医療専門家向け Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)

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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.

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).

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General Information About Childhood Kidney Tumors

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[ 1 ] For children younger than 15 years with Wilms tumor, the 5-year survival rate has increased over the same time from 74% to 88%.[ 1 ] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood kidney cancers account for about 7% of all childhood cancers. Most childhood kidney cancers are Wilms tumor, but in the 15- to 19-year age group, most tumors are renal cell carcinoma. Wilms tumor can affect one kidney (unilateral) or both kidneys (bilateral). Less common types of childhood kidney tumors include rhabdoid tumors, clear cell sarcoma, congenital mesoblastic nephroma, Ewing sarcoma of the kidney, primary renal myoepithelial carcinoma, cystic partially differentiated nephroblastoma, multilocular cystic nephroma, primary renal synovial sarcoma, and anaplastic sarcoma. Nephroblastomatosis of the kidney is a type of nonmalignant neoplasia.[ 2 ][ 3 ]

参考文献

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014.[PUBMED Abstract]
2. Ahmed HU, Arya M, Levitt G, et al.: Part I: Primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (8): 730-7, 2007.[PUBMED Abstract]
3. 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]

Wilms Tumor

Incidence of Wilms Tumor

Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years, or one case per 10,000 infants.[ 1 ] Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians.

The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in bilateral cases, it is 0.60 to 1.00. The mean age at diagnosis is 44 months in unilateral cases and 31 months in bilateral cases of Wilms tumor.[ 2 ][ 3 ] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[ 4 ]

Syndromes and Other Conditions Associated With Wilms Tumor

Wilms tumor typically develops in otherwise healthy children without any predisposition to developing cancer; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[ 4 ][ 5 ] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases.[ 6 ] Of 295 consecutive patients with Wilms tumor seen at the Institut Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes.[ 7 ]

Children with Wilms tumor may have associated hemihyperplasia and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have recognizable phenotypic syndromes such as overgrowth, aniridia, genetic malformations, and others. These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes and other conditions have been grouped into overgrowth and non-overgrowth categories (refer to Table 1). Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[ 8 ][ 9 ]

It is important to recognize that the absolute risk of Wilms tumor varies with the underlying condition or anomaly. For example, most patients with hemihyperplasia will not develop Wilms tumor.

Table 1. Syndromes and Conditions Associated With Wilms Tumor^a

Syndrome/Condition	Gene	Overgrowth Phenotype	Non-Overgrowth Phenotype
High Risk of Wilms Tumor (>20%)
CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities; MULIBREY = distinctive abnormalities of the (MU)scles, (LI)ver, (BR)ain, and (EY)es; WAGR = Wilms tumor, aniridia, genitourinary anomaly, and mental retardation.
aAdapted from Treger et al.[ 10 ]
WAGR syndrome	WT1 deletion		X
Denys-Drash syndrome	WT1 missense mutation		X
Perlman syndrome	DIS3L2 mutation	X
Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN)	BRCA2, PALB2		X
Premature chromatid separation/mosaic variegated aneuploidy	Biallelic BUB1B or TRIP13 mutation		X
Moderate Risk of Wilms Tumor (5%–20%)
Frasier syndrome	WT1 intron 9 splice mutation		X
Beckwith-Wiedemann syndrome	Uniparental disomy or H19 epimutation	X
Simpson-Golabi-Behmel syndrome	GPC3 mutation	X
Low Risk of Wilms Tumor (<5%)
Bloom syndrome	Biallelic BLM mutation		X
DICER1 syndrome	DICER1 mutation	X
Li-Fraumeni syndrome	TP53, CHEK2		X
Isolated hemihyperplasia		X
Hyperparathyroidism-jaw tumor syndrome	CDC73 (also known as HRPT2) mutation		X
MULIBREY nanism syndrome	TRIM37 mutation		X
PIK3CA-related segmental overgrowth including CLOVES syndrome	PIK3CA mutation	X
9q22.3 microdeletion syndrome	9q22.3	X
Sotos syndrome	NSD1	X
Familial Wilms tumor	FWT1		X
	FWT2
Genitourinary anomalies	WT1		X
Sporadic aniridia	WT1		X
Trisomy 18			X

For information about the genes associated with Wilms tumor, including WT1 and WT2, refer to the Genomics of Wilms Tumor section of this summary.

Syndromic causes of Wilms tumor

WT1-related syndromes include the following:

WT2-related syndromes include the following:

Other syndromic causes of Wilms tumor include the following:

Nonsyndromic causes of Wilms tumor

Nonsyndromic causes of Wilms tumor include the following:

Genomics of Wilms Tumor

Wilms tumors, similar to other pediatric embryonal neoplasms, typically arise after a limited number of genetic aberrations. One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors followed by targeted sequencing of 651 Wilms tumors.[ 59 ] The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:[ 59 ]

Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or WTX.[ 60 ][ 61 ] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[ 62 ][ 63 ][ 64 ][ 65 ] Other genes critical for early renal development that are recurrently mutated in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[ 62 ][ 63 ] EP300, CREBBP, and MYCN.[ 59 ] Of the mutations in Wilms tumors, 30% to 50% appear to converge on the process of transcriptional elongation in renal development and include the genes MLLT1, BCOR, MAP3K4, BRD7, and HDAC4.[ 59 ] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.

Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[ 66 ] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[ 50 ][ 67 ]

The genomic and genetic characteristics of Wilms tumor are summarized below.

WT1 gene

The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[ 68 ] WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[ 60 ][ 68 ][ 69 ]

Wilms tumor with a WT1 mutation is characterized by the following:

Germline WT1 mutations are more common in children with Wilms tumor and one of the following:

Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[ 17 ] and Frasier syndrome.[ 14 ]

Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[ 79 ][ 80 ]

Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[ 79 ][ 80 ] Bilateral Wilms tumor was more common in cases with WT1-truncating mutations (9 of 14 cases) than in cases with WT1 missense mutations (3 of 27 cases).[ 79 ][ 80 ] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.

Late effects associated with WAGR syndrome and Wilms tumor include the following:

(Refer to the Late effects after Wilms tumor therapy section of the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information about the late effects associated with Wilms tumor.)

CTNNB1 gene

CTNNB1 is the most commonly mutated gene in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[ 59 ][ 61 ][ 69 ][ 71 ][ 83 ] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[ 84 ] CTNNB1 mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1 mutations have a concurrent CTNNB1 mutation.[ 69 ][ 71 ][ 83 ] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation, except when associated with a MLLT1 mutation.[ 61 ][ 85 ] CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[ 74 ]

WTX gene on the X chromosome

WTX, which is also called AMER1, is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[ 60 ][ 61 ][ 69 ][ 86 ][ 87 ] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373).[ 88 ] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[ 88 ] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[ 85 ][ 89 ] WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[ 60 ][ 69 ][ 86 ] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[ 69 ]

WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[ 60 ]

Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[ 51 ]

Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[ 27 ][ 28 ][ 29 ] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[ 2 ][ 29 ]

Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[ 90 ] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[ 51 ][ 91 ]

Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[ 91 ] LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[ 51 ][ 90 ][ 91 ]

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[ 92 ]

The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:

1. ICR1 gain of methylation (ICR1-GoM). Five percent to 10% of cases are caused by telomeric ICR1-GoM, which causes both biallelic expression of the IGF2 gene (normally expressed by the paternal allele only) and reduced expression of the oncosuppressor H19 gene. The incidence of Wilms tumor is 22.8%.[ 93 ]
2. ICR2 loss of methylation (ICR2-LoM). Fifty percent of cases with Beckwith-Wiedemann syndrome are caused by ICR2-LoM, resulting in reduced expression of the CDKN1C gene, normally expressed by the maternal chromosome only. Tumor incidence is very low (2.5%).[ 93 ]
3. Uniparental disomy (UPD). Altered expression at both imprinted gene clusters is observed in mosaic UPD of chromosome 11p15.5, accounting for 20% to 25% of the cases. The incidence of Wilms tumor is 6.2%, followed by hepatoblastoma (4.7%) and adrenal carcinoma (1.5%).[ 93 ] Fewer than 1% of cases with Beckwith-Wiedemann syndrome are caused by chromosomal rearrangements involving the 11p15 region.
4. CDKN1C mutations. Maternally inheritable CDKN1C loss-of-function mutations account for approximately 5% of the cases. This type is associated with a 4.3% incidence of neuroblastoma.[ 93 ]

Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[ 21 ][ 25 ][ 94 ] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[ 29 ]

Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[ 95 ] Interestingly, Wilms tumor in Asian children, which occur at a lower incidence than in European children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.[ 96 ]

Other genes and chromosomal alterations

Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:

Figure 2 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[ 75 ] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-mutant tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with a mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both MLLT1 and with WT1/WTX/CTNNB1-mutated cases.

