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Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®) 1/2 —Health Professional Version - National Cancer Institute
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.)
Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
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]
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
The incidence of Wilms tumor is 7.1 cases per 1 million children younger than 15 years. 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.[1,2] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[3]
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.[3,4] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases.[5] Of 295 consecutive patients with Wilms tumor seen at the Institute 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.[6]
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.[7,8]
It is important to recognize that the absolute risk of Wilms tumor varies with the underlying condition or anomaly (e.g., most patients with hemihypertrophy will not develop Wilms tumor).
Table 1. Syndromes and Conditions Associated With Wilms Tumor
Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN)
BRCA2
X
PALB2
Frasier syndrome
WT1
X
Genitourinary anomalies
WT1
X
Li-Fraumeni syndrome
TP53
X
CHEK2
Sporadic aniridia
WT1
X
Trisomy 18
X
WAGR syndrome
WT1
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:
WAGR syndrome. WAGR syndrome is characterized by the following:
Wilms tumor.
Aniridia.
Genitourinary anomaly.
Mental Retardation.
The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del(11p13)) (prevalence is about 0.4% of children with Wilms tumor).[9,10] The incidence of bilateral Wilms tumor in children with WAGR syndrome is about 15%.[11] (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
Denys-Drash syndrome and Frasier syndrome. Genitourinary anomalies such as hypospadias, undescended testis, and others are associated with WT1 mutations (prevalence is about 8%–10% of children with Wilms tumor). Children with pseudo-hermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms tumor may have Denys-Drash or Frasier syndrome (characterized by male hermaphroditism, primary amenorrhea, chronic renal failure, and other abnormalities),[12] both of which are associated with mutations in the WT1 gene.[13] Specifically, germline missense mutations in the WT1 gene are responsible for most cases of Wilms tumor that occur as part of Denys-Drash syndrome.[14,15] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome.[15]
WT2-related syndromes include the following:
Beckwith-Wiedemann syndrome. Beckwith-Wiedemann syndrome is an overgrowth syndrome characterized by asymmetric growth of one or more parts of the body, large tongue, omphalocele or umbilical hernia at birth, creases or pits in the skin near the ears, kidney abnormalities, and hypoglycemia (in neonates). It is also characterized by the development of Wilms tumor, rhabdomyosarcoma, and hepatoblastoma in the first decade of life.
Beckwith-Wiedemann syndrome is caused by altered expression of two gene clusters involved in growth control and cell-cycle progression regulated by two independent imprinting control regions (ICR1 [termed telomeric ICR] and ICR2 [termed centromeric ICR]) at chromosome 11p15.5. The two ICRs are characterized by differential methylation of maternal and paternal alleles. A variety of molecular mechanisms are implicated in Beckwith-Wiedemann syndrome pathogenesis, leading to unbalanced expression of imprinted genes within these two domains. Tumor predisposition results primarily from dysregulation at the telomeric domain of 11p15 (ICR1 gain of methylation [ICR1-GoM] and paternal uniparental disomy [UPD]) rather than at the centromeric domain of 11p15 (ICR2 loss of methylation [ICR2-LoM] and CDKN1Cmutation).[16] Approximately 15% of cases with clear-cut phenotypes have no detectable molecular defect.[17,18]
The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes.[19-21]
There are four main molecular subtypes of Beckwith-Wiedemann syndrome characterized by specific genotype-phenotype correlations, including tumor risk:
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 H19gene. The incidence of Wilms tumor is 22.8%.[22]
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%).[22]
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%).[22] Fewer than 1% of cases with Beckwith-Wiedemann syndrome are caused by chromosomal rearrangements involving the 11p15 region.
CDKN1C mutation. 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.[22]
The prevalence of Beckwith-Wiedemann syndrome is about 1% of children with Wilms tumor.[23-26] Approximately 10% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor.[16] Beckwith-Wiedemann syndrome patients with hemihyperplasia have a fourfold increased tumor risk over that of Beckwith-Wiedemann syndrome patients without hemihyperplasia.[27] (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
Other syndromic causes of Wilms tumor include the following:
Perlman syndrome. Perlman syndrome—a rare, autosomal, recessively inherited, congenital overgrowth syndrome—is characterized by fetal gigantism, renal dysplasia and nephroblastomatosis, islet cell hypertrophy, multiple congenital anomalies, and mental retardation. Survivors have a high risk of developing Wilms tumor (75%).[28]
Germline inactivating mutations in DIS3L2 on chromosome 2q37 are associated with Perlman syndrome. Preliminary data suggest that DIS3L2 plays a role in normal kidney development and in a subset of sporadic Wilms tumor cases.[29]
Simpson-Golabi-Behmel syndrome. Simpson-Golabi-Behmel syndrome is characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers.
The syndrome is caused by mutations or deletions in glypican genes GPC3 and GPC4, and these genetic aberrations are believed to enhance the risk of Wilms tumor (8%).[30]
CLOVES syndrome. This syndrome is characterized by the following:
Congenital Lipomatous Overgrowth.
Vascular malformations.
Epidermal nevi.
Skeletal/spinal abnormalities.
This syndrome results from postzygotic, somatic mutations in PIK3CA, which may involve large or small regions of the child.[31]
Sotos syndrome. Sotos syndrome is characterized by cerebral gigantism and learning disability, ranging from mild to severe. Sotos syndrome is associated with behavioral problems, congenital cardiac anomalies, neonatal jaundice, and renal anomalies such as Wilms tumor, scoliosis, and seizures.
NSD1 is the only gene in which mutations are known to cause Sotos syndrome.[32]
9q22.3 microdeletion syndrome. 9q22.3 microdeletion syndrome is characterized by craniofacial abnormalities, metopic craniosynostosis, hydrocephalus, macrosomia, and learning disabilities.
Three patients presented with Wilms tumor in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. Although the size of the deletions was variable, all encompassed the PTCH1 gene.[33]
Bloom syndrome. Bloom syndrome is characterized by short stature and being thinner than other family members, sun-sensitive skin changes, and an increased risk of Wilms tumor.
