Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]
Wilms Tumor
Incidence of Wilms Tumor
Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years, or one case per 10,000 infants.[1] Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asian people.[1,2]
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.[3,4] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[5]
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.[5,6] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases.[7] Of 295 consecutive patients with Wilms tumor seen at the Institut Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes.[8]
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.[9,10]
It is important to recognize that the absolute risk of Wilms tumor varies with the underlying condition or anomaly. For example, most patients with hemihyperplasia will not develop Wilms tumor.
| Syndrome/Condition | Gene | Overgrowth Phenotype | Non-Overgrowth Phenotype |
|---|---|---|---|
| High Risk of Wilms Tumor (>20%) | |||
| CLOVES = congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/spinal abnormalities; MULIBREY = distinctive abnormalities of the (MU)scles, (LI)ver, (BR)ain, and (EY)es; WAGR = Wilms tumor, aniridia, genitourinary anomaly, and mental retardation. | |||
| a Adapted from Treger et al.[11] | |||
| WAGR syndrome | WT1deletion | X | |
| Denys-Drash syndrome | WT1missense mutation | X | |
| Perlman syndrome | DIS3L2mutation | X | |
| Fanconi anemia with biallelic mutations inBRCA2(FANCD1) orPALB2(FANCN) | BRCA2,PALB2 | X | |
| Premature chromatid separation/mosaic variegated aneuploidy | BiallelicBUB1BorTRIP13mutation | X | |
| Moderate Risk of Wilms Tumor (5%–20%) | |||
| Frasier syndrome | WT1intron 9 splice mutation | X | |
| Beckwith-Wiedemann syndrome | Uniparental disomy or H19 epimutation | X | |
| Simpson-Golabi-Behmel syndrome | GPC3mutation | X | |
| Low Risk of Wilms Tumor (<5%) | |||
| Bloom syndrome | BiallelicBLMmutation | X | |
| DICER1 syndrome | DICER1mutation | X | |
| Li-Fraumeni syndrome | TP53,CHEK2 | X | |
| Isolated hemihyperplasia | X | ||
| Hyperparathyroidism-jaw tumor syndrome | CDC73(also known asHRPT2) mutation | X | |
| MULIBREY nanism syndrome | TRIM37mutation | X | |
| PIK3CA-related segmental overgrowth including CLOVES syndrome | PIK3CAmutation | X | |
| 9q22.3 microdeletion syndrome | 9q22.3 | X | |
| Sotos syndrome | NSD1 | X | |
| Familial Wilms tumor | FWT1 | X | |
| FWT2 | |||
| Genitourinary anomalies | WT1 | X | |
| Sporadic aniridia | WT1 | X | |
| Trisomy 18 | X | ||
For information about the genes associated with Wilms tumor, including WT1 and WT2, refer to the Genomics of Wilms Tumor section of this summary.
Syndromic causes of Wilms tumor
WT1-related syndromes
WT1-related syndromes include the following:
- WAGR syndrome. WAGR syndrome is characterized by the following:
- W ilms tumor.
- A niridia.
- G enitourinary anomaly.
- Mental R etardation.
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).[12,13] The risk of Wilms tumor development in children with WAGR syndrome is approximately 50%; these children will present earlier (median age, 22 months) and have a higher incidence of bilateral Wilms tumors (37%) than will children with nonsyndromic Wilms tumors.[14,15] In 43 patients with WAGR syndrome who developed Wilms tumor or nephroblastomatosis, none of the patients developed metastases or exhibited anaplastic histology. Contralateral tumors developed in three patients, with one tumor occurring up to 7 years after initial diagnosis.[15] (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 XY genome 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),[16] both of which are associated with mutations in the WT1 gene.[17] Specifically, germline missense mutations in the WT1 gene are responsible for most cases of Wilms tumor that occur as part of Denys-Drash syndrome.[18,19] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome, with bilateral disease developing in 20% of patients.[19,20] In Frasier syndrome, splice-site WT1 mutations result in an imbalance of WT1 isoforms and a much lower incidence of Wilms tumor.[21]
WT2-related syndromes
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. Approximately 15% of children with Beckwith-Wiedemann syndrome will have bilateral tumors.[22]
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 CDKN1C mutation).[23] Approximately 15% of cases with clear-cut phenotypes have no molecular defects established so far.[24,25]
The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes.[26,27,28]
The prevalence of Beckwith-Wiedemann syndrome is about 1% of children with Wilms tumor.[22,29,30,31] Approximately 10% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor.[23] Beckwith-Wiedemann syndrome patients with hemihyperplasia have a fourfold increased tumor risk over Beckwith-Wiedemann syndrome patients without hemihyperplasia.[32] (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
Other syndromic causes of Wilms tumor
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%).[33]
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.[34]
- 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 the GPC3 and GPC4 genes, and these genetic aberrations are believed to enhance the risk of Wilms tumor (8%).[35]
- CLOVES syndrome. This syndrome is characterized by the following:
- C ongenital L ipomatous O vergrowth.
- V ascular malformations.
- E pidermal nevi.
- S keletal/spinal abnormalities.
This syndrome results from postzygotic, somatic mutations in PIK3CA, which may involve large or small regions of the child.[36]
- 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.
Mutations in the NSD1 gene are the only known cause of Sotos syndrome.[37]
- 9q22.3 microdeletion syndrome. 9q22.3 microdeletion syndrome is characterized by craniofacial abnormalities, metopic craniosynostosis, hydrocephalus, macrosomia, and learning disabilities.
Of 44 described patients with 9q22.3 deletions, 7 patients developed Wilms tumor, and there was an association with overgrowth in 4 of those 7 patients. Although the size of the deletions was variable, all of them encompassed the PTCH1 gene.[38]; [39][Level of evidence: 3iii] According to the authors of this study, surveillance for Wilms tumor should be considered in any patient with 9q22.3 microdeletion syndrome, especially in the presence of overgrowth.[39][Level of evidence: 3iii]
- 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.
Mutations in the BLM gene are the only known cause of Bloom syndrome.[40]
- 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.[41]
- 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.[42]
- 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.[43]
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 of Wilms tumor. Siblings of children with Wilms tumor have a less-than-1% chance of developing Wilms tumor.[44,45,46] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.[47]
Two distribution loci at 17q12-q21 (FWT1) and 19q13.4 (FWT2) have been identified by genetic linkage studies of families affected by Wilms tumor. Although the genes have yet to be characterized, in siblings with Wilms tumor, loss of function of the transcriptional corepressor TRIM28 was detected, which is located at FWT2.[48,49,50] Occasionally, Wilms tumor families have germline mutations in WT1. In these families, most, but not all, of the family members have genitourinary tract malformations.[51,52]
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.[53] A few families with familial Wilms tumor have germline microdeletion or microinsertion mutations in the H19 region of 11p15.3 that result in hypermethylation of the site.[54]
- Constitutional 11p15 abnormalities. Constitutional 11p15 abnormalities have been identified in lymphocyte DNA of 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases. All were de novo abnormalities and appeared to be postzygotic, except for one novel microdeletion in a child whose mother had the mutation and was not affected; however, a younger brother with the microdeletion had Beckwith-Wiedemann syndrome. This suggests that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.[54]
- 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 intellectual disability (i.e., not obviously WAGR syndrome). Therefore, many patients with sporadic aniridia develop Wilms tumor and are candidates for genetic testing. The relative risk of Wilms tumor in sporadic aniridia is 67-fold.[55] About one-half of individuals with sporadic aniridia and PAX6 and WT1 deletions develop Wilms tumor.[56]
- 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.[57] The prevalence is about 2.5% of children with Wilms tumor.[29,57]
- Trisomy 18.[58]
- 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.[59,60,61]
- Maternal pesticide exposure. In a French population study, the maternal use of any household pesticide during pregnancy was associated with a risk of Wilms tumor in children (odds ratio [OR], 1.6). Insecticides were the most commonly reported type of pesticide, and the association with Wilms tumor was stronger when insecticides were used more than once per month.[62][Level of evidence: 3iii]
Genomics of Wilms Tumor
Molecular Features of Wilms Tumor
Wilms tumor may arise during embryogenesis on the background of an otherwise genomically normal kidney, or it may arise from nongermline somatic genetic precursor lesions residing in histologically and functionally normal kidney tissue. Hypermethylation of H19, a known component of a subset of Wilms tumors, is a very common genetic abnormality found in these normal-appearing areas of precursor lesions.[63]
One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors followed by targeted sequencing of 651 Wilms tumors.[64] The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:[64]
- 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.[65,66] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[67,68,69,70] 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),[67,68]EP300, CREBBP, and MYCN.[64] 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.[64] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.
Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[71] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[53,72]
The genomic and genetic characteristics of Wilms tumor are summarized below.
WT1gene
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.[73]WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[65,73,74]
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.[74,75,76]
- 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.[74,77]
- 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.[78] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 mutations.[79,80]
- WT1 germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.[52,81]
- WT1 mutations and 11p15 LOH were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[82] 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,[19] or Frasier syndrome.[16]
- Genitourinary anomalies, including hypospadias and cryptorchidism.
- Bilateral Wilms tumor.
- Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
- Stromal and rhabdomyomatous differentiation.
Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[83,84] Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[19] and Frasier syndrome.[16]
- WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[5] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that include 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. Loss of the LMO2 gene has been associated with a more frequent development of Wilms tumor in patients with congenital aniridia and WAGR-region deletions.[85][Level of evidence: 3iii] 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.[29,86]
Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests, early age at diagnosis, and stromal-predominant histology in FH tumors.[14] The intellectual disability in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[54]
- Denys-Drash syndrome. Denys-Drash syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%).
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.[19]
- Frasier syndrome. Frasier syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.
WT1 mutations in Frasier syndrome typically occur in intron 9 at the KTS site, and create an alternative splicing variant, thereby preventing production of the usually more abundant WT1 +KTS isoform.[21]
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%).[83,84] 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).[83,84] 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.
CTNNB1gene
CTNNB1 is one of the most commonly mutated genes in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[64,66,74,76,87] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[88]CTNNB1 mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1 mutations have a concurrent CTNNB1 mutation.[74,76,87] 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.[66,89]CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[79]
WTXgene 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.[65,66,74,90,91] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373).[92] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[92] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[89,93]WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[65,74,90] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[74]
WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[65]
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.[54]
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[29,30,31] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[3,31]
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[94] 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).[54,95]
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[95] LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[54,94,95]
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.[96]
The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:
- ICR1 gain of methylation (ICR1-GoM). Five percent to 10% of cases are caused by telomeric ICR1-GoM, which causes both biallelic expression of the IGF2 gene (normally expressed by the paternal allele only) and reduced expression of the oncosuppressor H19 gene. The incidence of Wilms tumor is 22.8%.[97]
- ICR2 loss of methylation (ICR2-LoM). Fifty percent of cases with Beckwith-Wiedemann syndrome are caused by ICR2-LoM, resulting in reduced expression of the CDKN1C gene, normally expressed by the maternal chromosome only. Tumor incidence is very low (2.5%).[97]
- Uniparental disomy (UPD). Altered expression at both imprinted gene clusters is observed in mosaic UPD of chromosome 11p15.5, accounting for 20% to 25% of the cases. The incidence of Wilms tumor is 6.2%, followed by hepatoblastoma (4.7%) and adrenal carcinoma (1.5%).[97] Fewer than 1% of cases with Beckwith-Wiedemann syndrome are caused by chromosomal rearrangements involving the 11p15 region.
- CDKN1C mutations. Maternally inheritable CDKN1C loss-of-function mutations account for approximately 5% of the cases. This type is associated with a 4.3% incidence of neuroblastoma.[97]
Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[23,27,98] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[31]
Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[99] Interestingly, Wilms tumor in Japanese and East Asian children, which occurs at a lower incidence than in White children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.[100]
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.[101,102] 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.[101]
- 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 LOH for these regions in 17% and 11% of Wilms tumor cases, respectively.[103]
- 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 LOH.[104]
- 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.[105]
These conflicting results may arise from the greater prognostic significance of 1q gain described above. LOH of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, LOH of 16q and 1p retains their adverse prognostic impact.[101] The LOH of 16q and 1p appears to arise from complex chromosomal events that result in 1q LOH or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[106]
- miRNAPG. Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[64,67,68,69,70] The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 1).[107] 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.[67,68]
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.[108] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[108] 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.[109] Another study identified DICER1 mutations in 2 of 48 familial Wilms tumor families.[110] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 mutations.[68,69]
- Perlman syndrome is a rare overgrowth disorder caused by mutations in DIS3L2, which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA.[34,111] The prognosis of Perlman syndrome is poor, with a high neonatal mortality rate. In a survey of published cases of Perlman syndrome (N = 28), in infants who survived beyond the neonatal period, approximately two-thirds developed Wilms tumor, and all patients showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.[112]
Figure 1. The miRNA processing pathway is commonly mutated in Wilms tumor. Expression of mature miRNA is initiated by RNA polymerase–mediated transcription of DNA-encoded sequences into pri-miRNA, which form a long double-stranded hairpin. This structure is then cleaved by a complex of Drosha and DGCR8 into a smaller pre-miRNA hairpin, which is exported from the nucleus and then cleaved by Dicer (an RNase) and TRBP (with specificity for dsRNA) to remove the hairpin loop and leave two single-stranded miRNAs. The functional strand binds to Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides the complex to its target mRNA, while the nonfunctional strand is degraded. Targeting of mRNAs by this method results in mRNA silencing by mRNA cleavage, translational repression, or deadenylation. Let-7 miRNAs are a family of miRNAs highly expressed in ESCs with tumor suppressor properties. In cases in which LIN28 is overexpressed, LIN28 binds to pre-Let-7 miRNA, preventing DICER from binding and resulting in LIN28-activated polyuridylation by TUT4 or TUT7, causing reciprocal DIS3L2-mediated degradation of Let-7 pre-miRNAs. Genes involved in miRNA processing that have been associated with Wilms tumor are highlighted in blue (inactivating) and green (activating) and include DROSHA, DGCR8, XPO5 (encoding exportin-5), DICER1, TARBP2, DIS3L2, and LIN28. Copyright © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press. Genes Dev. 2015 Mar 1; 29(5): 467–482. doi: 10.1101/gad.256396.114. This article is distributed exclusively by Cold Spring Harbor Laboratory Press under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
- 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 SIX1 mutations is 3% to 4% in Wilms tumor, and the frequency of SIX2 mutations in Wilms tumor is 1% to 3%.[67,68] 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. In Wilms tumor, SIX1 and SIX2 mutations are associated with the high-risk blastemal subtype and with the presence of undifferentiated blastema in chemotherapy-naïve samples.[67,68]
- 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.[80] 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.[113,114,115]TP53 may be useful as an unfavorable prognostic marker.[113,114]
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 wtTP53 had a significantly lower relapse rate and mortality rate than did patients with TP53 abnormalities (P = .00006 and P = .00007, respectively). The TP53 status had no effect on patients with stage I or stage II tumors.[116]
- In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These wtTP53 tumors demonstrated gene expression evidence of p53 pathway activation. Retrospective pathology review of wtTP53 tumors 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.[116]
- FBXW7. FBXW7, a ubiquitin ligase component, is an established tumor suppressor gene that has been identified as recurrently mutated at low rates in Wilms tumor and other malignancies. Mutations of this gene have been associated with epithelial-type tumor histology.[117]; [118][Level of evidence: 3iii]
- TRIM28. TRIM28 encodes a multidomain protein involved in the regulation of many cellular processes and is an autosomal dominant Wilms tumor predisposition gene. TRIM28 accounts for about 8% of familial Wilms tumor and 2% of unselected Wilms tumor. A strong association between TRIM28 mutations and epithelial Wilms tumor has been observed; most individuals with a TRIM28 mutation have a Wilms tumor of predominantly epithelial histology. In 33 individuals with constitutional cancer-predisposing mutations, 21 had a mutation in TRIM28; there was a strong parent-of-origin effect, with all ten inherited mutations being maternally transmitted.[118][Level of evidence: 3iii]
- 9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[38,119] 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.[119] Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[38,120,121]
- 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%).[122] Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases.[122] Germline copy number gain at MYCN has been reported in a bilateral Wilms tumor case, and germline MYCN duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[123]
- CTR9. Inactivating CTR9 germline mutations were identified in 4 of 36 familial Wilms tumor pedigrees.[53,124]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.[72] 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.[72] 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 favorable histology (FH).[80] 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.