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Bilateral Wilms Tumor

Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes. For example, in 545 cases of bilateral Wilms tumors, bona fide pathogenic germline variants were found in 22% of patients.[ 120 ] The most common predisposition variants are mutations of WT1 and 11p15 loss of imprinting.[ 20 ][ 68 ]

Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. Three percent of patients with bilateral Wilms tumor have affected family members.[ 121 ]

Screening Children Predisposed to Wilms Tumor

Children with a significant increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihyperplasia) are usually screened with ultrasonography every 3 months until they reach at least age 8 years.[ 78 ][ 122 ] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.[ 122 ]

Tumor screening programs for each overgrowth syndrome have been suggested. These programs were based on published age, incidence of tumor type, and recommendations from the 2016 American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop. Although data about different cancer risks based on genetic or epigenetic subgroups for certain syndromes are emerging, and subgroup-specific recommendations have been developed in Europe, these practices have not been adopted in the United States. The AACR workshop committee proposed a uniform screening approach for all syndromes associated with a greater-than-1% risk of Wilms tumor. Additional screening for hepatoblastoma by serum alpha-fetoprotein (AFP) measurement and ultrasonography is also recommended for patients with Beckwith-Wiedemann syndrome, trisomy 18, and Simpson-Golabi-Behmel syndrome.[ 123 ]

Genetic counseling

The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.

A French study concluded that patients need to be referred for genetic counseling if they have one of the following:[ 7 ]

Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.[ 7 ]

After genetic counseling takes place, testing for WT1 mutations should be considered for patients who have the following:

Testing for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihyperplasia, or bilateral or familial Wilms tumor.

Clinical Features of Wilms Tumor

Most Wilms tumor patients present asymptomatically with an abdominal mass noticed by a parent or pediatrician on a well-child visit. In children with known predisposing clinical syndromes, renal tumors can be found during routine screening. Other findings include the following:

Children with Wilms tumor or other renal malignancies may also come to medical attention as a result of the following:

Diagnostic and Staging Evaluation for Wilms Tumor

Tests and procedures used to diagnose and stage Wilms tumor and other childhood kidney tumors include the following:

1. Physical exam and history. Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihyperplasia.
2. Complete blood count (CBC).
3. Liver function test.
4. Renal function test.
5. Urinalysis.
6. Abdominal imaging.
7. Chest x-ray is unnecessary if chest CT is performed initially.
8. CT scan of chest. The common sites of metastases for Wilms tumor are the lung and liver. Approximately 15% of patients will present with pulmonary metastases. CT scanning provides the most sensitive method of detecting metastatic lung nodules.
9. Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG PET-CT imaging adds clinically applicable information to conventional CT scan imaging. PET-CT may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.[ 138 ]
10. von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have an acquired form of von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[ 139 ] Some clinicians recommend evaluation for von Willebrand disease before surgery.
11. Biopsy or resection and the issue of bilateral Wilms. In children with a renal mass that clinically appears to be resectable Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. In North America, the initial treatment in most cases is primary nephrectomy. If a primary nephrectomy cannot be performed, a biopsy, either open or with multiple cores, is required. The contraindications to primary nephrectomy are the following:

    Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. However, the use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread and the histologic classification of the Wilms tumor cannot be determined by biopsy.[ 140 ]

    If a child undergoes a biopsy as the first procedure, they are considered stage III because they have gross residual tumors.

    In children with a renal mass that clinically appears to be stage I or stage II Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. Nephrectomy (in North America) or chemotherapy (in Europe) is performed instead. Therefore, the diagnostic pathology is first seen when the nephrectomy specimen is examined.

    Children who have bilateral Wilms tumor are often treated without a biopsy.[ 141 ]

    Biopsy of a renal mass may be indicated if the mass is atypical by radiographic appearance for Wilms tumor, and the patient is not going to undergo immediate nephrectomy. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions.[ 140 ]

    Anaplastic histology can be difficult to detect in any biopsy sample because of tumor heterogeneity. It is important to recognize that data from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) have shown that, because of the histologic heterogeneity of Wilms tumor, a significant number of patients have anaplastic histology that is missed during an upfront biopsy whether it be a core needle biopsy or an incisional biopsy [ 142 ] but revealed at the time of definitive surgery after chemotherapy.

    Detection of a contralateral renal lesion in a child with Wilms tumor can change the stage and initial management of the patient, indicating a role for a renal-sparing approach without up-front surgery. The detection of contralateral renal lesions is important at baseline imaging because routine intraoperative exploration of the contralateral kidney is no longer recommended on the basis of the results of the NWTS-4 study.[ 133 ][ 136 ] If the initial imaging studies suggests a bilateral process, treatment as a bilateral Wilms tumor is recommended by the authors. If the origin of the other lesion is indeterminate, the authors recommend pathological assessment of that lesion before proceeding with a nephrectomy.[ 133 ][ 136 ]

    In children with bilateral Wilms tumor, biopsy can be avoided if the child is of typical age and radiographic appearance. This was assessed on the COG AREN0534 (NCT00945009) study where 187 of 189 patients were treated initially without a biopsy. All had Wilms tumors. If after 6 weeks of therapy, response was less then 30% by RECIST1.1 criteria, bilateral biopsies were performed to assess for anaplasia, stromal differentiation, and rhabdomyomatous changes. If anaplasia was detected, the chemotherapy treatment was changed. If the other two were detected, further chemotherapy was unlikely to result in tumor shrinkage and definitive surgery was recommended by the authors.[ 141 ]

12. Lymph node sampling is required to locally stage all Wilms tumor patients. Lymph nodes have shown to be of major prognostic value for both short-term and long-term survival. Gross inspection is notoriously inaccurate, with a false-negative rate of 31.3% and a false-positive rate of 18.1%.[ 143 ]

About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[ 144 ]

For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess intravascular extension or rupture of Wilms tumor.[ 135 ]

Prognosis and Prognostic Factors for Wilms Tumor

Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with favorable histology (FH) has been consistently above 90%.[ 147 ] This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.[ 148 ]

The prognosis for patients with Wilms tumor depends on the following:[ 149 ][ 150 ][ 151 ][ 152 ]

Older adolescents and adults with Wilms tumor

Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million per year.[ 154 ] In Europe, the median age at diagnosis for adult patients with Wilms tumor (defined as age >15 years) is 34 years; however, patients older than 60 years have been reported.[ 154 ] Three percent of Wilms tumors occur in adults. Wilms tumor represents less than 1% of all renal tumors in adults and may be an unexpected finding after nephrectomy for presumed renal cell carcinoma, which is the most common adult renal cancer.

The outcome for adolescent and young adult (AYA) patients (aged 15 to 39 years) is inferior to the outcome for children. In an analysis of patients with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database, AYA patients (n = 104) had a statistically worse 5-year OS (69% vs. 94%; P < .001) than did pediatric patients (n = 2,574).[ 155 ][Level of evidence: 3iA] Better results have been reported for adults when they are treated in pediatric trials. The National Wilms Tumor Study (NWTS) Group reported the outcomes for adult patients with Wilms tumor from the NWTS-1, -2, and -3 trials. The 3-year OS rate for adults on the NWTS-1 trial was 24% (compared with 74% in children) and improved to a 5-year OS rate of 82.6% on the NWTS-3 trial, although the number of adult patients treated on each trial was 31 or fewer.[ 156 ][ 157 ][ 158 ] These data suggest that many adults with Wilms tumor, if treated appropriately, can expect to be cured, especially if the tumor has not spread and/or is completely resected. The inferior outcome of the adult patients may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), undertreatment/poor compliance (e.g., not receiving radiation therapy), unfamiliarity of medical oncologists and pathologists with Wilms tumors in adults (possibly leading to diagnostic error and delay), delays in initiating the appropriate risk-adapted therapy, and lack of specific treatment protocols for adults. For adults with refractory or recurrent disease, screening for potential therapeutic targets in the tumor should be considered.[ 159 ]

The following recommendations from the renal tumor committees of the International Society of Pediatric Oncology (SIOP) and COG encourage a uniform approach to improve outcome for adults with Wilms tumor.[ 160 ]

Histologic Findings in Wilms Tumor

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

Favorable histology (FH)

Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.

