Introduction
Nephroblastoma, or Wilms tumor (WT), is the most common primary renal malignancy in childhood and represents 6% of all childhood cancers. WTs comprise over 95% of all kidney tumors in children younger than 15 years old. , Usually found in children 1 to 5 years old, the tumor is still a rare finding. Overall, the incidence of WT is 1 in 10,000 children under 5 years of age and only 7 per million children under age 15 years. , The Children’s Oncology Group (COG) reports that in the United States, roughly 600 children are diagnosed with a primary renal tumor each year and that over 90% of these are WTs.
Named for Max Wilms, the disease is characterized by the presence of an embryonal tumor derived from the metanephros. Although historically a death sentence, WT is one of the greatest success stories of modern medicine: survival rates rose from less than 5% in 1900 to over 90% in modern times. The increased survival is the result of both improved diagnosis and identification, in addition to better surgical and chemotherapeutic approaches. Much of this improvement in outcomes is attributable to large research organizations, such as the Children’s Cancer Group, Société Internationale d’Oncologie Pédiatrique (SIOP), and the National Wilms’ Tumor Study Group (NWTS) (replaced by the renal tumor section of the COG) in 2001. For decades, these organizations have collected systematic databases for analysis and have supported large controlled treatment trials. This chapter will review the presentation, diagnosis, treatment, and outcomes of WT.
Diagnosis and histology
Nephroblastoma usually presents as a single kidney nodule, although multifocal unilateral or even bilateral tumors are possible. Bilateral tumors typically account for only 5% to 7% of all diagnosed WT. Clinical presentation may include hematuria or abdominal pain and roughly a quarter (25%) of patients present with hypertension. Grossly, WTs are often large masses, which can vary greatly in size ( Fig. 26.1 ). By the time they are diagnosed, tumors usually disrupt renal architecture. Typical histology includes blastemal, epithelial, and stromal tissue, although the proportion of each tissue type varies considerably between tumors. It is rare to see the classic histologic triad, and biphasic or even monophasic tumors are not uncommon.
When epithelial tissue predominates, differential diagnosis includes renal cell carcinoma (RCC) (rare in childhood), metanephric adenoma, or hyperplastic nephrogenic rest. Pure blastemal tumors, the least differentiated and likely most malignant, may resemble other types of embryonal “small round blue cell” tumors, such as neuroblastoma, desmoplastic small round cell tumor, primitive neuroectodermal tumor (PNET), and even lymphoma. There are several patterns of blastemal tumor growth, including serpentine, diffuse, nodular, and basaloid.
Histopathology
Predisposing nephrogenic rests are areas of embryonal tissue of metanephric origin still present after 36-weeks’ gestation. Only rarely will these nephrogenic rests develop clonal expansion to become malignant WTs. Up to 30% of patients with sporadic WT will have nephrogenic rests, although they are found in well over 90% of patients with multifocal or bilateral disease. The presence of multiple nephrogenic rests is referred to as nephroblastomatosis . WTs present with classic triphasic histopathologic components: blastemal, epithelial, and stromal. The proportion and degree of differentiation of these cell types is widely variant, such that each tumor is histologically unique. This significant histologic heterogeneity can make diagnosis challenging for pathologists. Nonetheless, morphologic appearance of WT is critical to appropriate staging and risk stratification. The blastemal cells are tightly packed with small, round nuclei and little cytoplasm ( Fig. 26.2 ). Blastemal-predominant tumors, among the “small round blue cell” tumors, may be difficult to distinguish from neuroblastoma, PNET, and desmosplastic small round cell tumors. These blastemal WTs are more aggressive and have a poorer outcome. In addition to blastemal type, WTs with diffuse anaplasia are considered “high risk” and are more aggressively treated (see later). The epithelial component is heterogeneously differentiated from normal appearing glomeruli to poorly defined tubules. In contrast, the stromal component resembles anything from immature fibroblasts to muscle or neural tissue. There may be spindle cells (mesenchymal embryo) with myxoid cytoplasm.
Although classic triphasic WT is relatively easy to identify, many tumors are biphasic or monophasic in appearance. Additional challenges to accurate diagnosis may also be introduced with preoperative chemotherapy, a cornerstone of SIOP treatment regimens. Because of this, there are separate classification schemes for pre- and postchemotherapy appearance.