BLM is the only gene in which mutations are known to cause Bloom syndrome.[34]
Li-Fraumeni syndrome. Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. The cancers most often associated with Li-Fraumeni syndrome include breast cancer, osteosarcoma, soft tissue sarcoma, brain tumor, leukemia, adrenocortical carcinoma, and Wilms tumor.
The TP53 gene mutation is present in most families with Li-Fraumeni syndrome. The CHEK2 gene mutation is also known to cause Li-Fraumeni syndrome.[35]
Alagille syndrome. Alagille syndrome includes congenital cardiopathy; facial dysmorphology; and vertebral, ocular, and renal abnormalities. It has been reported with Wilms tumor in two cases with identified mutations.[36]
Bohring-Opitz syndrome. Bohring-Opitz syndrome is a rare genetic condition characterized by distinctive facial features, variable microcephaly, hypertrichosis, nevus flammeus, severe myopia, unusual posture, severe intellectual disability, and feeding issues.
The syndrome is associated with ASXL1 mutations and an estimated 7% incidence of Wilms tumor.[37]
Nonsyndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor include the following:
Familial Wilms tumor. Despite the number of genes that appear to be involved in the development of Wilms tumor, familial Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a less-than-1% chance of developing Wilms tumor.[38-40] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.[41]
Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2(19q13.4).[42-44] Occasional Wilms tumor families have a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[45,46]
Inactivating mutations in CTR9 have been identified in 3 of 35 Wilms tumor families. CTR9 is located at 11p15.3 and is a key component of the polymerase-associated factor 1 (PAF1) complex, which has multiple roles in RNA polymerase II regulation and transcriptional elongation and is implicated in embryonic organogenesis.[47]
Sporadic aniridia. Sporadic aniridia may result from small germline deletions of one copy of the PAX6 gene that includes part or all of the adjacent WT1 gene but does not result in genitourinary abnormalities or retardation (i.e., not obviously WAGR syndrome). Therefore, many patients with sporadic aniridia develop Wilms tumor and are candidates for screening. The relative risk of Wilms tumor in sporadic aniridia is 67-fold.[48] About half of individuals with sporadic aniridia and PAX6 and WT1 deletions develop Wilms tumor.[49]
Constitutional 11p15 abnormalities. Constitutional 11p15 abnormalities have been identified in 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases. All were de novo abnormalities, except for one novel microdeletion in a child whose mother was not affected. This suggests that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.[50]
Isolated hemihyperplasia. Hemihyperplasia is an asymmetric overgrowth of one or more body parts and is associated with Wilms tumor. It can also be associated with other predisposition syndromes such as Beckwith-Wiedemann syndrome. Clinical signs may not be very evident, and hemihyperplasia may be noted after tumor diagnosis.
The overall Wilms tumor incidence was 5.9% in a study of 168 patients with isolated hemihyperplasia, although this result may have been affected by ascertainment bias.[51] The prevalence is about 2.5% of children with Wilms tumor.[23,51]
Fanconi anemia with biallelic mutations in BRCA2 (FANCD1) or PALB2 (FANCN).BRCA2 and PALB2 play central roles in homologous recombination DNA repair. Biallelic mutations in either BRCA2 or PALB2 lead to Fanconi anemia and to increased risks of selected childhood cancers, including Wilms tumor.[53-55]
Genomics of Wilms Tumor
Wilms tumors, similar to other pediatric embryonal neoplasms, typically arise after a limited number of genetic aberrations. One study showed the following:[56]
Wilms tumors commonly arise through more than one genetic event.
Wilms tumors show differences in gene expression and methylation patterns with different genetic aberrations.
Wilms tumors have a large number of candidate driver genes, most of which are mutated in less than 5% of Wilms tumors.
Wilms tumors have recurrent mutations in genes with common functions, with most involved in either early renal development or epigenetic regulation (e.g., chromatin modifications, transcription elongation, and miRNA).
Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or WTX.[57,58] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[59-62] 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),[59,60] EP300, CREBBP, and MYCN.[56] 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.[56] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.
Elevated rates of Wilms tumor are observed in 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.[63] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[47,64]
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.[65] WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[57,65,66]
Wilms tumor with a WT1 mutation is characterized by the following:
Evidence of WNT pathway activation by activating mutations in the CTNNB1 gene is common.[66-68]
Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.[66,69]
Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests occur in approximately 20% of Wilms tumor cases. They are observed at high rates in cases with genetic syndromes that have WT1 mutations such as WAGR and Denys-Drash syndromes.[70] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 mutations.[71,72]
WT1 germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.[46,73]
WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[74] These findings need validation but may provide biomarkers for stratifying patients in the future.
Germline WT1 mutations are more common in children with Wilms tumor and one of the following:
WAGR syndrome, Denys-Drash syndrome,[15] or Frasier syndrome.[12]
Genitourinary anomalies, including hypospadias and cryptorchidism.
Bilateral Wilms tumor.
Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
Stromal and rhabdomyomatous differentiation.
Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[15] and Frasier syndrome.[12]
WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[3] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that includes the WT1 and PAX6 genes.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[23,75]
Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests–associated favorable-histology (FH) tumors of mixed cell type, and early age at diagnosis.[11] The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[50]
Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[76,77]
Denys-Drash and Frasier syndromes. Denys-Drash syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%). Frasier syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.
WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1.[15] By contrast, WT1 mutations in Frasier syndrome typically occur in intron 9 at the KTS site, and they affect an alternative splicing, thereby preventing production of the usually more abundant WT1 +KTS isoform.[78]
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%).[76,77] 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).[76,77] 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:
Children with WAGR syndrome or other germline WT1 mutations are monitored throughout their lives because they are at increased risk of developing hypertension, nephropathy, and renal failure.[79]
Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.[80]
Children with Wilms tumor and any genitourinary anomalies are also at increased risk of late renal failure and are monitored. Features associated with germline WT1mutations that increase the risk of developing renal failure include the following:[79]
CTNNB1 is the most commonly mutated gene in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[56,58,66,68,81] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[82] CTNNB1mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1mutations have a concurrent CTNNB1 mutation.[66,68,81] 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.[58,83] CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[71]
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.[57,58,66,84,85] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373Exit Disclaimer).[86] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[86] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[83,87] WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[57,66,84] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[66]
WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[57]
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.[50]
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[88] 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).[50,89]
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[89] Loss of heterozygosity, 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.[50,88,89]
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.[90] The overall tumor risk in patients with Beckwith-Wiedemann syndrome has been estimated to be between 5% and 10%, with a risk between 1% (loss of imprinting at ICR2) and 30% (gain of methylation at ICR1 and paternal 11p15 isodisomy). For patients with Beckwith-Wiedemann syndrome, the risk of developing Wilms tumor is 4.1%. Development of Wilms tumor has been reported in patients with only ICR1 gain of methylation, whereas other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[16,20,91] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[25]
Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[92] Interestingly, Wilms tumor in Asian children is not associated with either nephrogenic rests or IGF2 loss of imprinting.[93]
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[23-25] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[1,25]
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:
1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome. In the presence of 1q gain, neither 1p nor 16q loss is significant.[94,95] Gain of chromosome 1q is one of the most common cytogenetic abnormalities in Wilms tumor and is observed in approximately 30% of tumors.
In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.[94]
The 8-year event-free survival (EFS) rate was 77% for patients with 1q gain and 90% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS.
The 8-year overall survival (OS) rate was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). OS was significantly inferior in cases with stage I disease (P < .0015) and stage IV disease (P = .011).
16q and 1p. Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumor cases, respectively.[96]
In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival and OS rates. Combined loss of 1p and 16q are used to select FH Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group (COG) study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q loss of heterozygosity.[97]
An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[98]
These conflicting results may arise from the greater prognostic significance of 1q gain described above. Loss of heterozygosity of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, loss of heterozygosity of 16q and 1p retains their adverse prognostic impact.[94] The loss of heterozygosity of 16q and 1p appears to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[99]
miRNAPG. Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[56,59-62] The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 1).[100] The most commonly mutated miRNAPG is DROSHA, with a recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of DROSHA-mutated tumors. Other miRNAPG that are mutated in Wilms tumor include DGCR8, DICER1, TARBP2, DIS3L2, and XPO5. These mutations are generally mutually exclusive, and they appear to be deleterious and result in impaired expression of tumor-suppressing miRNAs. A striking sex bias was noted in mutations for DGCR8 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.[59,60]
Germline mutations in miRNAPG are observed for DICER1 and DIS3L2, with mutations in the former causing DICER1 syndrome and mutations in the latter causing Perlman syndrome.
DICER1 syndrome is typically caused by inherited truncating mutations in DICER1, with tumor formation following acquisition of a missense mutation in a domain of the remaining allele of DICER1 (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs.[101] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[101] Wilms tumor is an uncommon presentation of the DICER1 syndrome. In one study, three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second DICER1 mutation in the RNase IIIb domain.[102] Another study identified DICER1 mutations in 2 of 48 familial Wilms tumor families.[103] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1mutations.[60,61]
SIX1 and SIX2.SIX1 and SIX2 are highly homologous transcription factors that play key roles in early renal development and are expressed in the metanephric mesenchyme, where they maintain the mesenchymal progenitor population. The frequency of SIX1mutations is 3% to 4% in Wilms tumor, and the frequency of SIX2 mutations in Wilms tumor is 1% to 3%.[59,60] Virtually all SIX1 and SIX2 mutations are in exon 1 and result in a glutamine-to-arginine mutation at position 177. Mutations in WT1, WTX, and CTNNB1 are infrequent in cases with SIX1/SIX2 or miRNAPG mutations. Conversely, SIX1/SIX2 mutations and miRNAPG mutations tend to occur together.
MLLT1. Approximately 4% of Wilms tumor cases have mutations in the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development.[72] The mutant MLLT1 protein shows altered binding to acetylated histone tails. Patients with MLLT1-mutant tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumor.
TP53 (tumor suppressor gene). Most anaplastic Wilms tumor cases show mutations in the TP53 tumor suppressor gene.[106-108] TP53 may be useful as an unfavorable prognostic marker.[106,107]
In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 mutations, 13 patients (11%) demonstrated TP53 segmental copy number loss without mutation, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 mutations were detected by sequencing alone. Patients with stage III or stage IV disease with wtTP53had a significantly lower relapse rate and mortality rate than did patients with TP53abnormalities (P = .00006 and P = .00007, respectively). There was no effect of TP53 status on patients with stage I or stage II tumors. In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These tumors demonstrated gene expression evidence of p53 pathway activation. Retrospective pathology review of wtTP53 revealed no or very low volume of anaplasia in six of seven tumors. These data support the key role of TP53 loss in the development of anaplasia in Wilms tumor and support its significant clinical influence in patients who have residual anaplastic disease after surgery.[109]
FBXW7.FBXW7, a ubiquitin ligase component, is a gene that has been identified as recurrently mutated at low rates in Wilms tumor. Mutations of this gene have been associated with epithelial-type tumor histology.[110]
9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[33,111] The chromosomal region with germline deletion includes PTCH1, the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome associated with osteosarcoma). 9q22.3 microdeletion syndrome is characterized by the clinical findings of Gorlin syndrome, as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, prenatal and postnatal macrosomia, and seizures.[111] Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[33,112,113]
MYCN.MYCN copy number gain was observed in approximately 13% of Wilms tumor cases, and it was more common in anaplastic cases (7 of 23 cases, 30%) than in nonanaplastic cases (11.2%).[114] Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases.[114] Germline copy number gain at MYCN has been reported in a bilateral Wilms tumor case, and germline MYCNduplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[115]
CTR9. Inactivating CTR9 germline mutations were identified in 4 of 36 familial Wilms tumor pedigrees.[47,116] CTR9, which is located at chromosome 11p15.3, is a key component of the polymerase-associated factor 1 complex (PAF1c), which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency.