While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.[ 161 ]

Anaplastic histology

Anaplastic histology accounts for about 10% of Wilms tumor cases. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology.[ 162 ] In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[ 163 ][ 164 ]

The following two histologic criteria must be present to confirm the diagnosis of anaplasia:

Changes on 17p consistent with mutations in the TP53 gene have been associated with foci of anaplastic histology.[ 109 ] Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions.[ 165 ] Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[ 151 ][ 166 ][ 167 ]

Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.[ 151 ]

Nephrogenic rests

Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumor, and nearly 100% of kidneys with bilateral Wilms tumor.[ 168 ][ 169 ] Preoperative chemotherapy does not appear to affect the overall prevalence of nephrogenic rests. Congenital anomalies have been reported in 12% of patients with nephrogenic rests, including in 9% of patients with unilateral Wilms tumor and in 33% of patients with bilateral disease.[ 6 ]

The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests can be subclassified according to the category of rest (intralobar or perilobar nephrogenic rests) and their growth phase (incipient or dormant nephrogenic rests, hyperplastic nephrogenic rests, and regressing or sclerosing nephrogenic rests). Diffuse hyperplastic perilobar nephroblastomatosis represents one unique category of nephroblastomatosis that forms a thick rind around one or both kidneys and is considered a preneoplastic condition. Distinguishing between Wilms tumor and diffuse hyperplastic perilobar nephrogenic rests may be a challenge, and it is critical to examine the juncture between the lesion and the surrounding renal parenchyma. Incisional biopsies are of no diagnostic value unless they include the margin between the lesion and the normal renal parenchyma.[ 170 ]

The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both).[ 81 ] Intralobar nephrogenic rests have been associated with stromal-type Wilms tumor and younger age at diagnosis.[ 6 ]

Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.[ 47 ]

Bilateral diffuse hyperplastic perilobar nephroblastomatosis is generally treated with chemotherapy to reduce the risk of developing Wilms tumor; however, the risk of developing Wilms tumor remains high, 55% in one series.[ 170 ] Patients who have been treated with chemotherapy for a prolonged period of time remain at high risk of developing Wilms tumor. If these patients develop Wilms tumor, they have a poorer prognosis than do other bilateral Wilms tumor patients, presumably because of the increased incidence of anaplasia in these cases (more than one-third of cases), and perhaps as a result of the development and selection of anaplasia in the surviving abnormal kidney cells.[ 170 ][ 171 ]

Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.[ 172 ]

Stage Information for Wilms Tumor

Both the results of the imaging studies and the surgical and pathologic findings at nephrectomy are used to determine the stage of disease. The stage is the same for tumors with FH or anaplastic histology. Thus, the stage information is characterized by a statement of both criteria (for example, stage II, FH or stage II, anaplastic histology).[ 161 ][ 173 ]

The staging system was originally developed by the NWTS Group and is still used by the COG. The staging system used in North America and incidence by stage are outlined below.[ 161 ]

Stage I

In stage I Wilms tumor (43% of patients), all of the following criteria must be met:

For a tumor to qualify for certain therapeutic protocols such as very low-risk stage I, regional lymph nodes must be examined microscopically. Lymph node sampling is strongly recommended for all patients, even in the absence of clinical abnormal nodes, to achieve the most accurate stage.

Stage II

In stage II Wilms tumor (20% of patients), the tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney as evidenced by any one of the following criteria:

All lymph nodes sampled are negative.

Rupture or spillage confined to the flank, including biopsy of the tumor, is now included in stage III by the COG Renal Tumor Committee (COG RTC); however, data to support this approach are controversial.[ 140 ][ 174 ]

Stage III

In stage III Wilms tumor (21% of patients), there is postsurgical residual nonhematogenous tumor that is confined to the abdomen. Any one of the following may occur:

Lymph node involvement and microscopic residual disease are reported as highly predictive of outcome in patients with stage III FH Wilms tumor.[ 175 ]

Stage IV

In stage IV Wilms tumor (11% of patients), one of the following is present:

The presence of tumor within the adrenal gland is not interpreted as metastasis and staging depends on all other staging parameters present. According to the criteria described above, the primary tumor is assigned a local stage, which determines local therapy. For example, a patient may have stage IV, local stage III disease.

Stage V

In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. The current paradigm treats all patients with bilateral Wilms tumor the same for the first 6 or 12 weeks. After definitive surgery, the treatment is based on the highest stage of the remaining kidneys and the posttreatment pathology.[ 141 ]

Treatment of Wilms Tumor

Treatment option overview for Wilms tumor

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

Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups (COG RTC and SIOP). Differences between the two groups affect staging and classification. There are two standard approaches to Wilms tumor treatment: the COG RTC uses immediate surgery for all unilateral tumors and the SIOP uses preoperative chemotherapy as the first step in treatment. Both groups use postoperative chemotherapy, except for selected cases who do not receive chemotherapy, and in advanced stages, radiation therapy is used in a risk-adapted approach.

This summary focuses on the NWTS (now COG RTC) results and studies.

The major treatment and study conclusions of NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 are as follows:

1. Routine, postoperative radiation therapy of the flank is not necessary for children with stage I tumors or stage II tumors with FH when postnephrectomy combination chemotherapy consisting of vincristine and dactinomycin is administered.[ 178 ]
2. The prognosis for patients with stage III FH is best when treatment includes either (a) dactinomycin, vincristine, doxorubicin, and 10.8 Gy of radiation therapy to the flank; or (b) dactinomycin, vincristine, and 20 Gy of radiation therapy to the flank. Whole abdominal radiation is indicated for extensive intraperitoneal disease or widespread intraperitoneal tumor spill with possible boost to gross residual disease.[ 178 ]
3. The addition of cyclophosphamide at the protocol dose (10 mg/kg/d for 3 days every 6 weeks) to the combination of vincristine, dactinomycin, and doxorubicin does not improve prognosis for patients with stage IV FH tumors.[ 178 ]
4. A single dose of dactinomycin per course (stages I–II FH, stage I anaplastic histology, stage III FH, stages III–IV, or stages I–IV clear cell sarcoma of the kidney) is equivalent to the divided-dose courses, results in the same EFS, achieves greater dose intensity, and is associated with less toxicity and expense.[ 182 ]
5. Eighteen weeks of therapy is adequate for patients with stage I and stage II FH, and stage III and IV patients can be treated with 6 months of therapy instead of 15 months.[ 148 ][ 176 ][ 182 ][ 183 ][ 184 ]
6. Gain of 1q is associated with inferior survival in unilateral FH Wilms tumor. It is the single most powerful predictor of outcome, and in the presence of 1q gain, neither 1p nor 16q loss is significant. In the absence of 1q gain in unilateral FH Wilms tumor, 1p and/or 16q loss retain some prognostic significance and are associated with a higher risk of recurrence.[ 97 ][ 99 ]

Surgery

The following operative principles have also evolved from NWTS trials:

1. The most important role for the surgeon is to ensure complete tumor removal without rupture and assess the extent of disease. Radical nephrectomy and lymph node sampling via a transabdominal or thoracoabdominal incision is the procedure of choice.[ 185 ] A flank incision is not performed because it provides limited exposure to the kidney.

   For patients with resectable tumors, preoperative biopsy or intraoperative biopsy is not performed because either would upstage the tumor in the current COG staging system.[ 185 ]

2. Routine exploration of the contralateral kidney is not necessary if technically adequate imaging studies do not suggest a bilateral process. If the initial imaging studies suggest bilateral kidney involvement, treatment approaches should facilitate renal-sparing surgery.[ 136 ]
3. About 2% of Wilms tumor cases have ureteral involvement. The presence of gross hematuria, nonfunctioning kidney, or hydronephrosis suggests the tumor may extend into the ureter, and cystoscopy is recommended. En bloc resection to avoid tumor spill is recommended.[ 186 ]
4. The surgeon needs to be aware of the risk of intraoperative spill, especially in patients who have right-sided and large tumors, as noted in a review of cases of intraoperative spill among 1,131 patients registered on COG study AREN03B2 (NCT00898365).[ 187 ]
5. Even if stage IV disease (e.g., pulmonary metastases) is evident on imaging, resection of the renal tumor should be considered. Treatment of local stage I or II Wilms tumor in the setting of distant metastasis does not require local radiation therapy.

Renal-sparing surgery remains controversial and is not recommended, except for children with the following:[ 188 ][ 189 ]; [ 190 ][Level of evidence: 3iiB]

Renal-sparing surgery does not appear to be feasible for most patients at the time of diagnosis because of the location of the tumor within the kidney, even in patients with very low-risk tumors.[ 192 ] In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor after administration of chemotherapy to shrink the tumor mass is considered investigational.[ 193 ][ 194 ]

Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[ 185 ][ 195 ] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.

Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is seldom indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This finding has led to the recommendation in current COG protocols that patients in whom nephrectomy will require removal of additional organs should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection.[ 196 ] Primary resection of liver metastasis is not recommended.[ 197 ]

Chemotherapy

Preoperative chemotherapy before nephrectomy is indicated in the following situations, which have been listed previously under situations requiring a biopsy (refer to the Diagnostic and Staging Evaluation for Wilms Tumor section of this summary for more information):[ 185 ][ 196 ][ 198 ][ 199 ][ 200 ][ 201 ]

Preoperative chemotherapy follows a biopsy. The biopsy may be performed through a flank approach.[ 145 ][ 202 ][ 203 ][ 204 ][ 205 ][ 206 ] Adequate tissue is essential for accurate histological assessment and molecular studies. Preoperative chemotherapy includes doxorubicin in addition to vincristine and dactinomycin unless anaplastic histology is present; in such cases, chemotherapy then includes treatment with regimen I (refer to Table 2). The chemotherapy generally makes tumor removal easier by decreasing the size and vascular supply of the tumor; it may also reduce the frequency of surgical complications.[ 140 ][ 145 ][ 196 ][ 198 ][ 207 ][ 208 ]

In North America, the use of preoperative chemotherapy in patients with evidence of a contained preoperative rupture has been suggested to avoid intraoperative spill, but this is controversial.[ 209 ][ 210 ] The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists.[ 134 ]

Newborns and all infants younger than 12 months who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children.[ 211 ] Dosing for infants (younger than 12 months) will be calculated per kilogram of weight, not body surface area. This reduction diminishes the toxic effects reported in children in this age group enrolled in NWTS studies while maintaining an excellent overall outcome.[ 212 ]

Liver function tests in children with Wilms tumor are monitored closely during the early course of therapy because hepatic toxic effects (sinusoidal obstructive syndrome, previously called veno-occlusive disease) have been reported in these patients.[ 213 ][ 214 ] Dactinomycin or doxorubicin should not be administered during radiation therapy. Patients who develop renal failure while undergoing therapy can continue receiving chemotherapy with vincristine, dactinomycin, and doxorubicin. Vincristine and doxorubicin can be given at full doses; however, dactinomycin is associated with severe neutropenia. Reductions in dosing these agents may not be necessary, but accurate pharmacologic and pharmacokinetic studies are needed while the patient is receiving therapy.[ 215 ][ 216 ]

Augmentation of therapy improves EFS for patients with FH Wilms tumor and loss of heterozygosity of 1p/16q. In the AREN0532 (NCT00352534) and AREN0533 (NCT00379340) trials, patients with stage I and stage II FH Wilms tumor who were treated with the DD-4A regimen (dactinomycin, vincristine, and doxorubicin) demonstrated a 4-year EFS rate of 87.3%, compared with the 4-year EFS rate of 68.8% (P = .042) for stage I and stage II patients treated on the NWTS-5 trial. Patients with stage III and stage IV disease had a 4-year EFS rate of 90.2% when treated with regimen M, compared with a 61.3% 4-year EFS rate (P = .001) for stage III and stage IV patients treated on the NWTS-5 trial. Trends toward improved 4-year survival rates were seen in stage I and II patients and in stage III and IV patients.[ 217 ][Level of evidence: 3iiiDi]

Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III. In a study of 1,488 patients with Wilms tumors who underwent surgery and radiation therapy, delay in starting radiation therapy after surgery of greater than 14 days was associated with an increased risk of mortality for patients with nonmetastatic Wilms tumor.[ 218 ][Level of evidence: 3iiiA]

Table 2 describes the accepted chemotherapy regimens used to treat Wilms tumor.

Table 2. Accepted Chemotherapy Regimens for Wilms Tumor

Regimen Name	Regimen Description
Regimen EE-4A [ ]	Vincristine, dactinomycin × 18 weeks postnephrectomy
Regimen DD-4A [ ]	Vincristine, dactinomycin, doxorubicin × 24 weeks; baseline nephrectomy or biopsy with subsequent nephrectomy
Regimen I [ ]	Vincristine, doxorubicin, cyclophosphamide, etoposide × 24 weeks postnephrectomy
Regimen M [ ]	Vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide with subsequent radiation therapy
Regimen UH1 [ ]	Vincristine, doxorubicin, cyclophosphamide, carboplatin, and etoposide × 30 weeks + radiation therapy
Regimen UH2 [ ]	Vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, vincristine, and irinotecan × 36 weeks + radiation therapy

Radiation therapy

Radiation therapy is used to improve local control and treat sites of metastatic disease. Radiation therapy has historically been dependent on stage and histology, but more recently is also guided by the tumor molecular signature.[ 221 ]

1. COG approach:

   Upfront surgery provides histologic confirmation and tumor extent, providing the rationale for adjuvant therapy, including radiation therapy. Besides histology, postoperative risk factors for worse local control include: (1) incomplete resection, (2) positive margins, and (3) nodal involvement. Radiation therapy is not used in patients with stage I or stage II FH Wilms tumor. For patients with FH Wilms tumor, flank or abdominal radiation therapy is used for treatment in stage III tumors. In cases of unfavorable histology (focal or diffuse anaplasia), flank or abdominal radiation therapy is indicated for all patients. (Refer to Table 3 for more information.)

   Table 3. Radiation Therapy Guidelines in Children’s Oncology Group AREN0532, AREN0533, and AREN0321 Protocols

   Local/Locoregional Disease
   XRT = radiation therapy.
   aRequires whole-abdominal XRT in 1.5 Gy daily fractions. Patients with diffuse unresectable peritoneal implants receive 21 Gy.
   bWhole-lung irradiation is given in 1.5 Gy daily fractions.
   cNot all patients receive radiation therapy.
   dA boost is given for macroscopic disease.
   	Stage I	Stage II	Stage III	Stage III (diffuse spill, peritoneal metastasis, preoperative rupture)a
   Favorable histology	No XRT	No XRT	10.8 Gy	10.5 Gy
   Focal anaplasia	10.8 Gy	10.8 Gy	10.8 Gy	10.5 Gy
   Diffuse anaplasia	10.8 Gy	10.8 Gy	19.8 Gy	10.5 Gy + 9 Gy boost
   	Metastatic Disease
   	Stage IV Lung	Stage IV Liver	Stage IV Brain	Stage IV Bone
   Favorable histology	10.5 Gy for age <12 monthsb,c; 12 Gy for age >12 monthsb,c	19.8 Gy +/- 5.4 to 10.8 Gy boostd	21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years	25.2 Gy for age <16 years; 30.6 Gy for age >16 years
   Focal or diffuse anaplasia	10.5 Gy for age <12 monthsb; 12 Gy for age >12 monthsb	19.8 Gy +/- 5.4 to 10.8 Gy boostd	21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years	25.2 Gy for age <16 years; 30.6 Gy for age >16 years

2. SIOP approach:

   Children who need radiation therapy undergo postoperative treatment to the flank and/or metastatic sites on the basis of the experience of previous SIOP trials. The SIOP 1 to 9 trials demonstrated that preoperative radiation therapy or preoperative chemotherapy decreased the proportion of patients who developed tumor spillage, from more than 20% to 5%. The noninferiority of preoperative chemotherapy to preoperative radiation therapy in the SIOP 5 trial, and the concern over secondary malignancies with preoperative radiation therapy, led SIOP to recommend preoperative chemotherapy as the standard initial treatment.[ 179 ] Over time, the percentage of children who were treated with postoperative radiation therapy decreased, from more than 90% to 15% and 25% in SIOP trials 6 to 9, SIOP 93-01, and SIOP-2001, respectively.[ 177 ]

Treatment of stage I Wilms tumor

Table 4 provides an overview of the standard treatment options and survival data for patients with stage I Wilms tumor, based on published results.

Table 4. Overview of Standard Treatment Options for Stage I Wilms Tumor^a

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[ 99 ] Shamberger et al.,[ 152 ] Fernandez et al.,[ 221 ] Dix et al.,[ 217 ] and Daw et al.[ 226 ]
bOne patient with a pulmonary relapse 4.12 years after diagnosis.
FH <24 mo/tumor weight <550g	90%	100%	Surgery, including lymph node biopsy only
FH >24 mo/tumor weight >550g	94% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
FH with LOH 1p/16q (n = 8)	100% EFS	100%	Nephrectomy + lymph node sampling followed by regimen DD-4A
FA	100%	100% (n = 8)	Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT
DA	100%b	100% (n = 10)	Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT

The COG validated the hypothesis that nephrectomy only is appropriate therapy for patients younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g in the AREN0532 (NCT00352534) trial. The NWTS-5 trial investigated this approach for children younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g.

Evidence (surgery only for children younger than 2 years at diagnosis with stage I FH tumor that weighed <550 g):

1. The AREN0532 (NCT00352534) trial was designed to confirm the findings from NWTS-5 that adjuvant chemotherapy could be omitted for children younger than 2 years at diagnosis with stage I FH Wilms tumor that weighed less than 550 g. A total of 116 patients met the criteria for very low-risk Wilms tumor and were enrolled on the study.[ 152 ][ 221 ][ 227 ]
2. The COG reported the outcomes for patients of all ages with stage I FH Wilms tumors showing epithelial-predominant histology. Approximately 20% of stage I FH Wilms tumors registered on AREN03B2 were epithelial predominant. In this group of 177 patients with stage I epithelial-predominant FH Wilms tumors, 117 patients were treated with EE4A, and 57 patients were classified as having a very low-risk Wilms tumor and were treated with observation only.[ 228 ][Level of evidence: 3iiiA]
3. The AREN0321 (NCT00335556) study demonstrated that outcomes for patients with stage I anaplastic Wilms tumor were improved with the addition of doxorubicin and flank radiation therapy to vincristine/dactinomycin therapy.[ 226 ]

Current Clinical Trials

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Treatment of stage II Wilms tumor

Table 5 provides an overview of the standard treatment options and survival data for patients with stage II Wilms tumor, based on published results.

