002611]) showed that time to recurrence and site of recurrence are no longer prognostically significant.[4,7] However, in an International Society of Pediatric Oncology (SIOP) study, patients who experienced a pulmonary relapse within 12 months of diagnosis had a poorer prognosis (5-year overall survival [OS], 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS, 75%).[8]

On the basis of these results, the following three risk categories have been identified:

• Standard risk: Patients with FH Wilms tumor who relapse after therapy with only vincristine and/or dactinomycin. These patients are expected to have an event-free survival (EFS) of 70% to 80%.[5] This group represents approximately 30% of recurrences.
• High risk: Patients with FH Wilms tumor who relapse after therapy with three or more agents. These patients account for 45% to 50% of children with Wilms tumor who relapse and have survival rates in the 40% to 50% range.[5]
• Very high risk: Patients with recurrent anaplastic or blastemal-predominant Wilms tumor. These patients are expected to have survival rates in the 10% range, and they experience 10% to 15% of all Wilms tumor relapses.[5,9]

Treatment of Standard-Risk Relapsed Wilms Tumor

In children who had small stage I Wilms tumor and were treated with surgery alone, the EFS was 84%. All but one child who relapsed was salvaged with treatment tailored to the site of recurrence.[7,10]

Successful retreatment can be accomplished for Wilms tumor patients whose initial therapy consisted of immediate nephrectomy followed by chemotherapy with vincristine and dactinomycin and who relapse.

Treatment options for standard-risk relapsed Wilms tumor include the following:

1. Surgery, radiation therapy, and chemotherapy.

Surgery, radiation therapy, and chemotherapy

Evidence (surgery, radiation therapy, and chemotherapy):

1. Fifty-eight patients were treated on the NWTS-5 relapse protocol with surgical excision when feasible, radiation therapy, and alternating courses of vincristine, doxorubicin, and cyclophosphamide; and etoposide and cyclophosphamide.[7]
   • Four-year EFS after relapse was 71%, and OS was 82%.
   • For patients whose site of relapse was only the lungs, the 4-year EFS rate was 68%, and the OS rate was 81%.

Treatment of High-Risk and Very High-Risk Relapsed Wilms Tumor

Treatment options for high-risk and very high-risk relapsed Wilms tumor include the following:

1. Chemotherapy, surgery, and/or radiation therapy.
2. Hematopoietic stem cell transplantation (HSCT).

Chemotherapy, surgery, and/or radiation therapy

Evidence (chemotherapy, surgery, and/or radiation therapy):

1. Approximately 50% of unilateral Wilms tumor patients who relapse or progress after initial treatment with vincristine, dactinomycin, and doxorubicin and radiation therapy can be successfully re-treated. Sixty patients with unilateral Wilms tumor were treated on the NWTS-5 relapse protocol with alternating courses of cyclophosphamide/etoposide and carboplatin/etoposide, surgery, and radiation therapy.[4][Level of evidence: 2A]
   • The 4-year EFS rate for patients with high-risk Wilms tumor was 42%, and the OS rate was 48%.
   • High-risk patients who relapsed in the lungs only had a 4-year EFS rate of 49% and an OS rate of 53%.

Patients with stage II, stage III, and stage IV anaplastic-histology tumors at diagnosis have a very poor prognosis upon recurrence.[9] The combination of ifosfamide, etoposide, and carboplatin demonstrated activity in this group of patients, but significant hematologic toxic effects have been observed.[11]

HSCT

High-dose chemotherapy followed by autologous HSCT has been utilized for recurrent high-risk patients.[12-14]

Evidence (HSCT):

1. 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 with FH tumors were assigned to maintenance chemotherapy with five cycles of alternating CE and PE, and the rest of the patients were assigned to ablative therapy and autologous stem cell rescue. All patients received local radiation therapy.[15]
   • The 3-year survival was 52% for all eligible patients, while the 3-year survival was 64% for the chemotherapy consolidation subgroup and 42% for the autologous stem cell rescue subgroup.
2. The outcomes of 253 patients with relapsed Wilms tumor who received high-dose chemotherapy followed by autologous HSCT between 1990 and 2013 were reported to and reviewed by the Center for International Blood and Marrow Transplantation Research.[16]
   • The 5-year estimate for EFS was 36%, and the 5-year estimate for OS was 45%.
   • Relapse of primary disease was the cause of death in 81% of the population.