REST. Inactivating germline mutations in REST (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees.[64] REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most REST mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. When screened for REST mutations, 9 of 519 individuals with Wilms tumor who had no history of relatives with the disease tested positive for the mutation; some had parents who also tested positive.[64] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.
Figure 2 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[72] 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.
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; however, 85% of individuals with WAGR or Beckwith-Wiedemann syndrome have unilateral tumors.[26,65]
Only 16% of persons with bilateral Wilms tumor have a WT1 germline mutation, and only 3% of persons with bilateral Wilms tumor have affected family members. 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 WT1nonsense mutations in exon 8.[117] The presence of bilateral or multifocal disease implies that a patient has a genetic predisposition for Wilms tumor.
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 ultrasound every 3 months until they reach at least age 8 years.[75,118] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.[75]
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.[118]
Beckwith-Wiedemann syndrome. Approximately 8% of patients with Beckwith-Wiedemann syndrome will develop a malignancy, with the most common being either Wilms tumor or hepatoblastoma, although adrenal tumors can also occur.[22] The AACR workshop committee has published screening guidelines that include Beckwith-Wiedemann syndrome.[118] Screening for hepatoblastoma or adrenal tumors with abdominal ultrasound and serum AFP usually begins at birth or when the syndrome is diagnosed and continues until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require fasting before the exam.[119] Screening for Wilms tumor usually continues until age 7 years. Physical examination by a specialist (geneticist or pediatric oncologist) is recommended twice per year, and ongoing education regarding tumor manifestations, reinforcing the rationale for screening and compliance with the screening regimen, is discussed.[118]
Proposed screening guidelines for Wilms tumor are available for patients with Beckwith-Wiedemann syndrome who have undergone molecular subtyping [22] (refer to the Genomics of Wilms Tumor section of this summary for more information about the molecular subtypes). The four main molecular subtypes of Beckwith-Wiedemann syndrome (ICR1-GoM, ICR2-LoM, UPD, and CDKN1C mutation) are characterized by specific genotype-phenotype correlations, including tumor risk.
Proposed screening for specific molecular subtypes of Beckwith-Wiedemann syndrome is as follows:
Patients with a defect of the ICR1 region (ICR1-GoM and UPD) should have an abdominal ultrasound every 3 months until age 8 to 10 years; a clinical examination of the abdomen and muscle mass occurs monthly for the first year and then at 3-month intervals, between ultrasound scans, until age 6 years.
For patients with loss of imprinting at ICR2 (ICR2-LoM), an abdominal ultrasound examination is performed at the time of clinical or molecular diagnosis; only patients with organomegaly or severe hemihyperplasia require surveillance by ultrasound scans. Monthly clinical examinations are performed for the first 2 years, followed by clinical examinations every 3 to 6 months until age 6 years.
Patients with a CDKN1C mutation are not at high risk of developing Wilms tumor. There are no data to support routine screening.
Hemihyperplasia. Children with hemihyperplasia are also at risk of developing liver tumors, adrenal tumors, and Wilms tumor (risk, 3%–4%). Screening with abdominal ultrasound and serum alpha-fetoprotein is suggested until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasound, which is quicker and does not require fasting before the exam.[118]
Sporadic aniridia. Newborns born with sporadic aniridia should undergo molecular testing for deletion analysis of PAX6 and WT1. If a deletion of WT1 is observed, the child should be screened with ultrasound every 3 months until age 8 years, and the parents should be educated about the need for early identification and treatment of Wilms tumor.[75,120,121]
Children of survivors of bilateral Wilms tumor. Although the risk for Wilms tumor in the children of survivors of bilateral Wilms tumor is unknown and likely varies with the gene in which the mutation occurred, some experts recommend screening such children with serial ultrasound examinations every 3 months until age 8 years.[63]
Bohring-Opitz syndrome. Bohring-Opitz syndrome is a rare genetic condition associated with ASXL1 mutations. Screening with abdominal ultrasounds every 3 to 4 months in the first 8 years of life has been suggested because of the 7% incidence of a renal neoplastic process in patients with Bohring-Opitz syndrome.[37]
Simpson-Golabi-Behmel syndrome. Affected males with Simpson-Golabi-Behmel syndrome with GPC3 mutations or deletions have an approximate 10% risk of Wilms tumor. Regular age-dependent screening for tumors, including abdominal ultrasound, urinalysis, and biochemical markers, is recommended for males with Simpson-Golabi-Behmel syndrome, although the true benefit has not been determined. Carrier females are not at increased risk of Wilms tumor and do not require surveillance.[75]
Klippel-Trénaunay syndrome. The risk of Wilms tumor in children with Klippel-Trénaunay syndrome (a unilateral limb overgrowth syndrome) was no different than the risk in the general population when assessed using the NWTS database. Routine ultrasound surveillance is not recommended.[122]
Perlman syndrome. Perlman syndrome is a rare congenital overgrowth syndrome that has an autosomal recessive inheritance pattern. A molecular diagnosis can be made by the presence of inactivating mutations in DIS3L2 on chromosome 2q37.1. Fifty-three percent of children will die in the neonatal period. The kidneys show nephroblastomatosis in about 75% of cases. It is recommended that patients who survive the neonatal period be offered regular surveillance similar to that offered to patients with Beckwith-Wiedemann syndrome.[118]
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 [6] concluded that patients need to be referred for genetic counseling if they have one of the following:
One major abnormality such as:
Beckwith-Wiedemann symptoms (macroglossia, neonatal or postnatal macrosomia, abdominal wall defects, or visceromegaly); or
One condition such as:
Hemihyperplasia.
Overgrowth syndrome.
Mental retardation.
Aniridia.
Diffuse mesangial sclerosis.
Two or more minor malformations such as:
Inguinal or umbilical hernia.