Table 5. Overview of Standard Treatment Options for Stage II Wilms Tumor^a

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[ 99 ] Dome et al.,[ 151 ] Dix et al.,[ 217 ] and Daw et al.[ 220 ]
FH	86% RFS	98%	Nephrectomy + lymph node sampling followed by regimen EE-4A
FH LOH 1p/16q (n = 24)	83% EFS	100%	Nephrectomy + lymph node sampling followed by regimen DD-4A
FA	80% EFS	80% (n = 5)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
DA	84% EFS	84% (n = 19)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen UH1

On NWTS-3, NWTS-4, and NWTS-5, patients with intraoperative spill were divided into two groups: (1) those with diffuse spillage involving the whole abdominal cavity; and (2) those with local spillage confined to the flank. Patients with diffuse spillage were treated with radiation therapy to the entire abdomen and three-drug chemotherapy (vincristine, dactinomycin, and doxorubicin), whereas patients with local spillage were treated with vincristine and dactinomycin only. On the basis of an analysis of patients treated on NWTS-3 and NWTS-4 indicating that patients with stage II disease and local spillage had inferior OS compared with patients with stage II disease without local spillage, COG studies treat patients with local spillage with doxorubicin and flank radiation.[ 229 ] This approach is controversial and has not been tested; therefore, it should not be considered standard.

In a review of 499 patients from NWTS-4 with stage II FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS rates for patients who experienced intraoperative tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy were lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.[ 174 ]

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Treatment of stage III Wilms tumor

Table 6 provides an overview of the standard treatment options and survival data for patients with stage III Wilms tumor, based on published results.

Table 6. Overview of Standard Treatment Options for Stage III Wilms Tumor^a

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[ 99 ] Dome et al.,[ 151 ] Fernandez et al.,[ 230 ] Dix et al.,[ 217 ] and Daw et al.[ 220 ]
FH (all patients)	88% EFS	97%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (without LOH of 1p and/or 16q) and positive lymph nodes	85% EFS	97%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (without LOH of 1p and/or 16q) and negative lymph nodes	97% EFS	99%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FH (with LOH of 1p and 16q) (n = 31)	87% EFS	94%	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen M
FA	88% RFS	100% (n = 8)	Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
FA (preoperative treatment)	71% RFS	71% (n = 7)	Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal XRT
DA	46% EFS	53% (n = 16)	Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal XRT
DA	82% EFS	91% (n = 23)	Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen UH1

Loss of heterozygosity of 1p or 16q was shown to influence EFS but not OS in 588 patients with stage III FH Wilms tumor treated on the COG AREN0532 protocol. When combined, lymph node status and loss of heterozygosity status provided a strong predictor of excellent EFS and OS when both were absent, with a 4-year EFS rate of 97%, and an OS rate of 99%.[ 230 ][Level of evidence: 2Di] The outcome was poorer for patients having both positive lymph nodes and loss of heterozygosity of 1p or 16q, with a 4-year EFS rate of 74%. However, the 4-year OS rate was not influenced, at 92%.[ 230 ] On the basis of these results, therapy was augmented for patients with loss of heterozygosity of 1p/16q for patients enrolled on the AREN0533 trial. Patients with stage III and stage IV Wilms tumor with loss of heterozygosity were treated with regimen M. The 4-year EFS rate was 90.2%, and the OS rate was 96.1%, compared with a 4-year EFS rate of 61.3% (P = .001) and a 4-year OS rate of 86.0% (P = .087) for patients in the NWTS-5 trial. There was a suggestion of improvement in survival; however, the study was not powered to detect differences in survival.[ 217 ][Level of evidence: 3iiiDi]

Early initiation of radiation therapy is a critical component of multimodal therapy for patients with nonmetastatic Wilms tumor. In a review of 1,488 patients with Wilms tumor who underwent surgery and radiation therapy, a surgery-to-radiation therapy interval of greater than 14 days was associated with an increased risk of mortality (hazard ratio, 2.13; P = .013). This underscores the importance of initiating radiation therapy within 14 days of surgery, which is specified in Wilms tumor treatment protocols.[ 218 ][Level of evidence: 3iiiA]

For patients classified as stage III purely on the basis of local spill, refer to the Treatment of stage II Wilms tumor section of this summary.

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Treatment of stage IV Wilms tumor

Table 7 provides an overview of the standard treatment options and survival data for patients with stage IV Wilms tumor, based on published results.

Table 7. Overview of Standard Treatment Options for Stage IV Wilms Tumor^a

Histology	4-Year RFS or EFS	4-Year OS	Treatment (refer to
CR = complete response; DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[ 99 ] Dome et al.,[ 151 ] Dix et al.,[ 219 ] Dix et al.,[ 217 ] and Daw et al.[ 220 ]
bAbdominal XRT is planned according to local stage of renal tumor.
cPulmonary XRT is reserved for patients with chest x-ray/chest computed tomography evidence of pulmonary metastases.
dRefer to the AREN0533 (NCT00379340) study for more information.
FH	76% RFS	86%	Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A
FH (with isolated lung nodules)	85% EFS	96%	Nephrectomy + lymph node sampling, followed by abdominal XRT,b +/- bilateral pulmonary XRT,c and regimen DD-4A or regimen Md
FH (with isolated lung nodules with CR to DD-4A)	83% EFS	94%	Nephrectomy + lymph node sampling, followed by abdominal XRTb and regimen DD-4A
FH (with isolated lung nodules with incomplete response to DD-4A)	92% EFS	96%	Nephrectomy + lymph node sampling, followed by abdominal XRTb and bilateral pulmonary XRTc and regimen M
FH (with LOH of 1p and/or 16q) (n = 20)	95% EFS	100%	Nephrectomy + lymph node sampling, abdominal XRTb radiation to sites of metastasesb, and regimen M
FA	61% EFS	72% (n = 11)	Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A
DA	33% EFS	33% (n = 10)	Immediate nephrectomy + lymph node sampling followed by abdominal XRT,b radiation to sites of metastases, whole-lung XRT,c and regimen I
DA (preoperative treatment)	60% EFS	70% (n = 10)	Preoperative treatment with regimen UH2 followed by nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, and whole-lung XRTc

Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. Historically, chest x-rays were used to detect pulmonary metastases. The introduction of CT created controversy because many patients had lung nodules detected by chest CT scans that were not seen on chest x-rays. Management of newly diagnosed patients with FH Wilms tumor who have lung nodules detected only by CT scans (with negative chest x-ray) has elicited controversy as to whether they need to be treated with additional intensive treatment that is accompanied by acute and late toxicities.

Evidence (treatment of pulmonary nodules detected by chest CT scan only):

1. A retrospective review of 186 patients from NWTS-4 and NWTS-5 with CT-only–detected lung nodules reported on the use of doxorubicin, vincristine, and dactinomycin versus the use of two drugs.[ 231 ]

Retrospective studies from Europe have examined the impact of omitting pulmonary radiation in patients with pulmonary metastases diagnosed by chest x-ray. European investigators omitted radiation from the treatment of most patients with Wilms tumor and pulmonary metastases as identified on chest x-ray who were treated on the SIOP-93-01 (NCT00003804) trial. The European approach to renal tumors differs from the approach used in North America. All patients who were shown to have a renal tumor by imaging underwent 9 weeks of prenephrectomy chemotherapy consisting of vincristine, dactinomycin, and doxorubicin.

Evidence (omission of pulmonary irradiation):

1. In a retrospective SIOP study, 234 newly diagnosed patients with Wilms tumor presenting with pulmonary metastases were treated according to the response of the pulmonary metastases to the prenephrectomy chemotherapy.[ 232 ]
   1. Patients who were in complete remission (67%) after 6 weeks of therapy continued with the same chemotherapy and did not require radiation to their lungs.
   2. Patients who had residual pulmonary metastases were evaluated for metastasectomy.
   3. Patients with residual pulmonary metastases that were incompletely resected or inoperable received more aggressive chemotherapy consisting of ifosfamide/anthracycline alternating with carboplatin/etoposide for 9 weeks.
2. The COG AREN0533 (NCT00379340) study applied a new strategy for patients with FH Wilms tumor and isolated lung metastases to improve EFS while reducing exposure to lung irradiation on the basis of the European experience. Therapy was adjusted on the basis of lung nodule response and tumor-specific loss of heterozygosity at 1p and 16q.[ 219 ][Level of evidence: 3iiiDi]

Although fewer patients were spared pulmonary radiation when treated in the COG trial than in the European trials, it is important to note several differences between the studies and why the studies cannot be directly compared.[ 219 ][ 232 ] Patients in Europe receive a more dose-dense regimen of dactinomycin and doxorubicin before their pulmonary metastases are reevaluated than do patients in North America (135 ug/kg dactinomycin and 100 mg/m² doxorubicin in Europe, compared with 45 ug/kg dactinomycin and 45 mg/m² of doxorubicin in North America). European studies allow lung radiation therapy to be omitted for patients with a complete remission achieved by chemotherapy or pulmonary metastasectomy, whereas radiation therapy was only omitted in the United States for patients with a complete remission with chemotherapy alone. Imaging studies were not centrally reviewed in the European studies, whereas they were in the United States, and the definition of complete remission may have been more stringent in the AREN0533 (NCT00379340) trial.