Figure 2. Unsupervised analysis of gene expression data. Non-negative Matrix Factorization (NMF) analysis of 75 FH Wilms tumor resulted in six clusters. Five of six MLLT1 mutant tumors with available gene expression data occurred in NMF cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors), in contrast to other clusters, where most cases showed 11p15 loss of heterozygosity or retention of imprinting. Almost all miRNAPG-mutated cases were in NMF cluster 2, and most WT1, WTX, and CTNNB1 mutations were in NMF clusters 3 and 4. Copyright © 2015 Perlman, E. J. et al. MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology wilms tumours. Nat. Commun. 6:10013 doi: 10.1038/ncomms10013 (2015). This article is distributed by Nature Publishing Group, a division of Macmillan Publishers Limited under a Creative Commons Attribution 4.0 International License, as described at http://creativecommons.org/licenses/by/4.0/.
Bilateral Wilms Tumor
Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes. For example, in 545 cases of bilateral Wilms tumors, bona fide pathogenic germline variants were found in 22% of patients.[125] The most common predisposition variants are mutations of WT1 and 11p15 loss of imprinting.[22,73]
Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. Three percent of patients with bilateral Wilms tumor have affected family members.[126]
Genomic analysis of kidney tissue in bilateral Wilms tumor indicates that a clonal expansion early in the nephrogenesis of normal-appearing but genetically aberrant precursor lesions occurred before the divergence of left and right kidney primordia.[63]
Screening Children Predisposed to Wilms Tumor
Children with a significant increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihyperplasia) are usually screened with ultrasonography every 3 months until they reach at least age 8 years.[86,127] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.[127]
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.[128]
On the basis of a literature search of patients with Beckwith-Wiedemann spectrum and Wilms tumor where the age at diagnosis was compared against data collected through the Surveillance, Epidemiology, and End Results (SEER) Program, screening patients with Beckwith-Wiedemann spectrum seems to significantly decrease the age and stage at the time of diagnosis in this population. Screening until age 7 years is effective in detecting close to 95% of all Wilms tumors in Beckwith-Wiedemann spectrum. Screening until age 30 months may also prove useful for patients with IC2 LoM, consistent with the recommendations for hepatoblastoma screening in this population.[129]
- 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.[97]
Screening for hepatoblastoma or adrenal tumors with abdominal ultrasonography 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 ultrasonography, which is quicker and does not require fasting before the exam.[130]
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.[128]
Proposed screening guidelines for Wilms tumor are available for patients with Beckwith-Wiedemann syndrome who have undergone molecular subtyping [97] (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 undergo abdominal ultrasonography 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 ultrasonography scans, until age 6 years.
- For patients with loss of imprinting at ICR2 (ICR2-LoM), an abdominal ultrasonography is performed at the time of clinical or molecular diagnosis; only patients with organomegaly or severe hemihyperplasia require surveillance by ultrasonography 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 ultrasonography and serum AFP is suggested until age 4 years. After age 4 years, most hepatoblastomas will have occurred, and imaging may be limited to renal ultrasonography, which is quicker and does not require fasting before the exam.[128]
- 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 ultrasonography every 3 months until age 8 years, and the parents should be educated about the need for early identification and treatment of Wilms tumor.[86,131,132]
- Children of survivors of bilateral Wilms tumor. Although the risk of 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 ultrasonography examinations every 3 months until age 8 years.[71]
- Bohring-Opitz syndrome. Bohring-Opitz syndrome is a rare genetic condition associated with ASXL1 mutations. Screening with abdominal ultrasonography 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.[43]
- 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 ultrasonography, 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.[86]
- 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 ultrasonography surveillance is not recommended.[133]
- 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.[128]
- DICER1 syndrome. Cystic nephroma is seen in 10% of families presenting with pleuropulmonary blastoma, typically occurring before age 4 years. Rare progression to anaplastic sarcoma of the kidney may occur. DICER1 syndrome includes an elevated risk of Wilms tumor, which is not a consequence of a prior cystic nephroma. Surveillance with abdominal ultrasonography, similar to Beckwith-Wiedemann syndrome, may be offered, but the age at which this should be stopped or reduced in frequency has not been established.[134,135] Thirteen years is the oldest reported age of a Wilms tumor diagnosis in a DICER1 mutation carrier.[110,136]
Genetic counseling
The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.
A French study concluded that patients need to be referred for genetic counseling if they have one of the following:[8]
- 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.[8]
After genetic counseling occurs, testing 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.
Testing for an 11p15 abnormality should be considered for patients exhibiting any symptoms of Beckwith-Wiedemann syndrome, hemihyperplasia, or bilateral or familial Wilms tumor.
Clinical Features of Wilms Tumor
Most Wilms tumor patients present asymptomatically with an abdominal mass noticed by a parent or pediatrician on a well-child visit. In children with known predisposing clinical syndromes, renal tumors can be found during routine screening. Clinical findings may include the following:
- 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.[137]
- 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 caused by lung metastasis.
- Abdominal pain caused by 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 examination and history. Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihyperplasia.
- Complete blood count (CBC).
- Liver function test.
- Renal function test.
- Urinalysis.
- Abdominal imaging.
- Abdominal x-ray.
- Ultrasonography exam of the abdomen. Ultrasonography 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. This procedure is unnecessary after the definitive diagnostic study has been performed.
- CT scan with contrast or MRI of abdomen.[138]
- CT scan of the abdomen will confirm the renal origin of the mass and determine whether there are bilateral tumors.[139] About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[140]
- A 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.[141]
- Preoperative assessment by imaging of intravascular extension of Wilms tumor is essential to guide management. Four percent of Wilms tumor patients present with inferior vena cava or atrial involvement and 11% with renal vein involvement, which may lead to differences in management. 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. A report from the COG shows that CT can accurately identify cavoatrial thrombus, obviating the need for ultrasonography if CT has already been performed.[142]
- Ascites beyond the cul-de-sac is most predictive of preoperative Wilms tumor rupture, regardless of attenuation. In the presence of ascites, fat stranding around the tumor and the presence of retroperitoneal fluid are highly predictive of rupture.[139]
- 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.
- Chest x-ray is unnecessary if chest CT is performed initially.
- Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG PET-CT imaging adds clinically applicable information to conventional CT scan imaging. PET-CT may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.[143]
- von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have an acquired form of von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[144] Some clinicians recommend evaluation for von Willebrand disease before surgery.
- Biopsy or resection. In children with a renal mass that clinically appears to be resectable or stage I or stage II Wilms tumor, a 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. If a primary nephrectomy cannot be performed, a biopsy, either open or with multiple cores, is required. The contraindications to primary nephrectomy are the following:
- Extension of tumor thrombus to the level of the hepatic veins. These patients should be considered for tumor resection after neoadjuvant chemotherapy when there is evidence of regression of the vena caval thrombus regardless of the degree of response of the primary tumor.