Hypospadias.
Renal abnormalities.
Ectopic testis.
Simple oncological follow-up is indicated when there is no malformation or when there is only one minor malformation.[6]
After genetic counseling takes place, a search for WT1 mutations should be considered for patients who have the following:
Bilateral Wilms tumor.
Familial Wilms tumor.
Wilms tumor and age younger than 6 months.
Genitourinary abnormality.
Mental retardation association.
A search 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.
A lump, swelling, or pain in the abdomen. Most children present with an asymptomatic mass that is noted when they are bathed or dressed. Abdominal pain is present in 40% of children.
Blood in the urine. Gross hematuria occurs in about 18% of children with Wilms tumor at presentation, and microscopic hematuria is seen in 24% of patients.[123]
Hypertension. About 25% of children have hypertension at presentation, which is attributed to activation of the renin-angiotensin system.
Hypercalcemia. Symptomatic hypercalcemia can sometimes be seen at presentation of rhabdoid tumors.
Constitutional symptoms such as fever, anorexia, and weight loss occur in 10% of cases.
Children with Wilms tumor or other renal malignancies may also come to medical attention as a result of the following:
Vascular obstruction or metastasis, including pulmonary symptoms due to lung metastasis.
Abdominal pain due to liver metastasis, prominent abdominal wall vessels, or varicocele due to inferior vena cava obstruction.
Pulmonary embolus (rare).
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:
Physical exam and history.
Complete blood count (CBC).
Liver function test.
Renal function test.
Urinalysis.
Abdominal imaging.
Abdominal x-ray.
Ultrasound exam of the abdomen. Ultrasound exam of the abdomen is often performed before a more definitive computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) with contrast of the abdomen is done. This procedure is unnecessary after the definitive diagnostic study has been performed.
About 4% of Wilms tumor patients present with inferior vena cava or atrial involvement and 11% with renal vein involvement. Embolization of a caval thrombus to the pulmonary artery is rare but can be lethal, and the presence of a thrombus must be identified preoperatively to prevent this occurrence and guide treatment. CT scan of the abdomen will confirm the renal origin of the mass and determine whether there are bilateral tumors. A report from the COG shows that CT can accurately identify cavoatrial thrombus, obviating the need for ultrasound if CT has already been performed.[125]
Review of children with bilateral Wilms tumor demonstrated that only 0.25% of bilateral tumors were missed with modern helical CT scans, all of which were small tumors.[126]
Chest x-ray.
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.
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 imaging, which 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.[127]
von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have acquired von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[128] Some clinicians recommend evaluation for von Willebrand disease before surgery.
Biopsy or resection. 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.
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. The use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread.[129] 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 unfavorable histology that is missed during an upfront biopsy 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.[124,126] If the initial imaging studies suggested a possible lesion on the contralateral kidney, the contralateral kidney is formally explored to rule out bilateral involvement. This is done to exclude bilateral Wilms tumor before nephrectomy.
Biopsy is also controversial in patients with bilateral tumors because biopsy rarely detects anaplasia in bilateral Wilms tumor,[130] and the incidence of bilateral tumors being other than Wilms is very low. The now closed COG AREN0534 (NCT00945009)study of bilateral Wilms tumor and of patients with unilateral Wilms tumor predisposed to developing bilateral tumors tried to avoid initial biopsy and mandated biopsy only after 6 weeks of three-drug chemotherapy if there was less than a 50% reduction in size and the tumor remained unresectable.
Lymph node sampling is required to locally stage all Wilms tumor patients.
Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihyperplasia. About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[131]
For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess intravascular extension or rupture of Wilms tumor.[132]
Intravascular extension of the Wilms tumor. Preoperative assessment of intravascular extension of Wilms tumor is essential to guide management. The presence of intravenous tumor thrombus in the lumen of the renal vein, inferior vena cava, and right atrium has been reported in up to 11.3% of Wilms tumor patients and may lead to differences in management.
In North America, local staging of Wilms tumor is performed with CT or MRI of the abdomen and pelvis. Contrast-enhanced CT for Wilms tumor patients has high sensitivity and specificity for detection of cavoatrial tumor thrombus that may impact surgical approach. Routine Doppler evaluation after CT has been performed but is not necessarily required.[125] Before surgical approach to the renal mass is performed, large tumor thrombi need to be controlled, especially when they extend above the hepatic vein, to avoid embolization of the tumor.
Wilms tumor rupture. Based on their similar diagnostic performances, either CT or MRI can be used for initial staging.[124] Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, irrespective of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.[133]
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%.[134] 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.[135]
The prognosis for patients with Wilms tumor depends on the following:[136-139]
Molecular features of the tumor such as 1q gain and loss of heterozygosity of 1p and 16q. 1q gain is the most powerful predictor of outcome and is associated with an adverse outcome.[94-96]
Age. Older age is associated with adverse prognosis.[140]
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.[141] 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.[141] 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 adults is inferior to the outcome for children. In an analysis of patients with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database, adults (n = 152) had a statistically worse OS (69% vs. 88%; P < .001) than did pediatric patients (n = 2,190).[142] 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.[142-144] The 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.
The inferior outcome of older patients is not explained entirely by inadequate treatment or not being treated according to the pediatric Wilms tumor protocol. In a U.K. study looking at the outcome of patients aged 10 to 16 years (N = 50) registered on the U.K. Wilms Tumor 3 and International Society of Pediatric Oncology (SIOP) 2001 Wilms tumor trials, patients in this age group had a higher percentage of diffuse anaplastic tumors. The overall 5-year survival was 63% for patients aged 10 to 16 years (43% for anaplastic tumors), which is significantly lower than the outcome for younger patients with FH Wilms tumor.[140] However, SEER 5-year relative survival of nephroblastoma between 2003 and 2009 did not show differences among age groups from younger than 1 year to age 10 to 14 years.[145]
The following recommendations from the renal tumor committees of the SIOP and COG encourage a uniform approach to improve outcome for adults with Wilms tumor.[146]
Consult with a pediatric oncologist who has experience with the treatment of Wilms tumor as soon as a histological diagnosis is suspected.