The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.[ 197 ]

In the AREN0321 (NCT00335556) study, the combination of vincristine and irinotecan (VI) was tested in an upfront window for patients with diffuse anaplastic Wilms tumor and measurable disease. Fourteen patients with stage IV diffuse anaplastic Wilms tumor with measurable disease received the window therapy; one patient achieved a complete response (CR), ten patients achieved partial responses (PRs), and no patients had stable disease. This resulted in a CR and PR rate of 79%. Patients who responded to VI in the window therapy had VI incorporated into their regimen (UH2). Because of the observed cardiac/pulmonary toxicities encountered in this trial, the study was interrupted and amended with reduced doses of doxorubicin, cyclophosphamide, and etoposide (when combined with carboplatin). Further study of the modified regimen is planned in patients with newly diagnosed diffuse anaplastic Wilms tumor.[ 220 ][Level of evidence: 3iiiDii]

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Treatment of stage V Wilms tumor and those predisposed to developing bilateral Wilms tumor

Currently, there is not a standard approach for the treatment of stage V Wilms tumor (bilateral Wilms tumor at diagnosis) and those predisposed to developing Wilms tumor; however, for the first time, a prospective study of the treatment of patients with bilateral Wilms tumor has been completed and provides guidance for the approach.[ 141 ]

Management of a child with bilateral Wilms tumor is very challenging. The goals of therapy are to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.[ 233 ]

Historically, based on the NWTS-4 and NWTS-5 trials and trials performed in Europe, patients with bilateral Wilms tumor have had a lower EFS and OS than have patients with localized Wilms tumor. The NWTS-4 study reported that the 8-year EFS rate for patients with bilateral FH Wilms tumor was 74%, and the OS rate was 89%; for patients with anaplastic histology, the EFS rate was 40%, and the OS rate was 45%.[ 164 ] The NWTS-5 study reported that the 4-year EFS rate for all bilateral Wilms tumor patients was 56%, and the OS rate was 81%; the 4-year EFS rates for patients with FH (65%), focal anaplastic histology (76%), and diffuse anaplastic histology (25%) were also reported.[ 99 ][ 151 ] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[ 163 ][ 234 ] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[ 234 ] The incidence of end-stage renal failure in the Dutch study may be a reflection of a longer follow-up period.

Treatment options for stage V Wilms tumor include the following:

1. Preoperative chemotherapy and resection for bilateral Wilms tumor.
2. Renal transplant.

Preoperative chemotherapy and resection for bilateral Wilms tumor

For patients with bilateral Wilms tumor, the goal of therapy is to preserve as much renal tissue as possible without compromising overall outcome. This approach is used to avoid the late effect of end-stage renal disease, which can be caused by underlying germline genetic aberrations and treatment-related loss of functional renal tissue. End-stage renal disease occurs more frequently in patients with bilateral Wilms tumor (12% nonsyndromic) than in patients with unilateral Wilms tumor (<1%). Functional renal outcome is considerably better after bilateral nephron-sparing surgery than after other types of surgery.[ 141 ]

Traditionally, patients have undergone bilateral renal biopsies, with staging of each kidney followed by preoperative chemotherapy. In the first prospective multi-institutional treatment trial (COG AREN0534 [NCT00945009]), pretreatment biopsies were not required if results of imaging tests were consistent with Wilms tumor.[ 141 ] This approach was taken because the bilateral occurrence of non-Wilms renal tumors is very low. Also, core-needle and wedge biopsies are not highly successful in identifying anaplasia in Wilms tumor.[ 142 ] In the setting of an unusual clinical situation, such as age older than 10 years or atypical imaging features, when a diagnosis other than Wilms should be considered, a tissue diagnosis is obtained.[ 141 ]

For patients who are treated with preoperative chemotherapy, the tumor pathology needs to be evaluated after 4 to 8 weeks. For patients not treated in a clinical trial, the ideal time to perform a biopsy or resection is unknown because minimal shrinkage may reflect chemotherapy-induced differentiation or anaplastic histology. A planned attempt at resection or biopsy of apparently unresectable tumor is undertaken no later than 12 weeks from diagnosis. Continuing therapy without evaluating tumor pathology in a patient with bilateral Wilms tumor may miss anaplastic histology or chemotherapy-induced differentiation (including rhabdomyomatous differentiation) and thus increase toxicity for the patient without providing additional benefit for tumor control. Anaplastic histology occurs in 10% of patients with bilateral Wilms tumor, and these tumors respond poorly to chemotherapy.[ 164 ]

Once the diagnosis is confirmed, a complete resection is performed. Histologic confirmation of the diagnosis is not straightforward. In a series of 27 patients from NWTS-4, discordant pathology (unilateral anaplastic tumor) was seen in 20 cases (74%), which highlights the need to obtain tissue from both kidneys. Seven children who were later diagnosed with diffuse anaplastic tumors had core biopsies performed to establish the diagnosis; however, anaplasia was not found. Anaplasia was identified in only three of the nine patients when an open-wedge biopsy was performed and in seven of nine patients who had a partial or complete nephrectomy.[ 164 ]

The decision to administer chemotherapy and/or radiation therapy after biopsy or a second-look operation is dependent on the tumor's response to initial therapy. More aggressive therapy is required for patients with inadequate response to initial therapy observed at the second procedure or in the setting of anaplasia.[ 173 ][ 235 ][ 236 ]

End-stage renal disease is the most clinically significant morbidity in patients with bilateral Wilms tumor and can be caused by underlying germline genetic aberrations, as well as treatment-related loss of functional renal tissue. Long-term monitoring of renal function is required after treatment for bilateral disease.

Evidence (preoperative chemotherapy and resection for bilateral Wilms tumor):

1. The first prospective study in bilateral Wilms tumor (AREN0534 [NCT00945009]) aimed to improve EFS and OS while preserving renal tissue by intensifying preoperative chemotherapy (utilizing three drugs—vincristine, dactinomycin, and doxorubicin), completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy on the basis of histologic response.[ 141 ]
2. In a retrospective review of 93 children with bilateral Wilms tumor registered at Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) centers over a 21-year period, 43 patients were treated with vincristine and dactinomycin preoperatively and 37 patients were treated with vincristine, dactinomycin, and doxorubicin. The duration of preoperative chemotherapy ranged from 1 week to 40 weeks (median, 12 weeks).[ 163 ]
3. In a retrospective review of 49 patients with Wilms tumor who received preoperative therapy according to the SIOP-93-01 (NCT00003804) guidelines, the timing of surgery was determined when there was no longer imaging evidence of tumor regression. The mean treatment duration was 80 days before renal-sparing surgery.[ 237 ]
4. In a retrospective review from St. Jude Children's Research Hospital, investigators described their experience with preoperative chemotherapy followed by renal-sparing procedures in children with bilateral FH Wilms tumor.[ 238 ]

Renal transplant

Renal transplant for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy because most relapses occur within 2 years of diagnosis.[ 240 ] Similarly, renal transplant for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.[ 240 ]

Treatment options under clinical evaluation

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.

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.

(Refer to the Treatment of Recurrent Childhood Kidney Tumors section of this summary for information about recurrent disease.)

Follow-up after treatment

For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasonography examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).

Late effects after Wilms tumor therapy

Children treated for Wilms tumor are at increased risk of developing the following:

(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

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241. Wong KF, Reulen RC, Winter DL, et al.: Risk of Adverse Health and Social Outcomes Up to 50 Years After Wilms Tumor: The British Childhood Cancer Survivor Study. J Clin Oncol 34 (15): 1772-9, 2016.[PUBMED Abstract]
242. 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]
243. Termuhlen AM, Tersak JM, Liu Q, et al.: Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 57 (7): 1210-6, 2011.[PUBMED Abstract]
244. Lange JM, Takashima JR, Peterson SM, et al.: Breast cancer in female survivors of Wilms tumor: a report from the national Wilms tumor late effects study. Cancer 120 (23): 3722-30, 2014.[PUBMED Abstract]
245. Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001.[PUBMED Abstract]
246. Green DM, Lange JM, Peabody EM, et al.: Pregnancy outcome after treatment for Wilms tumor: a report from the national Wilms tumor long-term follow-up study. J Clin Oncol 28 (17): 2824-30, 2010.[PUBMED Abstract]

Renal Cell Carcinoma (RCC)

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:

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 8.

