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Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For children younger than 15 years with Wilms tumor, the 5-year survival rate has increased over the same time from 74% to 88%.[1] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
Ahmed HU, Arya M, Levitt G, et al.: Part I: Primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (8): 730-7, 2007. [PUBMED Abstract]
Ahmed HU, Arya M, Levitt G, et al.: Part II: Treatment of primary malignant non-Wilms' renal tumours in children. Lancet Oncol 8 (9): 842-8, 2007. [PUBMED Abstract]
Wilms Tumor
Incidence of Wilms Tumor
Wilms tumor is the most frequent tumor of the kidney in infants and children. The incidence of Wilms tumor is 8.2 cases for every 1 million children younger than 15 years, or one case per 10,000 infants.[1] Approximately 650 cases of Wilms tumor are diagnosed in the United States each year. The incidence is substantially lower in Asians.
The male to female ratio in unilateral cases of Wilms tumor is 0.92 to 1.00, but in bilateral cases, it is 0.60 to 1.00. The mean age at diagnosis is 44 months in unilateral cases and 31 months in bilateral cases of Wilms tumor.[2,3] About 10% of children with Wilms tumor have an associated congenital malformation syndrome.[4]
Syndromes and Other Conditions Associated With Wilms Tumor
Wilms tumor typically develops in otherwise healthy children without any predisposition to developing cancer; however, approximately 10% of children with Wilms tumor have been reported to have a congenital anomaly.[4,5] In patients with congenital anomalies and Wilms tumor, nephrogenic rests have been reported in 60% of cases.[6] Of 295 consecutive patients with Wilms tumor seen at the Institut Curie in Paris, 52 (17.6%) had anomalies or syndromes, 43 of which were considered major, and 14 of which were genetically proven tumor predisposition syndromes.[7]
Children with Wilms tumor may have associated hemihyperplasia and urinary tract anomalies, including cryptorchidism and hypospadias. Children may have recognizable phenotypic syndromes such as overgrowth, aniridia, genetic malformations, and others. These syndromes have provided clues to the genetic basis of the disease. The phenotypic syndromes and other conditions have been grouped into overgrowth and non-overgrowth categories (refer to Table 1). Overgrowth syndromes and conditions are the result of excessive prenatal and postnatal somatic growth.[8,9]
It is important to recognize that the absolute risk of Wilms tumor varies with the underlying condition or anomaly. For example, most patients with hemihyperplasia will not develop Wilms tumor.
Table 1. Syndromes and Conditions Associated With Wilms Tumora
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.
PIK3CA-related segmental overgrowth including CLOVES syndrome
PIK3CA mutation
X
9q22.3 microdeletion syndrome
9q22.3
X
Sotos syndrome
NSD1
X
Familial Wilms tumor
FWT1
X
FWT2
Genitourinary anomalies
WT1
X
Sporadic aniridia
WT1
X
Trisomy 18
X
For information about the genes associated with Wilms tumor, including WT1 and WT2, refer to the Genomics of Wilms Tumor section of this summary.
Syndromic causes of Wilms tumor
WT1-related syndromes include the following:
WAGR syndrome. WAGR syndrome is characterized by the following:
Wilms tumor.
Aniridia.
Genitourinary anomaly.
Mental Retardation.
The constellation of WAGR syndrome occurs in association with an interstitial deletion on chromosome 11 (del(11p13)) (prevalence is about 0.4% of children with Wilms tumor).[11,12] The risk of Wilms tumor development in children with WAGR syndrome is approximately 50%; these children will present earlier and have a higher incidence of bilateral Wilms tumors (15%) than will children with nonsyndromic Wilms tumors.[13] (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),[14] both of which are associated with mutations in the WT1 gene.[15] Specifically, germline missense mutations in the WT1 gene are responsible for most cases of Wilms tumor that occur as part of Denys-Drash syndrome.[16,17] The risk of Wilms tumor is about 90% for children with Denys-Drash syndrome, with bilateral disease developing in 20% of patients.[17,18] In Frasier syndrome, splice-site WT1 mutations result in an imbalance of WT1 isoforms and a much lower incidence of Wilms tumor.[19]
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.[20]
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).[21] Approximately 15% of cases with clear-cut phenotypes have no molecular defects established so far.[22,23]
The molecular subtypes of the syndrome predispose patients to the development of different tumor histotypes.[24-26]
The prevalence of Beckwith-Wiedemann syndrome is about 1% of children with Wilms tumor.[20,27-29] Approximately 10% of Beckwith-Wiedemann syndrome patients will develop Wilms tumor.[21] Beckwith-Wiedemann syndrome patients with hemihyperplasia have a fourfold increased tumor risk over that of Beckwith-Wiedemann syndrome patients without hemihyperplasia.[30] (Refer to the Genomics of Wilms Tumor section of this summary for more information.)