Avoid delaying the start of chemotherapy. Ideally, chemotherapy, and radiation therapy if necessary, should be started by day 14 postnephrectomy, although delaying the start until day 30 is acceptable.
Be alert for toxicity of vincristine (neurotoxicity) and dactinomycin (hepatic toxicity) in adults.
Register patients in pediatric renal tumor trials if studies are available and the patients are eligible.
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:
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.[147]
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.[140] In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[148,149]
The following two histologic criteria must be present to confirm the diagnosis of anaplasia:
Presence of multipolar polyploid mitotic figures with marked nuclear enlargement.
Hyperchromasia.
Changes on 17p consistent with mutations in the TP53 gene have been associated with foci of anaplastic histology.[106] 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.[150] Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[138,151,152]
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.[138]
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.[153,154] 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.[5]
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.[155]
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).[79] Intralobar nephrogenic rests have been associated with stromal-type Wilms tumor and younger age at diagnosis.[5]
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.[44]
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. 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, perhaps as a result of the development and selection of anaplasia in the surviving abnormal kidney cells.[155,156]
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.[157]
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).[147,158]
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.[147]
Stage I
In stage I Wilms tumor (43% of patients), all of the following criteria must be met:
Tumor is limited to the kidney and is completely resected.
The renal capsule is intact.
The tumor is not ruptured or biopsied before being removed.
No involvement of renal sinus vessels.
No evidence of the tumor at or beyond the margins of resection.
All lymph nodes sampled are negative.
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:
There is regional extension of the tumor (i.e., penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below).
Blood vessels in the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor cells. Margins are clear.
Vascular extension of tumor is considered stage II only if it is completely removed en bloc in the nephrectomy specimen.
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; however, data to support this approach are controversial.[129,159]
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 nodes in the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax or other extra-abdominal sites is a criterion for stage IV.)
The tumor has penetrated through the peritoneal surface.
Tumor implants are found on the peritoneal surface.
Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination).
The tumor is not completely resectable because of local infiltration into vital structures.
Tumor spillage occurs either before or during surgery.
Any biopsy is performed, regardless of type—Tru-cut biopsy, open biopsy, or fine-needle aspiration—before the tumor is removed.
The tumor is removed in more than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus in the renal vein is removed separately from the nephrectomy specimen). Extension of the primary tumor in the vena cava into the thoracic vena cava and heart is considered stage III, rather than stage IV, even though outside the abdomen—and it can even be stage II if completely resected en bloc with the nephrectomy specimen.
Lymph node involvement and microscopic residual disease are reported as highly predictive of outcome in patients with stage III FH Wilms tumor.[160]
Stage IV
In stage IV Wilms tumor (11% of patients), one of the following is present:
Lymph node metastases outside the abdominopelvic region.
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. A previous attempt was made to stage each side according to the previously described criteria on the basis of the extent of local disease. In these patients, renal failure rates approach 15% at 15 years posttreatment, although standard approaches have not been accepted for renal-sparing treatment.[161]
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 Renal Tumor Committee [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 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.
COG RTC (includes the previous NWTS Group): The NWTS Group established standard treatment for Wilms tumor in North America, consisting of initial nephrectomy (when feasible) followed by chemotherapy and, in some patients, radiation therapy.[162-164] This approach allows for early and accurate histologic diagnosis, collection of biologic materials unaltered by therapy, and staging information, such as the presence of tumor spill or tumor involvement in lymph nodes, before chemotherapy is administered.
SIOP: SIOP is a European consortium whose trials provide preoperative chemotherapy before definitive resection for patients with renal tumors. This results in fewer tumor ruptures during surgery and lower postoperative stage.[165] When the histological features of Wilms tumors from patients who underwent immediate surgery were compared with the histological features of those who received preoperative chemotherapy, preoperative chemotherapy was shown to significantly alter the histology, with fewer blastemal and mixed histology types in the tumors. Additionally, there were fewer stage III tumors in the preoperative chemotherapy group.[166]
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:
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.[164]
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.[164]
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.[164]
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.[167]
Eighteen weeks of therapy is adequate for patients with stage I and II FH, and stage III and IV patients can be treated with 6 months of therapy instead of 15 months.[135,162,167-169]
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.[94,96]
Surgery
The following operative principles have also evolved from NWTS trials:
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.[170] 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.[170]
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.[126]
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.[171]
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).[172]
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:[173,174]; [175][Level of evidence: 3iiB]
A solitary kidney.
Predisposition to bilateral tumors. Some children who are predisposed to bilateral tumors and who have very small tumors detected by ultrasound screening may be considered for renal-sparing surgery to preserve renal tissue.[173]
Horseshoe kidney. Wilms tumor arising in a horseshoe kidney is rare, and accurate preoperative diagnosis is important for planning the operative approach. Primary resection is possible in most cases. Inoperable cases can usually be resected after chemotherapy.[176]
Wilms tumor in infants with Denys-Drash or Frasier syndrome (to delay the need for dialysis).
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.[177] In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor after administration of chemotherapy to shrink the tumor mass is considered investigational.[178,179]
Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[170,180] 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 has led to the recommendation in current COG protocols that these patients should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection.[181] Primary resection of liver metastasis is not recommended.[182]
Chemotherapy
Preoperative chemotherapy before nephrectomy is indicated in the following situations:[170,181,183-186]
Wilms tumor in a solitary kidney.
Synchronous bilateral Wilms tumor.
Extension of tumor thrombus in the inferior vena cava above the level of the hepatic veins. About 4% of Wilms tumor patients present with inferior vena cava or atrial involvement, and 11% of patients present with renal vein involvement. Embolization of a caval thrombus to the pulmonary artery is rare but can be lethal, and the presence of a thrombus must be identified preoperatively to prevent this occurrence and guide treatment.[125]
Tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structures (e.g., spleen, pancreas, or colon but excluding the adrenal gland).