- The tumor involves contiguous structures whereby the only means of removing the kidney tumor requires removal of the other structure (e.g., spleen, pancreas, colon but excluding the adrenal gland and diaphragm). While Wilms tumors are frequently adherent to adjacent organs, in most cases, there is not frank invasion by the tumor and the organs can be dissected freely from the tumor. Radical en bloc resection (e.g., partial hepatectomy) is not generally warranted. If removal of a small section of diaphragm, psoas muscle, or tip of the pancreas allows the tumor to be removed intact, this is considered safe and appropriate.
- The surgeon's judgment that nephrectomy would result in significant or unnecessary morbidity/mortality, significant tumor spill, or residual tumor.[145]
- If there is pulmonary compromise because of extensive pulmonary metastases or, in rare cases, hepatic disease.
If a child undergoes a biopsy as the first procedure, they are considered stage III because they have gross residual tumors.
Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. However, the use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread and the histologic classification of the Wilms tumor cannot be determined by biopsy.[145]
Anaplastic histology can be difficult to detect in any biopsy sample because of tumor heterogeneity. Data from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) demonstrated that, because of the histologic heterogeneity of Wilms tumor, a significant number of patients have anaplastic histology that is missed during an up-front biopsy whether it be a core needle biopsy or an incisional biopsy [146] 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.[138,141] Treatment as a bilateral Wilms tumor should be considered if the initial imaging studies suggests a bilateral process. If the origin of the other lesion is indeterminate, a pathological assessment of that lesion should be considered before proceeding with a nephrectomy.[138,141]
Children who have bilateral Wilms tumor are often treated without a biopsy.[147] Biopsy can be avoided if the child is of typical age and the tumor has the usual radiographic appearance. This was assessed on the COG AREN0534 (NCT00945009) study where 187 of 189 patients with Wilms tumor were treated initially without a biopsy. If after 6 weeks of therapy, response was less than 30% by RECIST1.1 criteria, bilateral biopsies were performed to assess for anaplasia, stromal differentiation, and rhabdomyomatous changes. If anaplasia was detected, the chemotherapy treatment was changed. If stromal differentiation or rhabdomyomatous changes were detected, further chemotherapy was unlikely to result in tumor shrinkage and definitive surgery was the suggested approach.[147]
For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess lymph node status, intravascular extension, and rupture of Wilms tumor.[140]
- Lymph node sampling is required to locally stage all Wilms tumor patients. Lymph nodes have shown to be of major prognostic value for both short-term and long-term survival. Gross inspection is notoriously inaccurate, with a false-negative rate of 31.3% and a false-positive rate of 18.1%.[148]
- 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.[142] If the tumor is at or above the hepatic veins, a biopsy with preoperative chemotherapy is suggested because of the lower rate of serious intraoperative complications. 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. In some cases, cardiopulmonary bypass is required.[149]
- Wilms tumors can rupture before surgery. The term rupture is used to imply a break in the tumor capsule before surgery, whereas the term spill refers to a break in the tumor during surgery. Based on their similar diagnostic performances, either CT or MRI can be used to detect rupture. Although imaging findings of rupture have high specificity (88%), the diagnosis of rupture has to be confirmed at surgery. Imaging alone cannot be used for initial staging because of the low sensitivity and specificity for preoperative rupture and lymph node status.[150]
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 greater than 90%.[151] This favorable outcome occurred with changes in therapy that included reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.[152]
The prognosis for patients with Wilms tumor depends on the following:[153,154,155,156]
- Histopathologic features of the tumor (FH vs. anaplastic histology). (Refer to the Histologic Findings in Wilms Tumor section of this summary for more information.)
- Stage of disease at diagnosis.
- Molecular features of the tumor such as 1q gain and loss of heterozygosity of 1p and 16q. 1q gain, affecting 28% of Wilms tumors, is the most powerful predictor of outcome and is associated with an adverse outcome.[101,102,103] (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
- Age. Older age is associated with an adverse prognosis.[157]
Older Adolescents and Adults With Wilms Tumor
Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million per year.[158] 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.[158] Three percent of Wilms tumors occur in adults. Wilms tumor represents less than 1% of all renal tumors in adults and may be an unexpected finding after nephrectomy for presumed renal cell carcinoma, which is the most common adult renal cancer.
The outcomes for adolescent and young adult (AYA) patients (aged 15 to 39 years) and adult patients are inferior to the outcomes for children.
- In an analysis of patients with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database, AYA patients (n = 104) had a statistically worse 5-year OS rate (69% vs. 94%; P < .001) than did pediatric patients (n = 2,574).[159][Level of evidence: 3iA]
The inferior outcome of the adult patients may be multifactorial, including 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.[160][Level of evidence: 3iii]
Treatment of adults with Wilms tumor
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.[161,162,163]
- 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.
- These data suggest that many adults with Wilms tumor, if treated appropriately, can expect to be cured, especially if the tumor has not spread and/or is completely resected.
For adults with refractory or recurrent disease, screening for potential therapeutic targets in the tumor should be considered.[164]
The following recommendations from the renal tumor committees of the International Society of Pediatric Oncology (SIOP) and COG encourage a uniform approach to improve outcome for adults with Wilms tumor.[165]
- 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:
- Favorable histology (FH).
- Anaplastic histology.
Favorable histology (FH)
Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.
While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.[166] A strong association between the epithelial subtype and TRIM28 mutations has been identified.[118][Level of evidence: 3iii]
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.[167] In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[168,169]
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.[113] 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.[170] Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[155,171,172]
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.[155]
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.[173,174] 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.[7]
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). Distinguishing between nephrogenic rests and Wilms tumors by imaging is challenging because there is an overlap in their appearance. In a retrospective study of 52 young children (aged <5 years) with nephrogenic rests and small Wilms tumors (all lesions <5 cm) that had been surgically sampled and pathologically evaluated before any medical intervention, investigators found that a Wilms tumor diagnosis should be favored over a nephrogenic rest diagnosis when a renal mass is spherical, exophytic, and larger than 1.75 cm in maximal diameter. Homogeneity by imaging favors the diagnosis of perilobar nephrogenic rests, whereas intralobar rests and Wilms tumors are more likely to be inhomogeneous.[175][Level of evidence: 3iii]
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.[176]
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).[177] Intralobar nephrogenic rests have been associated with stromal-type Wilms tumor and younger age at diagnosis.[7]
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.[178]
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 for patients who received chemotherapy (55% in one series) and for those who have been treated with chemotherapy for a prolonged period of time.[176] If these patients develop Wilms tumor, they have a poorer prognosis than do other bilateral Wilms tumor patients, presumably because of the increased incidence of anaplasia in these cases (more than one-third of cases), and perhaps as a result of the development and selection of anaplasia in the surviving abnormal kidney cells.[176,179]
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.[180]
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).[166,181]
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.[166] Lymph node sampling is strongly recommended for all patients, even in the absence of clinically abnormal nodes, to achieve the most accurate stage.
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.
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 (COG RTC); however, data to support this approach are controversial.[145,182]
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 rupture before surgery or any spill during surgery is considered stage III.
- 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.[183]
Stage IV
In stage IV Wilms tumor (11% of patients), one of the following is present:
- Hematogenous metastases (lung, liver, bone, brain).
- 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 (bilateral)
In stage V Wilms tumor (5% of patients), bilateral involvement by tumor is present at diagnosis. The current paradigm treats all patients with bilateral Wilms tumor the same for the first 6 or 12 weeks. After definitive surgery, the treatment is based on the highest stage of the remaining kidneys and the posttreatment pathology.[147]
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.
COG and SIOP approaches to Wilms tumor treatment
Most randomized clinical studies for treatment of children with Wilms tumor have been conducted by two large clinical groups (COG RTC and SIOP). Differences between the two groups affect staging and classification. There are two standard approaches to Wilms tumor treatment: the COG RTC uses immediate surgery for all unilateral tumors and the SIOP uses preoperative chemotherapy as the first step in treatment. Both groups use postoperative chemotherapy, except for selected cases who do not receive chemotherapy, and in advanced stages, radiation therapy is used in a risk-adapted approach.