Blastemas represent the least differentiated tumors and are considered the most malignant. Histologic patterns of blastemal WT include diffuse, nodular, serpentine, and basaloid. All four of these patterns may be present within the same tumor and pattern does not appear to affect prognosis. Diffusely growing blastemal WT may show significant infiltration and lack a pseudocapsule between affected and healthy kidney. Although these tumors may be aggressive, blastemal predominant tumors are usually considered “favorable histology” unless viable blastemal cells persist post standard chemotherapy (in the SIOP regimen).
Epithelial tumors also have a myriad of histologic presentations, from highly differentiated to primitive. These tumors may appear as nests of primitive rosette-like cells to fully formed tubules or glomeruli. Epithelial predominant tumors are also considered lower risk and thus “favorable histology.”
Stromal tumors consist of mesenchymal cells and loose myxoid areas. As with the epithelial component, cells may appear with heterogeneous differentiation, including muscle, cartilage, fat, or even bone tissue. These stromal structures, particularly, are greatly affected by preoperative chemotherapy. These chemotherapy-induced changes (CIC) include necrosis, fibrosis, or bleeding. Frustratingly, the classification of WT is not standard between the many pediatric oncology research groups. SIOP and COG each has a unique criterion, which are described later ( Table 26.1 and Box 26.1 ).
| Stage | Criteria |
|---|---|
| I |
|
| II |
|
| III |
|
| IV | Hematogenous metastases (lung, liver, bone, brain, etc.) or lymph node metastases outside the abdominopelvic region |
| V | Bilateral renal tumors at diagnosis |
Stage I
The tumor is limited to the kidney and has been completely resected
The tumor was not ruptured or biopsied before removal
No penetration of the renal capsule or involvement of renal sinus vessels
Stage II
The tumor extends beyond the capsule of the kidney but was completely resected with no evidence of tumor at or beyond the margins of resection
There is penetration of the renal capsule OR
There is invasion of the renal sinus vessels
Stage III
Gross or microscopic residual tumor remains postoperatively including inoperable tumor, positive surgical margins, tumor spillage surfaces, regional lymph node metastases, positive peritoneal cytology, or transected tumor thrombus
The tumor was ruptured or biopsied before removal
Stage IV
Hematogenous metastases or lymph node metastases outside the abdomen (e.g., lung, liver, bone, and brain)
Stage V
Bilateral renal involvement is present at diagnosis and each side may be considered to have a stage
Anaplasia, either focal or diffuse, is found in up to 10% of WTs. This finding has both prognostic and treatment implications and identification of this pathologic entity is critical. As the presence of anaplastic tumor is strongly associated with recurrent disease, patients with anaplasia are referred to as having “unfavorable histology.” Anaplasia is characterized by: (1) enlarged nuclei; (2) heterochromatic nuclei; and (3) multipolar mitotic figures. Patients with anaplastic tumors are often treated more aggressively.
Genetics of wilms
Much work has been done on genetics of WT and the field continues to advance rapidly. First cloned in 1990, WT1 at 11p13 was the first tumor suppressor gene identified in WT. The WT1 gene encodes a 55 kDa zinc finger transcription factor that helps control deoxyribonucleic acid (DNA) binding. The gene may also regulate posttranscription gene expression through messenger ribonucleic acid binding. With 10 exon regions, there are multiple splicing events that are disrupted. The WT1 gene is mutated in up to 12% of WTs. Other genes, such as CTNNB1 (15%) and WTX (18%), have also been identified. CTNNB1 on 3p21 encodes an 88 kDa beta-catenin protein heavily involved in Wnt/beta-catenin signaling pathway. In WT, mutated beta-catenin is found in approximately 15% of tumors.
WT on the X, also referred to as WTX , refers to mutations located on Xq11.1. This gene contributes to stabilization of beta-catenin and acts as a tumor suppressor independent of the Wnt signaling pathway and WTX inactivation has recently been found in up to 30% of WT pathology specimens.