Inoperable Wilms tumor.
Pulmonary compromise due to extensive pulmonary metastases.
Preoperative chemotherapy follows a biopsy. The biopsy may be performed through a flank approach.[187-192] 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.[129,181,183,192-194]
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.[195,196] The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists.[133]
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.[197] 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.[198]
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.[199,200] 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.[201,202]
Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III.
Table 2 describes the standard chemotherapy regimens used to treat Wilms tumor.
Table 2. Standard Chemotherapy Regimens for Wilms Tumor
Vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide with subsequent radiation therapy
Treatment of stage I Wilms tumor
Table 3 provides an overview of the standard treatment options and survival data for stage I Wilms tumor, based on published results.
Table 3. Overview of Standard Treatment Options for Stage I Wilms Tumora
Histology
4-Year RFS or EFS
4-Year OS
Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.,[96] Dome et al.,[138] Shamberger et al.,[139] and Fernandez et al.[204]
bFewer than five patients have survived 4 years; therefore, results should be interpreted with caution.
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
FA
68%b
89%
Nephrectomy + lymph node sampling followed by regimen EE-4A and XRT
DA
68% EFS
79% (n = 10)
Nephrectomy + lymph node sampling followed by regimen EE-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):
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.[139,204,205]
Twelve patients relapsed.
The estimated 4-year EFS was 89.7%, and the OS was 100%.
11p15 methylation status was associated with relapse (20% relapse with loss of heterozygosity, 25% relapse with loss of imprinting, and 3.3% relapse with retention of the normal imprinting [P = .011]).
Risk of developing metachronous Wilms tumor is very low in patients with very low-risk Wilms tumor who lack evidence of an underlying syndrome.
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Treatment of stage II Wilms tumor
Table 4 provides an overview of the standard treatment options and survival data for stage II Wilms tumor, based on published results.
Table 4. Overview of Standard Treatment Options for Stage II Wilms Tumora
Histology
4-Year RFS or EFS
4-Year OS
Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplastic; EFS = event-free survival; FA = focal anaplastic; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
Nephrectomy + lymph node sampling followed by regimen EE-4A
FA
80% EFS
80% (n = 5)
Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
DA
83% EFS
82%
Nephrectomy + lymph node sampling followed by abdominal XRT and regimen I
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.[206] 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 for patients who experienced 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.[159]
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Treatment of stage III Wilms tumor
Table 5 provides an overview of the standard treatment options and survival data for stage III Wilms tumor, based on published results.
Table 5. Overview of Standard Treatment Options for Stage III Wilms Tumora
Histology
4-Year RFS or EFS
4-Year OS
Treatment (refer to Table 2 for chemotherapy regimen descriptions)
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.,[96] Dome et al.,[138] and Fernandez et al.[207]
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)
91% EFS
97%
Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A
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
65% EFS
67%
Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen I
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 of 97% and OS of 99%.[207][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 of 74%. However, 4-year OS was not influenced, at 92%.[207]
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Treatment of stage IV Wilms tumor
Table 6 provides an overview of the standard treatment options and survival data for stage IV Wilms tumor, based on published results.
Table 6. Overview of Standard Treatment Options for Stage IV Wilms Tumora
Histology
4-Year RFS or EFS
4-Year OS
Treatment (refer to Table 2 for chemotherapy regimen descriptions)
DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; FH = favorable histology; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy.
aSource: Grundy et al.[96], Dome et al.[138], and Dix et al.[203]
bAbdominal XRT is planned according to local stage of renal tumor.
cPulmonary XRT is reserved for patients with chest x-ray/chest CT evidence of pulmonary metastases.
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,cand regimen DD-4A or regimen Md
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 = 15)
Immediate nephrectomy + lymph node sampling followed by abdominal XRT,b radiation to sites of metastases, whole-lung XRT,cand regimen I
DA (preoperative treatment)
31% EFS
44% (n = 13)
Preoperative treatment with regimen I 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):
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.[208]
Patients who received doxorubicin, vincristine, and dactinomycin with or without lung radiation had a 5-year EFS of 80% versus an EFS of 56% for patients receiving only two drugs (P = .004).
There was no difference in EFS according to whether the lung was irradiated.
There was no difference in the 5-year OS (87% vs. 86%).
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):
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.[209]
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.
The 5-year EFS was 77%, and the OS was 88%.
Patients who had residual pulmonary metastases were evaluated for metastasectomy.
Thirty-seven patients (17%) obtained complete remission with surgery, and their outcome was similar to that of the group of patients who were treated with chemotherapy. Tumor viability in the resected pulmonary metastases was not a factor for omitting radiation therapy.
The 5-year EFS was 84%, and the OS was 92%.
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.
Patients showing a complete remission at that time were spared pulmonary radiation and continued with chemotherapy, whereas patients with residual pulmonary metastases continued with additional chemotherapy (to complete 34 weeks) and pulmonary irradiation. The 5-year OS was 48%, compared with the OS for patients who responded to chemotherapy alone (88%) and those who underwent metastasectomy (92%) (P < .001).
Patients with high-risk histologies, such as anaplastic Wilms tumor, were treated with more aggressive chemotherapy but had a poorer outcome, compared with that of patients with nonanaplastic histologies (5-year OS, 87% vs. 33%; P < .001).
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.[203][Level of evidence: 3iiiDi]
Of the 292 patients enrolled in the study, 133 patients (42%) showed a complete lung nodule response after 6 weeks of DD4A (vincristine, dactinomycin, doxorubicin) and continued receiving the same chemotherapy without lung radiation therapy. The 4-year EFS was 80%, and OS was 96%.
Patients who had an incomplete lung nodule response (n = 145) or loss of heterozygosity at 1p/16q (n = 18) received lung radiation therapy and four cycles of cyclophosphamide/etoposide in addition to the DD4A drugs (regimen M). The 4-year EFS was 89% and OS was 95% for the incomplete lung nodule response group without loss of heterozygosity. Of the patients with pulmonary metastases only and loss of heterozygosity, the 4-year EFS and OS were 100%.