Other syndromic causes of Wilms tumor include the following:
Perlman syndrome. Perlman syndrome—a rare, autosomal, recessively inherited, congenital overgrowth syndrome—is characterized by fetal gigantism, renal dysplasia and nephroblastomatosis, islet cell hypertrophy, multiple congenital anomalies, and mental retardation. Survivors have a high risk of developing Wilms tumor (75%).[31]
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.[32]
Simpson-Golabi-Behmel syndrome. Simpson-Golabi-Behmel syndrome is characterized by macroglossia, macrosomia, renal and skeletal abnormalities, and increased risk of embryonal cancers.
The syndrome is caused by mutations or deletions in glypican genes GPC3 and GPC4, and these genetic aberrations are believed to enhance the risk of Wilms tumor (8%).[33]
CLOVES syndrome. This syndrome is characterized by the following:
Congenital Lipomatous Overgrowth.
Vascular malformations.
Epidermal nevi.
Skeletal/spinal abnormalities.
This syndrome results from postzygotic, somatic mutations in PIK3CA, which may involve large or small regions of the child.[34]
Sotos syndrome. Sotos syndrome is characterized by cerebral gigantism and learning disability, ranging from mild to severe. Sotos syndrome is associated with behavioral problems, congenital cardiac anomalies, neonatal jaundice, and renal anomalies such as Wilms tumor, scoliosis, and seizures.
NSD1 is the only gene in which mutations are known to cause Sotos syndrome.[35]
9q22.3 microdeletion syndrome. 9q22.3 microdeletion syndrome is characterized by craniofacial abnormalities, metopic craniosynostosis, hydrocephalus, macrosomia, and learning disabilities.
Three patients presented with Wilms tumor in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. Although the size of the deletions was variable, all encompassed the PTCH1 gene.[36]
Bloom syndrome. Bloom syndrome is characterized by short stature and being thinner than other family members, sun-sensitive skin changes, and an increased risk of Wilms tumor.
BLM is the only gene in which mutations are known to cause Bloom syndrome.[37]
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.[38]
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.[39]
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.[40]
Nonsyndromic causes of Wilms tumor
Nonsyndromic causes of Wilms tumor include the following:
Familial Wilms tumor. Despite the number of genes that appear to be involved in the development of Wilms tumor, familial Wilms tumor is uncommon, with approximately 2% of patients having a positive family history for Wilms tumor. Siblings of children with Wilms tumor have a less-than-1% chance of developing Wilms tumor.[41-43] The risk of Wilms tumor among offspring of persons who have had unilateral (sporadic) tumors is less than 2%.[44]
Two familial Wilms tumor genes have been localized to FWT1 (17q12-q21) and FWT2 (19q13.4).[45-47] Occasional Wilms tumor families have a germline mutation in WT1. In these families, most, but not all, family members have genitourinary tract malformations.[48,49]
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.[50]
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.[51]
Sporadic aniridia. Sporadic aniridia may result from small germline deletions of one copy of the PAX6 gene that includes part or all of the adjacent WT1 gene but does not result in genitourinary abnormalities or retardation (i.e., not obviously WAGR syndrome). Therefore, many patients with sporadic aniridia develop Wilms tumor and are candidates for genetic testing. The relative risk of Wilms tumor in sporadic aniridia is 67-fold.[52] About half of individuals with sporadic aniridia and PAX6 and WT1 deletions develop Wilms tumor.[53]
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 subsequently born brother with the microdeletion had Beckwith-Wiedemann syndrome. This suggests that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.[51]
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.[54] The prevalence is about 2.5% of children with Wilms tumor.[27,54]
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.[56-58]
Genomics of Wilms Tumor
Wilms tumors, similar to other pediatric embryonal neoplasms, typically arise after a limited number of genetic aberrations. One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors followed by targeted sequencing of 651 Wilms tumors.[59] The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:[59]
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.[60,61] Another subset of Wilms tumor cases results from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[62-65] Other genes critical for early renal development that are recurrently mutated in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[62,63] EP300, CREBBP, and MYCN.[59] Of the mutations in Wilms tumors, 30% to 50% appear to converge on the process of transcriptional elongation in renal development and include the genes MLLT1, BCOR, MAP3K4, BRD7, and HDAC4.[59] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.
Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[66] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[50,67]
The genomic and genetic characteristics of Wilms tumor are summarized below.
WT1 gene
The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[68] WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[60,68,69]
Wilms tumor with a WT1 mutation is characterized by the following:
Evidence of WNT pathway activation by activating mutations in the CTNNB1 gene is common.[69-71]
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.[69,72]
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.[73] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 mutations.[74,75]
WT1 germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.[49,76]
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.[77] 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,[17] or Frasier syndrome.[14]
Genitourinary anomalies, including hypospadias and cryptorchidism.
Bilateral Wilms tumor.
Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
Stromal and rhabdomyomatous differentiation.
Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[17] and Frasier syndrome.[14]
WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[4] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that includes the WT1 and PAX6 genes.
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[27,78]
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.[13] The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[51]
Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[79,80]
Denys-Drash and Frasier syndromes. Denys-Drash syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%). Frasier syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.
WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1.[17] By contrast, 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.[19]
Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[79,80] Bilateral Wilms tumor was more common in cases with WT1-truncating mutations (9 of 14 cases) than in cases with WT1 missense mutations (3 of 27 cases).[79,80] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.
Late effects associated with WAGR syndrome and Wilms tumor include the following:
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.[81]
Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.[82]
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:[81]
CTNNB1 is the most commonly mutated gene in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[59,61,69,71,83] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[84] CTNNB1 mutations commonly occur with WT1 mutations, and most cases of Wilms tumor with WT1 mutations have a concurrent CTNNB1 mutation.[69,71,83] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation, except when associated with a MLLT1 mutation.[61,85] CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[74]
WTX gene on the X chromosome
WTX, which is also called AMER1, is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[60,61,69,86,87] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373Exit Disclaimer).[88] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[88] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[85,89] WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[60,69,86] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[69]
WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[60]
Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome
A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[51]
Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[27-29] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[2,29]
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[90] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[51,91]
Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[91] LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[51,90,91]
A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[92]
The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:
ICR1 gain of methylation (ICR1-GoM). Five percent to 10% of cases are caused by telomeric ICR1-GoM, which causes both biallelic expression of the IGF2 gene (normally expressed by the paternal allele only) and reduced expression of the oncosuppressor H19 gene. The incidence of Wilms tumor is 22.8%.[93]
ICR2 loss of methylation (ICR2-LoM). Fifty percent of cases with Beckwith-Wiedemann syndrome are caused by ICR2-LoM, resulting in reduced expression of the CDKN1C gene, normally expressed by the maternal chromosome only. Tumor incidence is very low (2.5%).[93]
Uniparental disomy (UPD). Altered expression at both imprinted gene clusters is observed in mosaic UPD of chromosome 11p15.5, accounting for 20% to 25% of the cases. The incidence of Wilms tumor is 6.2%, followed by hepatoblastoma (4.7%) and adrenal carcinoma (1.5%).[93] Fewer than 1% of cases with Beckwith-Wiedemann syndrome are caused by chromosomal rearrangements involving the 11p15 region.