Table 8. Indications for Germline Genetic Analysis (Screening) of Children and Adolescents with Renal Cell Carcinoma (RCC)^a

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 BHD gene	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 ][ 29 ] These carcinomas are characterized by translocations involving the TFE3 gene located on Xp11.2. The TFE3 gene may partner with one of the following genes:

Another less-common translocation subtype, t(6;11)(p21;q12), involving a TFEB gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[ 30 ]

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.[ 31 ][ 32 ]

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 translocation-associated RCC, a meta-analysis reported that these patients have poorer outcomes.[ 33 ][ 34 ][ 35 ] 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.[ 36 ] 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 TFE3 and 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:[ 37 ][ 38 ][ 39 ][ 40 ]

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.[ 41 ]

RCC in children and young adults has a different genetic and morphologic spectrum than that seen in older adults.[ 3 ][ 32 ][ 41 ][ 42 ]

Prognosis and Prognostic Factors for RCC

Prognostic factors for RCC include the following:

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. The 5-year overall survival (OS) rates were 100% for patients with stage I and stage II disease, 71% for stage III disease, and 8% for stage IV disease.[ 43 ] 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).[ 43 ] 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 rate 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. The survival rates at 5 years were 96% for patients with localized disease, 75% for patients with positive regional lymph nodes, and 33% for patients with distant metastatic RCC.[ 44 ]

Clinical Features and Diagnostic Evaluation of RCC

RCC may present with the following:

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.[ 32 ][ 45 ]

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.[ 46 ][ 47 ] Spontaneous regression of pulmonary metastasis rarely occurs with resection of the primary tumor.

Several targeted therapies (e.g., sorafenib, sunitinib, bevacizumab, temsirolimus, pazopanib, axitinib, 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 translocation–positive RCC suggest responsiveness to multiple tyrosine kinase inhibitors.[ 29 ][ 48 ][ 49 ] Disease regression and improvement in symptoms have been reported with the use of cabozantinib in pediatric patients with translocation-positive RCC expressing MET.[ 50 ] 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.[ 37 ]

(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:

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.

参考文献

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3. Bruder E, Passera O, Harms D, et al.: Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 28 (9): 1117-32, 2004.[PUBMED Abstract]
4. Schimke RN, Collins DL, Stolle CA: Von Hippel-Lindau syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds.: GeneReviews. Seattle, Wash: University of Washington, 1993-2018, pp. Available online. Last accessed June 08, 2020.[PUBMED Abstract]
5. 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]
6. Park HK, Zhang S, Wong MK, et al.: Clinical presentation of epithelioid angiomyolipoma. Int J Urol 14 (1): 21-5, 2007.[PUBMED Abstract]
7. Pea M, Bonetti F, Martignoni G, et al.: Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22 (2): 180-7, 1998.[PUBMED Abstract]
8. Wang N, Perkins KL: Involvement of band 3p14 in t(3;8) hereditary renal carcinoma. Cancer Genet Cytogenet 11 (4): 479-81, 1984.[PUBMED Abstract]
9. Ricketts C, Woodward ER, Killick P, et al.: Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst 100 (17): 1260-2, 2008.[PUBMED Abstract]
10. Linehan WM, Bratslavsky G, Pinto PA, et al.: Molecular diagnosis and therapy of kidney cancer. Annu Rev Med 61: 329-43, 2010.[PUBMED Abstract]
11. Swartz MA, Karth J, Schneider DT, et al.: Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology 60 (6): 1083-9, 2002.[PUBMED Abstract]
12. Sandberg JK, Mullen EA, Cajaiba MM, et al.: Imaging of renal medullary carcinoma in children and young adults: a report from the Children's Oncology Group. Pediatr Radiol 47 (12): 1615-1621, 2017.[PUBMED Abstract]
13. Hakimi AA, Koi PT, Milhoua PM, et al.: Renal medullary carcinoma: the Bronx experience. Urology 70 (5): 878-82, 2007.[PUBMED Abstract]
14. Strouse JJ, Spevak M, Mack AK, et al.: Significant responses to platinum-based chemotherapy in renal medullary carcinoma. Pediatr Blood Cancer 44 (4): 407-11, 2005.[PUBMED Abstract]
15. Rathmell WK, Monk JP: High-dose-intensity MVAC for Advanced Renal Medullary Carcinoma: Report of Three Cases and Literature Review. Urology 72 (3): 659-63, 2008.[PUBMED Abstract]
16. Ezekian B, Englum B, Gilmore BF, et al.: Renal medullary carcinoma: A national analysis of 159 patients. Pediatr Blood Cancer 64 (11): , 2017.[PUBMED Abstract]
17. Alrashdi I, Levine S, Paterson J, et al.: Hereditary leiomyomatosis and renal cell carcinoma: very early diagnosis of renal cancer in a paediatric patient. Fam Cancer 9 (2): 239-43, 2010.[PUBMED Abstract]
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. Ambalavanan M, Geller JI: Treatment of advanced pediatric renal cell carcinoma. Pediatr Blood Cancer 66 (8): e27766, 2019.[PUBMED Abstract]
30. 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]
31. 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]
32. 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]
33. 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]
34. 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]
35. 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]
36. 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]
37. 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]
38. 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]
39. 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]
40. 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]
41. Estrada CR, Suthar AM, Eaton SH, et al.: Renal cell carcinoma: Children's Hospital Boston experience. Urology 66 (6): 1296-300, 2005.[PUBMED Abstract]
42. Carcao MD, Taylor GP, Greenberg ML, et al.: Renal-cell carcinoma in children: a different disorder from its adult counterpart? Med Pediatr Oncol 31 (3): 153-8, 1998.[PUBMED Abstract]
43. Rialon KL, Gulack BC, Englum BR, et al.: Factors impacting survival in children with renal cell carcinoma. J Pediatr Surg 50 (6): 1014-8, 2015.[PUBMED Abstract]
44. Selle B, Furtwängler R, Graf N, et al.: Population-based study of renal cell carcinoma in children in Germany, 1980-2005: more frequently localized tumors and underlying disorders compared with adult counterparts. Cancer 107 (12): 2906-14, 2006.[PUBMED Abstract]
45. Cook A, Lorenzo AJ, Salle JL, et al.: Pediatric renal cell carcinoma: single institution 25-year case series and initial experience with partial nephrectomy. J Urol 175 (4): 1456-60; discussion 1460, 2006.[PUBMED Abstract]
46. Fyfe G, Fisher RI, Rosenberg SA, et al.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 13 (3): 688-96, 1995.[PUBMED Abstract]
47. Coppin C, Porzsolt F, Awa A, et al.: Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev (1): CD001425, 2005.[PUBMED Abstract]
48. De Pasquale MD, Pessolano R, Boldrini R, et al.: Continuing response to subsequent treatment lines with tyrosine kinase inhibitors in an adolescent with metastatic renal cell carcinoma. J Pediatr Hematol Oncol 33 (5): e176-9, 2011.[PUBMED Abstract]
49. Chowdhury T, Prichard-Jones K, Sebire NJ, et al.: Persistent complete response after single-agent sunitinib treatment in a case of TFE translocation positive relapsed metastatic pediatric renal cell carcinoma. J Pediatr Hematol Oncol 35 (1): e1-3, 2013.[PUBMED Abstract]
50. Wedekind MF, Ranalli M, Shah N: Clinical efficacy of cabozantinib in two pediatric patients with recurrent renal cell carcinoma. Pediatr Blood Cancer 64 (11): , 2017.[PUBMED Abstract]

Rhabdoid Tumors of the Kidney

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 ]

(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 Tumor section 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. SMARCB1 encodes 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 SMARCA4 have also been reported in patients with rhabdoid tumors.[ 8 ][ 17 ]

Rhabdoid Tumor Predisposition Syndrome

Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid tumor 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; 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 ]

To date, there is little evidence regarding the effectiveness of surveillance for patients with rhabdoid tumor predisposition syndrome, type 1 caused by loss-of-function germline SMARCB1 mutations. However, because of the aggressive nature of the tumors with significant lethality and young age of onset in SMARCB1 carriers with truncating mutations, consensus recommendations have been developed. 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. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[ 19 ][ 20 ][ 21 ]

Surveillance for patients with germline SMARCB1 mutations includes the following:

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 ]

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.[ 22 ]

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.[ 23 ][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.[ 24 ][ 25 ]
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).[ 26 ]
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.[ 27 ]

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:

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.