In a post hoc analysis of 1q gain in 212 patients enrolled in AREN0533 who had DNA available, patients with lung nodule complete remission with 1q gain had a significantly worse 4-year EFS (86% vs. 57%, P = .001) and trend toward inferior OS (97% vs. 89%). Relapses were predominantly pulmonary. There was no difference in outcome for patients with incomplete lung nodule response on the basis of 1q gain.
Regimen M has a higher potential for late effects (increased risk of secondary leukemias and risk of infertility related to a cumulative dose of cyclophosphamide of 8.8 g/m2).
COG showed that initial lung radiation therapy could be avoided in approximately 40% of patients. OS was excellent; however, there was a trend toward more events than expected (expected, 15% and observed, 20%; P = .052).
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.[203,209] 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.[182]
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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.
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.[161]
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 for patients with bilateral FH Wilms tumor was 74% and the OS was 89%; for patients with anaplastic histology, the EFS was 40% and the OS was 45%.[149] The NWTS-5 study reported that the 4-year EFS for all bilateral Wilms tumor patients was 56% and the OS was 81%; the 4-year EFS rates for patients with FH (65%), focal anaplastic histology (76%), and diffuse anaplastic histology (25%) were also reported.[96,138] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[148,210] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[210] 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 may include the following:
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.[211]
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.[211] 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.[130] 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.[211]
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.[149]
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.[149]
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.[158,212,213]
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):
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.[211]
For the arm that treated children with bilateral Wilms tumor, results showed that central review of imaging, surgical resection within 12 weeks of diagnosis, and response-based and histology-based postoperative therapy improved EFS and OS, when compared with the historical outcomes of children with bilateral Wilms tumor.
For the 189 patients with bilateral Wilms tumor, 4-year EFS was 82.1% (95%confidence interval [CI], 73.5%–90.8%), and OS was 94.9% (95% CI, 90.1%–99.7%).
One of the aims of the study was that 75% of patients undergo definitive surgery by 12 weeks. After induction chemotherapy, 163 of 189 patients (84%) underwent definitive surgical treatment in at least one kidney by 12 weeks, and 39% of patients retained parts of both kidneys.
Chemotherapy after surgery was tailored according to histologic response. Four-year EFS was 84.1% for FH tumors, 58.2% for anaplastic-histology tumors, and 82% for blastemal-type tumors.
Because of the higher risk of renal failure in patients with bilateral Wilms tumor than in patients with unilateral Wilms tumor, one of the goals of the study was that 50% of the patients undergo bilateral nephron-sparing surgery. This threshold was not met, with only 39% of patients successfully treated with bilateral nephron-sparing surgery.
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).[148]
The 4-year DFS was 67%, and OS was 80%.
There was a trend toward better EFS in nonmetastatic patients receiving vincristine, dactinomycin, and doxorubicin preoperatively (4-year EFS, 84%) than for patients receiving vincristine and dactinomycin (4-year EFS, 65%), but this was not significant.
The bilateral renal parenchyma was preserved in 48% of patients.
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.[214]
The 5-year EFS rate was 83.4%, and the OS rate was 89.5%.
All but one of the patients had renal-sparing surgery in at least one kidney.
Despite the good survival, 14% of the patients developed end-stage renal disease.
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.[215]
In a series, 39 of 42 patients with bilateral FH Wilms tumor underwent successful bilateral renal-sparing procedures after receiving preoperative chemotherapy. Three patients underwent unilateral nephrectomy with contralateral nephron-sparing surgery. Three patients required early (within 4 months) repeat nephron-sparing surgery for residual tumor. In the long term, seven patients had local tumor recurrence, and three patients had intestinal obstruction.
OS was 86% (mean follow-up, 4.1 years). Of the six patients who died, five had diffuse anaplastic histology.
All of the patients had an estimated glomerular filtration rate of more than 60 mL/min/1.73m2 at the last follow-up; none of the patients developed end-stage renal disease.
The authors concluded that bilateral renal-sparing surgery is almost always feasible and can be done safely with good oncologic outcomes in patients with synchronous, bilateral Wilms tumor. It should be considered even if preoperative imaging studies suggest that the lesions are unresectable. Sparing of renal parenchyma is likely to help preserve renal function in children who are at significant risk of chronic renal insufficiency. Careful long-term follow-up is required to fully assess the potential progression of renal dysfunction.
Renal transplantation
Renal transplantation 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.[216] Similarly, renal transplantation for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.[216]
Treatment options under clinical evaluation
There is no current standard treatment for children with stage V Wilms tumor and for those predisposed to developing Wilms tumor.
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For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasound 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:
Premature mortality after Wilms tumor diagnosis. In 1,441 5-year survivors of Wilms tumor, a substantial increase in cumulative mortality from 5.4% to 22.7% was noted from 30 to 50 years after Wilms tumor diagnosis. Excess deaths after 30 years were attributed to subsequent malignant neoplasms (50%) and cardiac-related causes (25%).[217] Radiation therapy was a risk factor for both outcomes.
Subsequent malignant neoplasms.[217-219] Digestive cancers and breast cancer are the most frequent subsequent neoplasms, and radiation therapy is a risk factor. Women treated with lower doses of radiation to large volumes of breast tissue for a childhood cancer have a risk of breast cancer that is higher than previously recognized. The cumulative incidence of invasive breast cancer in Wilms tumor survivors who had received pulmonary radiation for metastatic Wilms tumor is nearly 15% by age 40 years.[220]
Congestive heart failure. The risk of congestive heart failure is influenced by dose of doxorubicin received, radiation to the heart, and female sex.[219,221]
End-stage renal disease. The cumulative incidence of end-stage renal disease caused by chronic renal failure at 20 years from diagnosis of Wilms tumor is low, at 3.1% for patients with bilateral Wilms tumor and less than 1% for those with unilateral Wilms tumor.[79] Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.
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