CDKN1C mutations. Maternally inheritable CDKN1C loss-of-function mutations account for approximately 5% of the cases. This type is associated with a 4.3% incidence of neuroblastoma.[93]
Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[21,25,94] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[29]
Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[95] Interestingly, Wilms tumor in Asian children, which occur at a lower incidence than in European children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.[96]
Other genes and chromosomal alterations
Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:
1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome. In the presence of 1q gain, neither 1p nor 16q loss is significant.[97,98] 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.[97]
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.[99]
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.[100]
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.[101]
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.[97] 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.[102]
miRNAPG. Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[59,62-65] The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 1).[103] 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.[62,63]
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.[104] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[104] 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.[105] Another study identified DICER1 mutations in 2 of 48 familial Wilms tumor families.[106] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 mutations.[63,64]
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%.[62,63] 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.[62,63]
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.[75] 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.[109-111] TP53 may be useful as an unfavorable prognostic marker.[109,110]
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). There was no effect of TP53 status on patients with stage I or stage II tumors. In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These 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.[112]
FBXW7.FBXW7, a ubiquitin ligase component, is a gene that has been identified as recurrently mutated at low rates in Wilms tumor. Mutations of this gene have been associated with epithelial-type tumor histology.[113]
9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[36,114] 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.[114] Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[36,115,116]
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%).[117] Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases.[117] 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.[118]
CTR9. Inactivating CTR9 germline mutations were identified in 4 of 36 familial Wilms tumor pedigrees.[50,119] 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.[67] 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.[67] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.
Figure 2 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[75] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-mutant tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with a mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both MLLT1 and with WT1/WTX/CTNNB1-mutated cases.
Approximately 5% to 10% of individuals with Wilms tumor have bilateral or multicentric tumors. The prevalence of bilateral involvement is higher in individuals with genetic predisposition syndromes than in those without predisposition syndromes. For example, in 545 cases of bilateral Wilms tumors, bona fide pathogenic germline variants were found in 22% of patients.[120] The most common predisposition variants are mutations of WT1 and 11p15 loss of imprinting.[20,68]
Bilateral Wilms tumor with WT1 mutations are associated with early presentation in pediatric patients (age 10 months vs. age 39 months for those without a mutation) and a high frequency of WT1 nonsense mutations in exon 8. Three percent of patients with bilateral Wilms tumor have affected family members.[121]
Screening Children Predisposed to Wilms Tumor
Children with a significant increased predisposition to develop Wilms tumor (e.g., most children with Beckwith-Wiedemann syndrome or other overgrowth syndromes, WAGR syndrome, Denys-Drash syndrome, sporadic aniridia, or isolated hemihyperplasia) are usually screened with ultrasonography every 3 months until they reach at least age 8 years.[78,122] Early-stage, asymptomatic, small Wilms tumors may be discovered and potentially removed with renal-sparing surgery.[122]
Tumor screening programs for each overgrowth syndrome have been suggested. These programs were based on published age, incidence of tumor type, and recommendations from the 2016 American Association for Cancer Research (AACR) Childhood Cancer Predisposition Workshop. Although data about different cancer risks based on genetic or epigenetic subgroups for certain syndromes are emerging, and subgroup-specific recommendations have been developed in Europe, these practices have not been adopted in the United States. The AACR workshop committee proposed a uniform screening approach for all syndromes associated with a greater-than-1% risk of Wilms tumor. Additional screening for hepatoblastoma by serum alpha-fetoprotein (AFP) measurement and ultrasonography is also recommended for patients with Beckwith-Wiedemann syndrome, trisomy 18, and Simpson-Golabi-Behmel syndrome.[123]
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.[93]
The AACR workshop committee has published screening guidelines that include Beckwith-Wiedemann syndrome.[123] 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.[124] 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.[123]
Proposed screening guidelines for Wilms tumor are available for patients with Beckwith-Wiedemann syndrome who have undergone molecular subtyping [93] (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.
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.[125]
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.[123]
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.[78,126,127]
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.[66]
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.[40]
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.[78]
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.[128]
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.[123]
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.[129,130] Thirteen years is the oldest reported age of a Wilms tumor diagnosis in a DICER1 mutation carrier.[106,131]
Genetic counseling
The frequency of malformations observed in patients with Wilms tumor underlines the need for genetic counseling, molecular and genetic explorations, and follow-up.
A French study concluded that patients need to be referred for genetic counseling if they have one of the following:[7]
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.[7]
After genetic counseling takes place, 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. Other findings 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.[132]
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 exam and history. Children with a renal mass are carefully assessed for signs of associated syndromes such as aniridia, developmental delay, hypospadias, cryptorchidism, pseudohermaphrodism, overgrowth, and hemihyperplasia.
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 is done. This procedure is unnecessary after the definitive diagnostic study has been performed.