- 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.[184,185,186] 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 spills during surgery and lower postoperative stage.[187] When the histological features of Wilms tumors from patients who underwent immediate surgery were compared with the histological features of patients 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.[188]
- Both SIOP and COG treat infants younger than 6 months with a primary nephrectomy.[189]
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.[186]
- 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.[186]
- 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.[186]
- 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.[190]
- Eighteen weeks of therapy is adequate for patients with stage I and stage II FH, and stage III and IV patients can be treated with 6 months of therapy instead of 15 months.[152,184,190,191,192]
- 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.[101,103]
Surgery
The following operative principles have also evolved from NWTS (COG) 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.[193] 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.[193]
- 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.[141]
- 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.[194]
- 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).[195]
- 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 supported by the data, except for children with the following:[196,197]; [198][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 screening ultrasonography may be considered for renal-sparing surgery to preserve renal tissue.[196]
- 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.[199]
- 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 tumors.[200] In North America, renal-sparing surgery (partial nephrectomy) of unilateral Wilms tumor after administration of chemotherapy to shrink the tumor mass is considered investigational.[201,202]
Hilar and periaortic lymph node sampling is appropriate even if the nodes appear normal.[193,203] Furthermore, any suspicious node basin is sampled. Margins of resection, residual tumor, and any suspicious node basins are marked with titanium clips.
Wilms tumor rarely invades adjacent organs; therefore, resection of contiguous organs is seldom indicated. There is an increased incidence of complications occurring in more extensive resections that involve removal of additional organs beyond the diaphragm and adrenal gland. This finding has led to the recommendation in current COG protocols that patients in whom nephrectomy will require removal of additional organs should be considered for initial biopsy, neoadjuvant chemotherapy, and then secondary resection.[204] Primary resection of liver metastasis is not recommended.[205]
Chemotherapy
Preoperative chemotherapy before nephrectomy is indicated in the following situations, which have been listed previously under situations requiring a biopsy (refer to the Diagnostic and Staging Evaluation for Wilms Tumor section of this summary for more information):[193,204,206,207,208,209]
- 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.[142,149]
- 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 resulting from extensive pulmonary metastases.
Preoperative chemotherapy follows a biopsy. The biopsy may be performed through a flank approach.[149,210,211,212,213,214] 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.[145,149,204,206,215,216]
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.[217,218] The preoperative diagnosis of a contained retroperitoneal rupture on CT is difficult, even for experienced pediatric radiologists.[139]
All infants younger than 12 months (including newborns) who will be treated with chemotherapy require a 50% reduction in chemotherapy dose compared with the dose given to older children.[219] Dosing for infants (younger than 12 months) is 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.[220]
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.[221,222] 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.[223,224]
Augmentation of therapy improves EFS for patients with FH Wilms tumor and loss of heterozygosity of 1p/16q. In the AREN0532 (NCT00352534) and AREN0533 (NCT00379340) trials, patients with stage I and stage II FH Wilms tumor who were treated with the DD-4A regimen (dactinomycin, vincristine, and doxorubicin) demonstrated a 4-year EFS rate of 87.3%, compared with the 4-year EFS rate of 68.8% (P = .042) for stage I and stage II patients treated on the NWTS-5 trial. Patients with stage III and stage IV disease had a 4-year EFS rate of 90.2% when treated with regimen M (refer to Table 2), compared with a 61.3% 4-year EFS rate (P = .001) for stage III and stage IV patients treated on the NWTS-5 trial. Trends toward improved 4-year OS rates were seen in stage I and II patients and in stage III and IV patients.[225][Level of evidence: 3iiiDi]
Postoperative radiation therapy to the tumor bed is required when a biopsy is performed or in the setting of local tumor stage III. In a study of 1,488 patients with Wilms tumors who underwent surgery and radiation therapy, delay in starting radiation therapy after surgery of greater than 14 days was associated with an increased risk of mortality for patients with nonmetastatic Wilms tumor.[226][Level of evidence: 3iiiA]
Table 2 describes the accepted chemotherapy regimens used to treat Wilms tumor.
| Regimen Name | Regimen Description |
|---|---|
| Regimen EE-4A[103] | Vincristine, dactinomycin × 18 weeks postnephrectomy |
| Regimen DD-4A[103] | Vincristine, dactinomycin, doxorubicin × 24 weeks; baseline nephrectomy or biopsy with subsequent nephrectomy |
| Regimen I[155] | Vincristine, doxorubicin, cyclophosphamide, etoposide × 24 weeks postnephrectomy |
| Regimen M[227] | Vincristine, dactinomycin, doxorubicin, cyclophosphamide, and etoposide with subsequent radiation therapy |
| Regimen UH1[228] | Vincristine, doxorubicin, cyclophosphamide, carboplatin, and etoposide × 30 weeks + radiation therapy |
| Regimen UH2[228] | Vincristine, doxorubicin, cyclophosphamide, carboplatin, etoposide, vincristine, and irinotecan × 36 weeks + radiation therapy |
Radiation therapy
Radiation therapy is used to improve local control and treat sites of metastatic disease. Radiation therapy has historically been dependent on stage and histology, but more recently is also guided by the tumor molecular signature.[229]
COG approach
Up-front surgery provides histologic confirmation and tumor extent, providing the rationale for adjuvant therapy, including radiation therapy. Besides histology, postoperative risk factors for worse local control include: (1) incomplete resection, (2) positive margins, and (3) nodal involvement. Radiation therapy is not used in patients with stage I or stage II FH Wilms tumor. For patients with FH stage III Wilms tumor, flank or abdominal radiation therapy is used for treatment. In cases of unfavorable histology (focal or diffuse anaplasia), flank or abdominal radiation therapy is indicated for all patients. (Refer to Table 3 for more information.)
Results of NWTS (COG RTS) trials have shown the following:
- Flank radiation therapy covers the tumor bed, involved nodal region, and entire adjacent vertebral bodies at 10.8 Gy in 1.8-Gy fractions. The dose of radiation therapy is based on the results of the NWTS-3 study in which there was no increase in abdominal relapse for stage III FH patients receiving 10 Gy versus 20 Gy with DD-4A chemotherapy.[230]
- Whole-abdominal radiation therapy is 10.5 Gy in 1.5-Gy fractions and is used to treat diffuse spill or peritoneal metastasis.[225]
- In the closed COG AREN0321 (NCT00335556) study, the radiation therapy dose to the tumor bed was 10.8 Gy in 1.8-Gy fractions, with the exception of patients with stage III diffuse anaplasia, where a dose of 19.8 Gy in 1.8-Gy fractions was used. This remains the current standard of treatment.[228]
- Results of the early NWTS studies (1 and 2) suggested that a radiation therapy delay of more than 10 days after surgery resulted in worse local control, particularly in unfavorable histology Wilms tumor.[231,232] However, no difference in local control was found if radiation therapy was delayed more than 10 days after surgery for patients with stages II to IV FH tumors treated on the NWTS-3 or NWTS-4 trials.[97] More recent data from the National Cancer Database confirmed improved survival in patients with nonmetastatic Wilms tumor who received adjuvant radiation therapy less than or equal to 14 days postoperatively.[226]
- Results from the NWTS-3 and NWTS-4 trials indicated that there was no survival benefit of whole-lung irradiation in the setting of lung metastases seen on CT scan only.[233] Current COG guidelines allow for omission of whole-lung irradiation in cases of FH disease without extrapulmonary metastases, loss of heterozygosity at 1p and 16q, and complete response at 6 weeks after vincristine, dactinomycin, and doxorubicin.[229] When whole-lung irradiation is given, a dose of 12 Gy in 1.5-Gy fractions is indicated for children older than 12 months and 10.5 Gy in 1.5-Gy fractions for patients younger than 12 months with pulmonary metastasis.