The outcome of autologous stem cell rescue in selected patients is favorable; however, patients with gross residual disease going into transplant do not do as well.[12,14,17] No randomized trials of chemotherapy versus transplant have been reported, and case series suffer from selection bias.

Patients in whom such salvage attempts fail should be offered treatment on available phase I or phase II studies.

Treatment Options Under Clinical Evaluation for Recurrent Wilms Tumor

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Treatment of Recurrent Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney has been characterized by late relapses. However, in trials after 1992, most relapses occurred within 3 years, and the most common sites of recurrence were the brain and the lungs.[18,19] In a series of 37 patients with clear cell sarcoma of the kidney who relapsed, the 5-year EFS after relapse was 18%, and the OS after relapse was 26%.[19]

The optimal treatment of relapsed clear cell sarcoma of the kidney has not been established. Treatment of patients with recurrent clear cell sarcoma of the kidney depends on initial therapy and site of recurrence.

Treatment options for recurrent clear cell sarcoma of the kidney include the following:

1. Chemotherapy, complete surgical resection (if possible), and/or radiation therapy.

Cyclophosphamide and carboplatin should be considered if not used initially. Patients with recurrent clear cell sarcoma of the kidney, in some cases involving the brain, have responded to treatment with ifosfamide, carboplatin, and etoposide (ICE) coupled with local control consisting of surgical resection, radiation therapy, or both.[19]; [20][Level of evidence: 2A]

The use of high-dose chemotherapy followed by stem cell transplant is undefined in patients with recurrent clear cell sarcoma of the kidney. A total of 24 patients with relapsed clear cell sarcoma of the kidney received high-dose chemotherapy followed by autologous stem cell transplant. Of those patients, 12 (50%) were alive without disease after a median of 52 months. It should be noted that patients who had already achieved a second complete remission were more likely to receive high-dose chemotherapy.[13,19,20]

Treatment options under clinical evaluation for recurrent clear cell sarcoma of the kidney

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Treatment of Recurrent Congenital Mesoblastic Nephroma

Relapses were reported in 4% of patients with congenital mesoblastic nephroma, and all relapses occurred within 12 months after diagnosis. Most relapses occur locally, although metastatic relapses have been reported.[21] About 70% of patients who relapsed survived with individualized treatment comprising combinations of surgery, chemotherapy, and radiation therapy.[21]

Treatment options under clinical evaluation for recurrent congenital mesoblastic nephroma

Consideration should be given to targeted therapy for patients with recurrent or refractory disease containing the ETV6/NTRK3 fusion.

Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
  Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
  The cellular subtype of congenital mesoblastic nephroma, which commonly harbors the ETV6-NTRK3 fusion, is associated with relapsed disease. Patients should consider enrolling on this trial because one of the treatment arms (APEC1621A [NCT03213704]) uses larotrectinib, which inhibits NTRK fusions.
• LOXO-TRK-15003 (NCT02637687) (Oral TRK Inhibitor LOXO-101 for Treatment of Advanced Pediatric Solid or Primary Central Nervous System [CNS] Tumors): This is a multicenter, open-label, phase I study of pediatric patients with advanced solid or primary CNS tumors. LOXO-101 will be administered orally twice daily, with the dose adjusted by body surface area.
• RXDX-101-03 (NCT02650401) (Study of RXDX-101 in Children With Recurrent or Refractory Solid Tumors and Primary CNS Tumors): This is a four-part, open-label, phase I/Ib, dose-escalation study in pediatric patients with relapsed or refractory solid tumors, primary CNS tumors, neuroblastoma, and non-neuroblastoma, extracranial solid tumors with NTRK1/2/3, ROS1, or ALK gene rearrangements. The study is designed to explore the safety, maximum tolerated dose or recommended phase II dose, pharmacokinetics, and antitumor activity of entrectinib (RXDX-101).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. 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]
2. Venkatramani R, Chi YY, Coppes MJ, et al.: Outcome of patients with intracranial relapse enrolled on national Wilms Tumor Study Group clinical trials. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
3. Iaboni DSM, Chi YY, Kim Y, et al.: Outcome of Wilms tumor patients with bone metastasis enrolled on National Wilms Tumor Studies 1-5: A report from the Children's Oncology Group. Pediatr Blood Cancer : e27430, 2018. [PUBMED Abstract]
4. 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]
5. Reinhard H, Schmidt A, Furtwängler R, et al.: Outcome of relapses of nephroblastoma in patients registered in the SIOP/GPOH trials and studies. Oncol Rep 20 (2): 463-7, 2008. [PUBMED Abstract]
6. 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]
7. 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]
8. Warmann SW, Furtwängler R, Blumenstock G, et al.: Tumor biology influences the prognosis of nephroblastoma patients with primary pulmonary metastases: results from SIOP 93-01/GPOH and SIOP 2001/GPOH. Ann Surg 254 (1): 155-62, 2011. [PUBMED Abstract]
9. 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]
10. Shamberger RC, Anderson JR, Breslow NE, et al.: Long-term outcomes for infants with very low risk Wilms tumor treated with surgery alone in National Wilms Tumor Study-5. Ann Surg 251 (3): 555-8, 2010. [PUBMED Abstract]
11. 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]
12. 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]
13. 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]
14. 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]
15. 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.
16. Malogolowkin MH, Hemmer MT, Le-Rademacher J, et al.: Outcomes following autologous hematopoietic stem cell transplant for patients with relapsed Wilms' tumor: a CIBMTR retrospective analysis. Bone Marrow Transplant 52 (11): 1549-1555, 2017. [PUBMED Abstract]
17. Spreafico F, Bisogno G, Collini P, et al.: Treatment of high-risk relapsed Wilms tumor with dose-intensive chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic stem cell support: experience by the Italian Association of Pediatric Hematology and Oncology. Pediatr Blood Cancer 51 (1): 23-8, 2008. [PUBMED Abstract]
18. 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.
19. Gooskens SL, Furtwängler R, Spreafico F, et al.: Treatment and outcome of patients with relapsed clear cell sarcoma of the kidney: a combined SIOP and AIEOP study. Br J Cancer 111 (2): 227-33, 2014. [PUBMED Abstract]
20. 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]
21. Gooskens SL, Houwing ME, Vujanic GM, et al.: Congenital mesoblastic nephroma 50 years after its recognition: A narrative review. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer need to be referred to medical centers that have multidisciplinary teams of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

• Primary care physicians.
• Pediatric surgical subspecialists.
• Radiation oncologists.
• Pediatric medical oncologists/hematologists.
• Rehabilitation specialists.
• Pediatric nurse specialists.
• Social workers.

Refer to the PDQ summaries on Supportive and Palliative Care 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.[2] 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 and their 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 under the auspices of cooperative groups such as the Children's Oncology GroupExit Disclaimer (COG) and the International Society of Pediatric OncologyExit Disclaimer (SIOP). Information about ongoing clinical trials is available from the NCI website.

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Changes to This Summary (06/13/2019)

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.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Wilms Tumor and Other Childhood Kidney Tumors Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Christopher N. Frantz, MD (Alfred I. duPont Hospital for Children)
• Andrea A. Hayes-Jordan, MD, FACS, FAAP (University of North Carolina - Chapel Hill School of Medicine)
• Nita Louise Seibel, MD (National Cancer Institute)
• Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

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 Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Wilms Tumor and Other Childhood Kidney Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/wilms-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389282]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.

• Updated: June 13, 2019