参考文献

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. Mitchell SG, Pencheva B, Porter CC: Germline Genetics and Childhood Cancer: Emerging Cancer Predisposition Syndromes and Psychosocial Impacts. Curr Oncol Rep 21 (10): 85, 2019.[PUBMED Abstract]
21. Foulkes WD, Kamihara J, Evans DGR, et al.: Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome. Clin Cancer Res 23 (12): e62-e67, 2017.[PUBMED Abstract]
22. 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]
23. 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]
24. 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]
25. 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]
26. 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]
27. 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

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 ][ 3 ][ 4 ][ 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, accounts for approximately 20 new cases per year in the United States, and is observed most often before age 3 years.[ 1 ] 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:

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.[ 14 ]
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 ]
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 OS rate of 100% with a wide variety of chemotherapy and radiation therapy regimens.[ 15 ]

(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.

参考文献

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 66 (1): e27450, 2019.[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. Argani P, Kao YC, Zhang L, et al.: Primary Renal Sarcomas With BCOR-CCNB3 Gene Fusion: A Report of 2 Cases Showing Histologic Overlap With Clear Cell Sarcoma of Kidney, Suggesting Further Link Between BCOR-related Sarcomas of the Kidney and Soft Tissues. Am J Surg Pathol 41 (12): 1702-1712, 2017.[PUBMED Abstract]
8. 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]
9. 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]
10. 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]
11. 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]
12. Kao YC, Sung YS, Zhang L, et al.: Recurrent BCOR Internal Tandem Duplication and YWHAE-NUTM2B Fusions in Soft Tissue Undifferentiated Round Cell Sarcoma of Infancy: Overlapping Genetic Features With Clear Cell Sarcoma of Kidney. Am J Surg Pathol 40 (8): 1009-20, 2016.[PUBMED Abstract]
13. Argani P, Pawel B, Szabo S, et al.: Diffuse Strong BCOR Immunoreactivity Is a Sensitive and Specific Marker for Clear Cell Sarcoma of the Kidney (CCSK) in Pediatric Renal Neoplasia. Am J Surg Pathol 42 (8): 1128-1131, 2018.[PUBMED Abstract]
14. 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]
15. 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

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 the following three histologic subtypes:

A frequent genetic alteration is the translocation t(12;15)(q13;q25), resulting in a fusion of the ETV6 and NTRK3 genes on 15p15 that occurs almost exclusively in the cellular type of mesoblastic nephroma. In a cohort of 79 mesoblastic nephromas analyzed for the translocation, all classical (n = 38) and mixed (n = 12) mesoblastic nephromas were translocation negative.[ 8 ] The same translocation was initially described in infantile fibrosarcoma, and besides the similar morphologic appearance, cases of cellular mesoblastic nephroma and infantile fibrosarcoma share other genetic changes such as gains of chromosome 11.[ 9 ]

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 ] In an International Society of Pediatric Oncology (SIOP) series of 79 patients with congenital mesoblastic nephromas, patients within the cellular subgroup who had translocation-positive tumors had a significantly superior relapse-free survival (RFS) rate when compared with patients who did not have the gene fusion (100% vs. 73%, respectively).[ 8 ]

(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

The OS of patients with congenital mesoblastic nephroma is excellent; however, reported causes of death in about one-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. In a SIOP/Gesellschaft für Pädiatrische Hämatologie und Onkologie (GPOH) nephroblastoma study, 111 patients with congenital mesoblastic nephromas demonstrated a 5-year RFS rate of 93.2% and a 5-year OS rate of 96.8%.[ 8 ]

Adjuvant chemotherapy

Adjuvant chemotherapy has been recommended for patients with stage III cellular subtype mesoblastic nephromas 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 ][ 10 ] Cyclophosphamide and ifosfamide have been combined with these agents and have shown activity.[ 11 ]

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.)

Treatment options under clinical evaluation for congenital mesoblastic nephroma

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:

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.

参考文献

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. Vokuhl C, Nourkami-Tutdibi N, Furtwängler R, et al.: ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study. Pediatr Blood Cancer 65 (4): , 2018.[PUBMED Abstract]
9. Knezevich SR, Garnett MJ, Pysher TJ, et al.: ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 58 (22): 5046-8, 1998.[PUBMED Abstract]
10. 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]
11. 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

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 ][ 2 ][ 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.

参考文献

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

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 ]

参考文献

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

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 ]

参考文献

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

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 DICER1 mutations, 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 ][ 3 ][ 4 ][ 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.

参考文献

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

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) SS18-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 ] A second alternative gene fusion variant, SS18-NEDD4, has been identified in a primary renal synovial sarcoma.[ 2 ] 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. The chemotherapy regimens used for primary renal synovial sarcoma differ from those traditionally used for Wilms tumor.[ 3 ]

参考文献

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, Zhang L, Sung YS, et al.: Novel SS18-NEDD4 gene fusion in a primary renal synovial sarcoma. Genes Chromosomes Cancer 59 (3): 203-208, 2020.[PUBMED Abstract]
3. 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

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 PDQ summary on Childhood Pleuropulmonary Blastoma Treatment 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 Cancer Treatment for 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 ]

参考文献

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

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 ]

   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 ]

参考文献

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

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 9 describes the treatment options for recurrent childhood kidney tumors.

Table 9. 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:

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] rate, 47%) than did patients who experienced a pulmonary relapse 12 months or more after diagnosis (5-year OS rate, 75%).[ 8 ]

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

Treatment of Standard-Risk Relapsed Wilms Tumor

In children who had small stage I Wilms tumor and were treated with surgery alone, the EFS rate 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 ]

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]

Patients with stage II, stage III, and stage IV anaplastic 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 ][ 13 ]; [ 14 ][Level of evidence: 3ii]

Evidence (HSCT):

1. 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.[ 15 ]
2. In a single-institution series of 24 patients with relapsed and refractory Wilms tumor who were treated with high-dose chemotherapy followed by autologous stem cell rescue (HD-ASCR), the following results were reported:[ 14 ][Level of evidence: 3ii]

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

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.[ 16 ][ 17 ] In a series of 37 patients with clear cell sarcoma of the kidney who relapsed, the 5-year EFS rate after relapse was 18%, and the OS rate after relapse was 26%.[ 17 ]

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.[ 17 ]; [ 18 ][Level of evidence: 2A]

The use of high-dose chemotherapy followed by HSCT 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 HSCT. 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 ][ 17 ][ 18 ]

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:

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.[ 19 ] About 70% of patients who relapsed survived with individualized treatment comprising combinations of surgery, chemotherapy, and radiation therapy.[ 19 ]

Targeted therapy should be considered for patients with recurrent or refractory disease containing the ETV6-NTRK3 fusion. Larotrectinib and entrectinib are NTRK inhibitors that are approved for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, who are either metastatic or when surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed after treatment.[ 20 ][ 21 ]

Treatment options under clinical evaluation for recurrent congenital mesoblastic nephroma

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:

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.

参考文献

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 66 (1): e27430, 2019.[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. Rossoff J, Tse WT, Duerst RE, et al.: High-dose chemotherapy and autologous hematopoietic stem-cell rescue for treatment of relapsed and refractory Wilms tumor: Re-evaluating outcomes. Pediatr Hematol Oncol 35 (5-6): 316-321, 2018 Aug - Sep.[PUBMED Abstract]
15. 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]
16. 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.[PUBMED Abstract]
17. 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]
18. 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]
19. 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]
20. Drilon A, Laetsch TW, Kummar S, et al.: Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 378 (8): 731-739, 2018.[PUBMED Abstract]
21. Entrectinib Shows Pediatric Potential. Cancer Discov 9 (7): OF4, 2019.[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:

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 Group (COG) and the International Society of Pediatric Oncology (SIOP). Information about ongoing clinical trials is available from the NCI website.

参考文献

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 (06/08/2020)

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.

Wilms Tumor

Revised Table 2 to include the descriptions of regimen UH1 and regimen UH2 (cited Daw et al. as reference 220).

Revised text about the radiation doses used by the Children's Oncology Group (COG). Also added text to state that the radiation therapy regimen used in the COG AREN0321 trial remains the current standard of treatment.

Added text about the radiation therapy approach used by the International Society of Pediatric Oncology (SIOP).

Added text about the results of the COG study that reported the outcome for patients of all ages with stage I favorable-histology Wilms tumors showing epithelial-predominant histology (cited Parsons et al. as reference 228 and level of evidence 3iiiA).

Revised Table 5 to include the outcome results for patients with stage II diffuse anaplastic Wilms tumors in the COG AREN0321 study.

Revised Table 6 to include the outcome results for patients with stage III diffuse anaplastic Wilms tumors in the COG AREN0321 study.

Revised Table 7 to include the outcome results for patients with stage IV diffuse anaplastic Wilms tumors in the COG AREN0321 study.

Added text about the results of the AREN0321 study that tested the combination of vincristine and irinotecan in an upfront window for patients with diffuse anaplastic Wilms tumor and measurable disease (added level of evidence 3iiiDii).

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:

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.

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.

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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]

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