- Other sites of metastatic disease in Wilms tumor are uncommon and may include liver, extra-abdominal nodes, brain, and bone. In the COG AREN0533 (NCT00379340) study, the radiation therapy doses being used for patients younger than 16 years are 19.8 Gy in 1.8-Gy fractions to liver and gross residual nodes, 21.6 Gy in 1.8-Gy fractions to the whole brain with a boost of 10.8 Gy in 1.8-Gy fractions to gross metastatic disease in the brain, and 25.2 Gy in 14 fractions for bone metastasis. For patients older than 16 years, the radiation therapy dose to the whole brain and bone is increased to 30.6 Gy in 1.8-Gy fractions.
| Local/Locoregional Disease | ||||
|---|---|---|---|---|
| XRT = radiation therapy. | ||||
| a Requires whole-abdominal XRT in 1.5 Gy daily fractions. Patients with diffuse unresectable peritoneal implants receive 21 Gy. | ||||
| b Whole-lung irradiation is given in 1.5 Gy daily fractions. | ||||
| c Not all patients receive radiation therapy. | ||||
| d A boost is given for macroscopic disease. | ||||
| Stage I | Stage II | Stage III | Stage III (diffuse spill, peritoneal metastasis, preoperative rupture)a | |
| Favorable histology | No XRT | No XRT | 10.8 Gy | 10.5 Gy |
| Focal anaplasia | 10.8 Gy | 10.8 Gy | 10.8 Gy | 10.5 Gy |
| Diffuse anaplasia | 10.8 Gy | 10.8 Gy | 19.8 Gy | 10.5 Gy + 9 Gy boost |
| Metastatic Disease | ||||
| Stage IV Lung | Stage IV Liver | Stage IV Brain | Stage IV Bone | |
| Favorable histology | 10.5 Gy for age <12 monthsb,c; 12 Gy for age >12 monthsb,c | 19.8 Gy +/- 5.4 to 10.8 Gy boostd | 21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years | 25.2 Gy for age <16 years; 30.6 Gy for age >16 years |
| Focal or diffuse anaplasia | 10.5 Gy for age <12 monthsb; 12 Gy for age >12 monthsb | 19.8 Gy +/- 5.4 to 10.8 Gy boostd | 21.6 Gy + 10.8 Gy boost for age <16 years; 30.6 Gy for age >16 years | 25.2 Gy for age <16 years; 30.6 Gy for age >16 years |
SIOP approach
Based on the experience of previous SIOP trials, children who need radiation therapy undergo postoperative treatment to the flank and/or metastatic sites. The SIOP 1 to 9 trials demonstrated that preoperative radiation therapy or preoperative chemotherapy decreased the proportion of patients who developed tumor spillage, from more than 20% to 5%. The noninferiority of preoperative chemotherapy to preoperative radiation therapy in the SIOP 5 trial, and the concern over secondary malignancies with preoperative radiation therapy, led SIOP to recommend preoperative chemotherapy as the standard initial treatment.[187] Over time, the percentage of children who were treated with postoperative radiation therapy decreased, from more than 90% to 15% and 25% in SIOP trials 6 to 9, SIOP 93-01, and SIOP-2001, respectively.[185]
Abdominal radiation therapy has been omitted for patients with metastatic, local stage III Wilms tumor who had complete necrosis after 6 weeks of preoperative chemotherapy. The outcome of patients with stage IV, local stage III, completely necrotic Wilms tumors was excellent (5-year EFS and OS rates of 95%).[234]
Treatment of stage I Wilms tumor
Table 4 provides an overview of the standard treatment options and survival data for patients with stage I Wilms tumor, based on published results.
| Histology | 4-Year RFS or EFS | 4-Year OS | Treatment (refer to Table 2for 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. | |||
| a Source: Grundy et al.,[103]Shamberger et al.,[156]Fernandez et al.,[229]Dix et al.,[225]and Daw et al.[235] | |||
| b One patient with a pulmonary relapse 4.12 years after diagnosis. | |||
| FH <24 mo/tumor weight <550g | 90% | 100% | Surgery, including lymph node biopsy only |
| FH >24 mo/tumor weight >550g | 94% RFS | 98% | Nephrectomy + lymph node sampling followed by regimen EE-4A |
| FH with LOH 1p/16q (n = 8) | 100% EFS | 100% | Nephrectomy + lymph node sampling followed by regimen DD-4A |
| FA | 100% | 100% (n = 8) | Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT |
| DA | 100%b | 100% (n = 10) | Nephrectomy + lymph node sampling followed by regimen DD-4A and XRT |
Evidence (surgery only for children younger than 2 years at diagnosis with stage I FH tumor that weighed <550 g):
In the AREN0532 (NCT00352534) trial, the COG validated the findings from the NWTS-5 trial 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.
- 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.[156,229,236]
- Twelve patients relapsed.
- The estimated 4-year EFS rate was 89.7%, and the OS rate 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.
Evidence (treatment of stage I epithelial-predominant favorable-histology Wilms tumor):
- The COG reported the outcomes for patients of all ages with stage I FH Wilms tumors showing epithelial-predominant histology. Approximately 20% of stage I FH Wilms tumors registered on AREN03B2 were epithelial predominant. In this group of 177 patients with stage I epithelial-predominant FH Wilms tumors, 117 patients were treated with EE4A, and 57 patients were classified as having a very low-risk Wilms tumor and were treated with observation only.[237][Level of evidence: 3iiiA]
- The 4-year EFS rate was 96.2%, and the OS rate was 100%.
- There was no statistical difference in EFS and OS based on age at diagnosis (<48 months and >48 months) or treatment (EE4A vs. observation only).
- There were six events: three patients developed contralateral tumors after their initial diagnosis, and two of these patients had received adjuvant chemotherapy for their initial tumors. Three patients developed metastatic disease, and all of these patients had previously received EE4A as their primary therapy.
Evidence (treatment of anaplastic stage I Wilms tumor):
- The AREN0321 (NCT00335556) study demonstrated that outcomes for patients with stage I anaplastic Wilms tumor were improved with the addition of doxorubicin and flank radiation therapy to vincristine/dactinomycin therapy.[235]
- Four-year EFS and OS rate estimates were 100% in AREN0321, compared with 70% and 81.5%, respectively, in an updated analysis of 27 patients from NWTS-5 (median follow up, 13.3 years). One patient with diffuse anaplasia relapsed 4.12 years after diagnosis on the AREN0321 trial.
- The addition of doxorubicin and radiation therapy to AREN0321 was on the basis of the pattern of relapse observed in stage I anaplastic Wilms tumor in the abdomen and distant sites in the NWTS-5 trial.
- Retrospective analysis of all patients with stage I anaplastic Wilms tumor treated on NWTS-1 through NWTS-5 and AREN0321 showed a significant improvement in EFS for patients treated with doxorubicin (4-year EFS rate, 97.2% vs. 77.5%; P = .01), but no difference in EFS according to flank radiation therapy was shown (4-year EFS rate, 91.7% vs. 80.2%; P = .15).
- The rate of local recurrence was low (3.6%) and appeared to be similar for patients who received flank radiation therapy (4%) and patients who did not receive flank radiation therapy (6.2%). Local relapse occurred only in patients with diffuse anaplasia.
Current Clinical Trials
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Treatment of stage II Wilms tumor
Table 5 provides an overview of the standard treatment options and survival data for patients with stage II Wilms tumor, based on published results.
| Histology | 4-Year RFS or EFS | 4-Year OS | Treatment (refer to Table 2for 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. | |||
| a Source: Grundy et al.,[103]Dome et al.,[155]Dix et al.,[225]and Daw et al.[228] | |||
| FH | 86% RFS | 98% | Nephrectomy + lymph node sampling followed by regimen EE-4A |
| FH LOH 1p/16q (n = 24) | 83% EFS | 100% | Nephrectomy + lymph node sampling followed by regimen DD-4A |
| FA | 80% EFS | 80% (n = 5) | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A |
| DA | 84% EFS | 84% (n = 19) | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen UH1 |
Treatment of stage II patients with intraoperative spill
In a review of 499 patients from NWTS-4 with stage II FH Wilms tumor, 95 of the patients experienced tumor spill. The 8-year RFS and OS rates for patients who experienced intraoperative tumor spill and were treated with vincristine and dactinomycin without flank radiation therapy were lower, at 75.7% and 90.3%, than the 85% and 95.6% rates for those who did not experience tumor spill. None of these differences achieved statistical significance.[182]
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.[238] This approach is controversial and has not been tested; therefore, it should not be considered standard.