CT scan of the abdomen will confirm the renal origin of the mass and determine whether there are bilateral tumors.[134] About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[135]
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.[136]
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.[137]
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.[134]
Chest x-ray is unnecessary if chest CT is performed initially.
CT scan of chest. The common sites of metastases for Wilms tumor are the lung and liver. Approximately 15% of patients will present with pulmonary metastases. CT scanning provides the most sensitive method of detecting metastatic lung nodules.
Fluorine F 18-fludeoxyglucose (18F-FDG) positron emission tomography (PET)-CT. Wilms tumor is 18F-FDG avid, and 18F-FDG PET-CT imaging adds clinically applicable information to conventional CT scan imaging. PET-CT may be particularly helpful in patients with bilateral disease or those receiving preoperative chemotherapy. 18F-FDG PET-CT highlights FDG-avid areas in the tumor and metastases, which corresponds to histologically confirmed active disease.[138]
von Willebrand disease work-up. About 1% to 8% of patients presenting with Wilms tumor have an acquired form of von Willebrand disease, although many are asymptomatic. von Willebrand multimers bind to Wilms tumor, reducing the plasma concentration to low levels.[139] Some clinicians recommend evaluation for von Willebrand disease before surgery.
Biopsy or resection and the issue of bilateral Wilms. In children with a renal mass that clinically appears to be resectable Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. In North America, the initial treatment in most cases is primary nephrectomy. If a primary nephrectomy cannot be performed, a biopsy, either open or with multiple cores, is required. The contraindications to primary nephrectomy are the following:
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.[140]
If there is pulmonary compromise because of extensive pulmonary metastases or, in rare cases, hepatic disease.
Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions. However, the use of biopsy to determine histology in an inoperable tumor remains controversial because biopsy may cause local tumor spread and the histologic classification of the Wilms tumor cannot be determined by biopsy.[140]
If a child undergoes a biopsy as the first procedure, they are considered stage III because they have gross residual tumors.
In children with a renal mass that clinically appears to be stage I or stage II Wilms tumor, biopsy is not performed so that tumor cells are not spread during the biopsy. A biopsy would upstage such a patient to stage III. Nephrectomy (in North America) or chemotherapy (in Europe) is performed instead. Therefore, the diagnostic pathology is first seen when the nephrectomy specimen is examined.
Children who have bilateral Wilms tumor are often treated without a biopsy.[141]
Biopsy of a renal mass may be indicated if the mass is atypical by radiographic appearance for Wilms tumor, and the patient is not going to undergo immediate nephrectomy. Biopsy tissue from inoperable Wilms tumor obtained before chemotherapy may be used for histologic review and initial treatment decisions.[140]
Anaplastic histology can be difficult to detect in any biopsy sample because of tumor heterogeneity. It is important to recognize that data from NWTS-4 and NWTS-5 (COG-Q9401/NCT00002611) have shown that, because of the histologic heterogeneity of Wilms tumor, a significant number of patients have anaplastic histology that is missed during an upfront biopsy whether it be a core needle biopsy or an incisional biopsy [142] but revealed at the time of definitive surgery after chemotherapy.