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Treatment of stage III Wilms tumor
Table 6 provides an overview of the standard treatment options and survival data for patients with stage III Wilms tumor, based on published results.
For patients classified as stage III purely on the basis of local spill, refer to the Treatment of stage II Wilms tumor section of this summary.
| Histology | 4-Year RFS or EFS | 4-Year OS | Treatment (refer to Table 2for 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. | |||
| a Source: Grundy et al.,[103]Dome et al.,[155]Fernandez et al.,[239]Dix et al.,[225]and Daw et al.[228] | |||
| FH (all patients) | 88% EFS | 97% | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A |
| FH (without LOH of 1p and/or 16q) and positive lymph nodes | 85% EFS | 97% | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A |
| FH (without LOH of 1p and/or 16q) and negative lymph nodes | 97% EFS | 99% | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A |
| FH (with LOH of 1p and 16q) (n = 31) | 87% EFS | 94% | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen M |
| FA | 88% RFS | 100% (n = 8) | Nephrectomy + lymph node sampling followed by abdominal XRT and regimen DD-4A |
| FA (preoperative treatment) | 71% RFS | 71% (n = 7) | Preoperative treatment with regimen DD-4A followed by nephrectomy + lymph node sampling and abdominal XRT |
| DA | 46% EFS | 53% (n = 16) | Preoperative treatment with regimen I followed by nephrectomy + lymph node sampling and abdominal XRT |
| DA | 82% EFS | 91% (n = 23) | Immediate nephrectomy + lymph node sampling followed by abdominal XRT and regimen UH1 |
Radiation therapy
Early initiation of radiation therapy is a critical component of multimodal therapy for patients with nonmetastatic Wilms tumor. In a review of 1,488 patients with Wilms tumor who underwent surgery and radiation therapy, a surgery-to-radiation therapy interval of greater than 14 days was associated with an increased risk of mortality (hazard ratio, 2.13; P = .013). This underscores the importance of initiating radiation therapy within 14 days of surgery, which is specified in Wilms tumor treatment protocols.[226][Level of evidence: 3iiiA]
Loss of heterozygosity of 1p or 16q
Loss of heterozygosity of 1p or 16q was shown to influence EFS but not OS in 588 patients with stage III FH Wilms tumor treated on the COG AREN0532 protocol. When combined, lymph node status and loss of heterozygosity status provided a strong predictor of excellent EFS and OS when both were absent, with a 4-year EFS rate of 97%, and an OS rate of 99%.[239][Level of evidence: 2Di] The outcome was poorer for patients having both positive lymph nodes and loss of heterozygosity of 1p or 16q, with a 4-year EFS rate of 74%. However, the 4-year OS rate was not influenced, at 92%.[239] On the basis of these results, therapy was augmented for patients with loss of heterozygosity of 1p/16q for patients enrolled on the AREN0533 trial. Patients with stage III and stage IV Wilms tumor with loss of heterozygosity were treated with regimen M. The 4-year EFS rate was 90.2%, and the OS rate was 96.1%, compared with a 4-year EFS rate of 61.3% (P = .001) and a 4-year OS rate of 86.0% (P = .087) for patients in the NWTS-5 trial. There was a suggestion of improvement in survival; however, the study was not powered to detect differences in survival.[225][Level of evidence: 3iiiDi]
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Treatment of stage IV Wilms tumor
Table 7 provides an overview of the standard treatment options and survival data for patients with stage IV Wilms tumor, based on published results.
| Histology | 4-Year RFS or EFS | 4-Year OS | Treatment (refer to Table 2for chemotherapy regimen descriptions) |
|---|---|---|---|
| CR = complete response; DA = diffuse anaplasia; EFS = event-free survival; FA = focal anaplasia; FH = favorable histology; LOH = loss of heterozygosity; OS = overall survival; RFS = relapse-free survival; XRT = radiation therapy. | |||
| a Source: Grundy et al.,[103]Dome et al.,[155]Dix et al.,[227]Dix et al.,[225]and Daw et al.[228] | |||
| b Abdominal XRT is planned according to local stage of renal tumor. | |||
| c Pulmonary XRT is reserved for patients with chest x-ray/chest computed tomography evidence of pulmonary metastases. | |||
| d Refer to theAREN0533 (NCT00379340)study for more information. | |||
| FH | 76% RFS | 86% | Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A |
| FH (with isolated lung nodules) | 85% EFS | 96% | Nephrectomy + lymph node sampling, followed by abdominal XRT,b +/- bilateral pulmonary XRT,c and regimen DD-4A or regimen Md |
| FH (with isolated lung nodules with CR to DD-4A) | 83% EFS | 94% | Nephrectomy + lymph node sampling, followed by abdominal XRTb and regimen DD-4A |
| FH (with isolated lung nodules with incomplete response to DD-4A) | 92% EFS | 96% | Nephrectomy + lymph node sampling, followed by abdominal XRTb and bilateral pulmonary XRTc and regimen M |
| FH (with LOH of 1p and/or 16q) (n = 20) | 95% EFS | 100% | Nephrectomy + lymph node sampling, abdominal XRTb radiation to sites of metastasesb, and regimen M |
| FA | 61% EFS | 72% (n = 11) | Nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, bilateral pulmonary XRT,c and regimen DD-4A |
| DA | 33% EFS | 33% (n = 10) | Immediate nephrectomy + lymph node sampling followed by abdominal XRT,b radiation to sites of metastases, whole-lung XRT,c and regimen I |
| DA (preoperative treatment) | 60% EFS | 70% (n = 10) | Preoperative treatment with regimen UH2 followed by nephrectomy + lymph node sampling, followed by abdominal XRT,b radiation to sites of metastases, and whole-lung XRTc |
Stage IV disease is defined by the presence of hematogenous metastases to the lung, liver, bone, brain, or other sites, with the lung being the most common site. The presence of liver metastases at diagnosis is not an independent adverse prognostic factor in patients with stage IV Wilms tumor.[205]
Treatment of pulmonary nodules and metastases
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.[240]
- Patients who received doxorubicin, vincristine, and dactinomycin with or without lung irradiation had a 5-year EFS rate of 80% versus an EFS rate 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 rate (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.[241]
- 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 rate was 77%, and the OS rate 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 rate was 84%, and the OS rate 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 rate was 48%, compared with the OS rates 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 rate, 33% vs. 87%; P < .001).
- 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.
- Based on the European experience, 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. Therapy was adjusted on the basis of lung nodule response and tumor-specific loss of heterozygosity at 1p and 16q.[227][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 DD-4A (vincristine, dactinomycin, doxorubicin) and continued receiving the same chemotherapy without lung radiation therapy. The 4-year EFS rate was 80%, and OS rate 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 DD-4A drugs (regimen M). The 4-year EFS rate was 89%, and the OS rate 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 rates 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 rate (57% vs. 86%, P = .001) and trend toward inferior OS rates (89% vs. 97%). 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 (refer to Table 2) 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.[227,241] 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.
Treatment of stage IV diffuse anaplastic Wilms tumor
In the AREN0321 (NCT00335556) study, the combination of vincristine and irinotecan (VI) was tested in an up-front window for patients with diffuse anaplastic Wilms tumor and measurable disease.[228][Level of evidence: 3iiiDii]
- Fourteen patients with stage IV diffuse anaplastic Wilms tumor with measurable disease received the window therapy; one patient achieved a complete response (CR), ten patients achieved partial responses (PRs), and no patients had stable disease. This resulted in a CR and PR rate of 79%.