Detection of a contralateral renal lesion in a child with Wilms tumor can change the stage and initial management of the patient, indicating a role for a renal-sparing approach without up-front surgery. The detection of contralateral renal lesions is important at baseline imaging because routine intraoperative exploration of the contralateral kidney is no longer recommended on the basis of the results of the NWTS-4 study.[133,136] If the initial imaging studies suggests a bilateral process, treatment as a bilateral Wilms tumor is recommended by the authors. If the origin of the other lesion is indeterminate, the authors recommend pathological assessment of that lesion before proceeding with a nephrectomy.[133,136]
In children with bilateral Wilms tumor, biopsy can be avoided if the child is of typical age and radiographic appearance. This was assessed on the COG AREN0534 (NCT00945009) study where 187 of 189 patients were treated initially without a biopsy. All had Wilms tumors. If after 6 weeks of therapy, response was less then 30% by RECIST1.1 criteria, bilateral biopsies were performed to assess for anaplasia, stromal differentiation, and rhabdomyomatous changes. If anaplasia was detected, the chemotherapy treatment was changed. If the other two were detected, further chemotherapy was unlikely to result in tumor shrinkage and definitive surgery was recommended by the authors.[141]
Lymph node sampling is required to locally stage all Wilms tumor patients. Lymph nodes have shown to be of major prognostic value for both short-term and long-term survival. Gross inspection is notoriously inaccurate, with a false-negative rate of 31.3% and a false-positive rate of 18.1%.[143]
About 5% of renal masses thought to be Wilms tumor on the basis of clinical and radiological findings are diagnosed as another condition.[144]
For patients with suspected Wilms tumor, additional preoperative staging studies are performed to assess intravascular extension or rupture of Wilms tumor.[135]
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.[137] 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.[145]
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.[146]
Prognosis and Prognostic Factors for Wilms Tumor
Wilms tumor is a curable disease in most affected children. Since the 1980s, the 5-year survival rate for Wilms tumor with favorable histology (FH) has been consistently above 90%.[147] This favorable outcome occurred despite reductions in the length of therapy, dose of radiation, extent of fields irradiated, and the percentage of patients receiving radiation therapy.[148]
The prognosis for patients with Wilms tumor depends on the following:[149-152]
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.[97-99]
Age. Older age is associated with adverse prognosis.[153]
Older adolescents and adults with Wilms tumor
Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million per year.[154] In Europe, the median age at diagnosis for adult patients with Wilms tumor (defined as age >15 years) is 34 years; however, patients older than 60 years have been reported.[154] Three percent of Wilms tumors occur in adults. Wilms tumor represents less than 1% of all renal tumors in adults and may be an unexpected finding after nephrectomy for presumed renal cell carcinoma, which is the most common adult renal cancer.
The outcome for adolescent and young adult (AYA) patients (aged 15 to 39 years) is inferior to the outcome for children. In an analysis of patients with Wilms tumor in the Surveillance, Epidemiology, and End Results (SEER) database, AYA patients (n = 104) had a statistically worse 5-year OS (69% vs. 94%; P < .001) than did pediatric patients (n = 2,574).[155][Level of evidence: 3iA] Better results have been reported for adults when they are treated in pediatric trials. The National Wilms Tumor Study (NWTS) Group reported the outcomes for adult patients with Wilms tumor from the NWTS-1, -2, and -3 trials. The 3-year OS rate for adults on the NWTS-1 trial was 24% (compared with 74% in children) and improved to a 5-year OS rate of 82.6% on the NWTS-3 trial, although the number of adult patients treated on each trial was 31 or fewer.[156-158] These data suggest that many adults with Wilms tumor, if treated appropriately, can expect to be cured, especially if the tumor has not spread and/or is completely resected. The inferior outcome of the adult patients may be the result of differences in tumor biology between children and adults, incorrect diagnosis, inadequate staging (e.g., more likely to be staged as localized disease or to not receive lymph node sampling), undertreatment/poor compliance (e.g., not receiving radiation therapy), unfamiliarity of medical oncologists and pathologists with Wilms tumors in adults (possibly leading to diagnostic error and delay), delays in initiating the appropriate risk-adapted therapy, and lack of specific treatment protocols for adults. For adults with refractory or recurrent disease, screening for potential therapeutic targets in the tumor should be considered.[159]
The following recommendations from the renal tumor committees of the International Society of Pediatric Oncology (SIOP) and COG encourage a uniform approach to improve outcome for adults with Wilms tumor.[160]
Consult with a pediatric oncologist who has experience with the treatment of Wilms tumor as soon as a histological diagnosis is suspected.
Avoid delaying the start of chemotherapy. Ideally, chemotherapy, and radiation therapy if necessary, should be started by day 14 postnephrectomy, although delaying the start until day 30 is acceptable.
Be alert for toxicity of vincristine (neurotoxicity) and dactinomycin (hepatic toxicity) in adults.
Register patients in pediatric renal tumor trials if studies are available and the patients are eligible.
Histologic Findings in Wilms Tumor
Although most patients with a histologic diagnosis of Wilms tumor do well with current treatment, approximately 10% of patients have histopathologic features that are associated with a worse prognosis, and in some types, with a high incidence of relapse and death. Wilms tumor can be separated into the following two prognostic groups on the basis of tumor and kidney histopathology:
Histologically, Wilms tumor mimics the triphasic development of a normal kidney consisting of blastemal, epithelial (tubules), and stromal cell types. Not all tumors are triphasic, and monophasic patterns may present diagnostic difficulties.