- Patients who responded to VI in the window therapy had VI incorporated into their regimen (UH2).
- Because of the observed cardiac/pulmonary toxicities encountered in this trial, the study was interrupted and amended with reduced doses of doxorubicin, cyclophosphamide, and etoposide (when combined with carboplatin).
- Further study of the modified regimen is planned in patients with newly diagnosed diffuse anaplastic Wilms tumor.
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
- AREN1921 (NCT04322318) (A Study of Combination Chemotherapy for Patients With Newly Diagnosed Diffuse Anaplastic Wilms Tumors and Relapsed Favorable-Histology Wilms Tumors): This clinical trial aims to improve survival by intensifying treatment for patients with diffuse anaplastic Wilms tumors. This trial will expand on the overall improvement observed with the revised UH1/UH2 regimen from the AREN0321 trial, which was modified along with the addition of vincristine/irinotecan.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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 bilateral Wilms tumor; however, for the first time, a prospective study of the treatment of patients with bilateral Wilms tumor has been completed and provides guidance for the approach.[147]
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.[242]
Historically, based on the NWTS-4 and NWTS-5 trials and trials performed in Europe, patients with bilateral Wilms tumor have had a lower EFS and OS than have patients with localized Wilms tumor. The NWTS-4 study reported that the 8-year EFS rate for patients with bilateral FH Wilms tumor was 74%, and the OS rate was 89%; for patients with anaplastic histology, the EFS rate was 40%, and the OS rate was 45%.[169] The NWTS-5 study reported that the 4-year EFS rate for all bilateral Wilms tumor patients was 56%, and the OS rate was 81%; the 4-year EFS rates for patients with FH (65%), focal anaplastic histology (76%), and diffuse anaplastic histology (25%) were also reported.[103,155] Similar outcomes for patients with bilateral Wilms tumor have been reported in Europe.[168,243] In a single-institution experience in the Netherlands (N = 41), there was significant morbidity in terms of renal failure (32%) and secondary tumors (20%).[243] 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 (bilateral) Wilms tumor include the following:
- Preoperative chemotherapy and resection.
- Renal transplant.
Preoperative chemotherapy and resection
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.[147]
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.[147] 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.[146] 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.[147]
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.[169]
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.[169]
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.[181,244,245]
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.[147]
- 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, the 4-year EFS rate was 82.1% (95% confidence interval [CI], 73.5%–90.8%), and the OS rate was 94.9% (95% CI, 90.1%–99.7%). Because biopsy was not performed before treatment in this series, some of the patients enrolled may have had only nephrogenic rests and not a true Wilms tumor. This finding may have improved these survival figures over historical controls.
- 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. The 4-year EFS rate 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.
- Based on the above study, the recommendation was to continue with three-drug preoperative chemotherapy for 6 to 12 weeks followed by nephron-sparing surgery whenever possible. After resection, postoperative therapy is based on the histology of the resected specimen. The disappointing use of nephron-sparing surgery in this study may have been because of the level of experience of the surgeons in this multi-institutional study.
- 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).[168]
- The 4-year DFS rate was 67%, and the OS rate was 80%.
- There was a trend toward better EFS in nonmetastatic patients receiving vincristine, dactinomycin, and doxorubicin preoperatively (4-year EFS rate, 84%) than for patients receiving vincristine and dactinomycin (4-year EFS rate, 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.[246]
- 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.[247]
- 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.
- The OS rate 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.
- A follow-up review of these patients revealed the following: 8 of 36 patients underwent repeat nephron-sparing surgery, and an additional two patients required a third nephron-sparing surgery. Six of these patients were alive without disease at the 4.5-year follow-up. The two patients who died had blastemal-predominant histology.[248]
(Refer to the Treatment of Recurrent Childhood Kidney Tumors section of this summary for information about recurrent disease.)
Treatment of patients with multicentric or bilaterally predisposed unilateral Wilms tumors
On the basis of an identified subpopulation of patients with Wilms tumor who are at risk for metachronous disease, coupled with an increased risk of end-stage renal disease, the COG conducted the largest prospective study (AREN0534 [NCT00945009]) of these patients. The goal of this study was to preserve renal tissue while maintaining excellent overall outcomes.[3,86]
Patients were identified by the treating institution as having a predisposition syndrome. Induction chemotherapy was determined by the presence of localized or metastatic disease found on imaging (and histology if a biopsy had been performed) at the time of diagnosis. Surgery, including renal-sparing surgery, was based on the radiographic response at 6 or 12 weeks, and additional chemotherapy was determined by histology. Patients with favorable histology and stage III or IV disease or any patient with anaplasia received radiation therapy.[249][Level of evidence: 3iiiA]
- Thirty-four patients were enrolled with the following underlying conditions: Beckwith-Wiedemann syndrome (n = 9), hemihypertrophy (n = 9), multicentric tumors (n = 10), WAGR syndrome (n = 2), solitary kidney (n = 2), Denys-Drash syndrome (n = 1), and Simpson-Golabi-Behmel syndrome (n = 1).
- The 4-year EFS and OS rates were 94% and 100%, respectively, with a median follow-up of 4.49 years. Two patients relapsed (one in the tumor bed and one in the abdomen); none of the deaths occurred during induction.
- Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%). Eleven partial nephrectomies were performed after two cycles of chemotherapy, and nine partial nephrectomies were performed after four cycles of chemotherapy. Two of the tumors completely resolved after treatment with chemotherapy and required no subsequent surgery.
- There were 22 patients with a known predisposition syndrome for which routine ultrasonography screening would have been expected. Sixteen of these patients had stage I disease, three had stage II disease, and three had stage III disease. Thirteen of the tumors were detected through routine ultrasonography.
- These results suggest that a standardized treatment approach that includes preoperative chemotherapy, surgical resection within 6 to 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.
Renal transplant
Renal transplant for children with stage V Wilms tumor is usually delayed until 1 to 2 years have passed without evidence of malignancy because most relapses occur within 2 years of diagnosis.[250] Similarly, renal transplant for children with Denys-Drash syndrome and Wilms tumor, all of whom require bilateral nephrectomy, is generally delayed 1 to 2 years after completion of initial treatment.[250]
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Follow-up after treatment
For patients who have completed therapy for Wilms tumor and exhibit features consistent with genetic predisposition, such as bilateral Wilms tumor, screening involves renal ultrasonography examination every 3 months for metachronous tumors during the risk period for that particular syndrome (5 years for WT1-related syndromes; 8 years for Beckwith-Wiedemann syndrome).
Late effects after Wilms tumor therapy
Children treated for Wilms tumor are at increased risk of developing the following:
- 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%).[251] Radiation therapy was a risk factor for both outcomes.
- Subsequent malignant neoplasms.[251,252,253] 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.[254]
- Congestive heart failure. The risk of congestive heart failure is influenced by dose of doxorubicin received, radiation to the heart, and female sex.[253,255]
- Complications of pregnancy.[256]
- 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.[177] Efforts, therefore, have been aimed toward reducing the intensity of therapy when possible.
- Neurocognitive impairment. A St. Jude Lifetime Cohort study of long-term survivors of pediatric Wilms tumor (n = 158; median years since diagnosis, 29 years; median age, 33 years) demonstrated that survivors had lower neurocognitive function than did community controls. The affected areas were verbal reasoning, academics, attention, memory, and executive function. Wilms tumor survivors were less likely to graduate from college (OR, 2.23) and had more moderate-to-severe neurologic conditions than controls (18.4% vs. 8.2%, P < .001).[257]
Late renal effects in patients with Wilms and underlying genetic abnormalities 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.[177]
- Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.[258]
- Children with Wilms tumor and any genitourinary anomalies are also at increased risk of late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:[177]
- Stromal predominant histology.
- Bilateral disease.
- Intralobar nephrogenic rests.
- Wilms tumor diagnosed before age 2 years.
(Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
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