While associations between histologic features and prognosis or responsiveness to therapy have been suggested, with the exception of anaplasia, none of these features have reached statistical significance in North American treatment algorithms, and therefore, do not direct the initial therapy.[161]
Anaplastic histology
Anaplastic histology accounts for about 10% of Wilms tumor cases. Anaplastic histology is the single most important histologic predictor of response and survival in patients with Wilms tumor. Tumors occurring in older patients (aged 10–16 years) have a higher incidence of anaplastic histology.[162] In bilateral tumors, 12% to 14% have been reported to have anaplastic histology in one kidney.[163,164]
The following two histologic criteria must be present to confirm the diagnosis of anaplasia:
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.[109] Focal anaplasia is defined as the presence of one or more sharply localized regions of anaplasia in a primary tumor. All of these factors lend support to the hypothesis that anaplasia evolves as a late event from a subpopulation of Wilms tumor cells that have acquired additional genomic lesions.[165] Focal anaplasia does not confer as poor a prognosis as does diffuse anaplasia.[151,166,167]
Anaplasia correlates best with responsiveness to therapy rather than to tumor aggressiveness. It is most consistently associated with poor prognosis when it is diffusely distributed and when identified at advanced stages. These tumors are more resistant to the chemotherapy traditionally used in children with FH Wilms tumor.[151]
Nephrogenic rests
Nephrogenic rests are abnormally retained embryonic kidney precursor cells arranged in clusters. Nephrogenic rests are found in about 1% of unselected pediatric autopsies, 35% of kidneys with unilateral Wilms tumor, and nearly 100% of kidneys with bilateral Wilms tumor.[168,169] Preoperative chemotherapy does not appear to affect the overall prevalence of nephrogenic rests. Congenital anomalies have been reported in 12% of patients with nephrogenic rests, including in 9% of patients with unilateral Wilms tumor and in 33% of patients with bilateral disease.[6]
The term nephroblastomatosis is defined as the presence of diffuse or multifocal nephrogenic rests. Nephrogenic rests can be subclassified according to the category of rest (intralobar or perilobar nephrogenic rests) and their growth phase (incipient or dormant nephrogenic rests, hyperplastic nephrogenic rests, and regressing or sclerosing nephrogenic rests). Diffuse hyperplastic perilobar nephroblastomatosis represents one unique category of nephroblastomatosis that forms a thick rind around one or both kidneys and is considered a preneoplastic condition. Distinguishing between Wilms tumor and diffuse hyperplastic perilobar nephrogenic rests may be a challenge, and it is critical to examine the juncture between the lesion and the surrounding renal parenchyma. Incisional biopsies are of no diagnostic value unless they include the margin between the lesion and the normal renal parenchyma.[170]
The type and percentage of nephrogenic rests vary in patients with unilateral or bilateral disease. Patients with bilateral Wilms tumor have a higher proportion of perilobar rests (52%) than of intralobar or combined rests (32%) and higher relative proportions of rests, compared with patients with unilateral tumors (18% perilobar and 20% intralobar or both).[81] Intralobar nephrogenic rests have been associated with stromal-type Wilms tumor and younger age at diagnosis.[6]
Patients with any type of nephrogenic rest in a kidney removed for nephroblastoma are considered at increased risk for tumor formation in the remaining kidney. This risk decreases with patient age.[47]
Bilateral diffuse hyperplastic perilobar nephroblastomatosis is generally treated with chemotherapy to reduce the risk of developing Wilms tumor; however, the risk of developing Wilms tumor remains high, 55% in one series.[170] Patients who have been treated with chemotherapy for a prolonged period of time remain at high risk of developing Wilms tumor. If these patients develop Wilms tumor, they have a poorer prognosis than do other bilateral Wilms tumor patients, presumably because of the increased incidence of anaplasia in these cases (more than one-third of cases), and perhaps as a result of the development and selection of anaplasia in the surviving abnormal kidney cells.[170,171]
Extrarenal nephrogenic rests are rare and may develop into extrarenal Wilms tumor.[172]
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