Taken together, genetic variations in one of these three genes ( WT1 , CTNNB1 , and WTX ) is found in up to one-third of the cases of WT. , In addition to these genes that are associated with the presence of WT, there are other genes that are markers of outcome. Disease progression in WT has been associated with expression of several genes, including TP53 , MYCN , CITED1 , SIX2 , TOP2A , and CRABP2 . These genes are involved in renal development, chromatin remodeling, DNA methylation, and other cellular functions. Mutations in p53 is the most frequent finding in human malignancy. Located on 17p13.1, the gene encodes TP53, a protein involved in many cellular events, such as DNA repair, apoptosis, and differentiation/proliferation. p53 in WT is associated with relapse, progression, anaplasia, and metastasis. Up to 75% of anaplastic WTs have been reported to have p53 mutations.
Interestingly, not all of the genetic changes seen in WT are the result of genetic mutations. Large scale loss of heterozygosity (LOH) was the first aberration identified. LOH is a common finding in many types of cancer. Even when there exists the genetic loss of one allele, the remaining unaffected allele is able to “cover” protein synthesis and hide the defect. If some second “hit” damages or alters the function of this other allele, then a recessive trait, often a tumor suppressor, becomes manifest. This LOH can be the result of mitotic errors, gene conversion, faulty DNA repair or replication, or some other mishap. LOH for 1p and 16q was identified more frequently among subjects with adverse outcomes in the NWTS-4 trial. Given these findings of worse outcome with these genetic findings, COG uses these LOH markers as a molecular marker for risk stratification. In recent COG protocols, patients having double positive tumors receive increased treatment intensity.
Epidemiology
First described by Max Wilms in 1899, WTs are one of the most common solid tumors in childhood. It is currently the third most common malignancy in children. WT comprises 95% of all renal cancers among children younger than 15 years old. The disease affects approximately 1 in 10,000 children and its incidence is 7 per million and there are roughly 600 children newly diagnosed annually in the United States. WT is usually a sporadic disease, although family history is present in up to 2% of cases. Approximately 10% of WTs are related to germline mutations or other congenital abnormalities that result in a syndromic inheritance (see later).
WT is the second most common solid abdominal tumor (behind neuroblastoma) in children. The mean age at diagnosis is just 3 years old. Presentation is usually an asymptomatic mass detected by parents, primary care providers, or more recently, incidentally found on abdominal imaging.
Syndromic wilms tumors
WTs are frequently seen as part of a generalized overgrowth syndrome. Many of these conditions are related to a chromosomal abnormality, most often identified on chromosome 11. Although occasionally isolated, several named syndromes are strongly associated with the development of WT. Although many of these syndromes are rare (for example Perlman syndrome, Simpson-Golabi-Behmel syndrome, and 9q22.3 microdeletion), several conditions are common enough to warrant specific discussion.
Denys-drash and frasier
Both Denys-Drash syndrome and Frasier syndrome are characterized by renal disease, intersex, and predisposition to develop tumors. Each is also associated with WT1 mutations, with 96% of Denys-Drash and 100% of Frasier patients having constitutional heterozygosity mutations of the WT1 gene. Before the age of molecular diagnostics, it was unclear if they actually represent separate entities or are in fact the same disorder, although there are notable differences in clinical presentation, not the least of which is risk of WT.
Denys-Drash syndrome consists of WTs, intersex, and the nephrotic syndrome. Characteristic glomerular damage leads to nephrotic syndrome at an early age, and progressive sclerosis leading to renal failure is inevitable. Most patients, although not all, develop early WT, usually before age 2 years. In general, XX chromosomal patients are phenotypic girls, whereas the XY patients often have ambiguous genitalia or male pseudo-hermaphroditism.
In contrast to Denys-Drash, Frasier syndrome is not associated with WT. Patients with Frasier syndrome present in similar fashion to Denys-Drash, but have more gradual decline in kidney function and lack the risk for WT. Instead of kidney tumors, these patients are at increased risk of gonadal tumors, specifically gonadoblastoma. The disorder is caused by specific WT1 mutations that disrupt gene splicing at the second alternative splice donor site. These mutations are located in intron 9 of the WT1 gene and result in deficiency of the positive KTS isoforms of lysine, threonine, and serine (from 2:1 to 1:2). This minor change highlights the complicated epigenetics of this condition, because the WT1 protein is both normal in structure and binding ability. The lack of KTS positive isoforms in the affected cells leads to the clinical manifestation of Frasier syndrome without increasing tumorigenicity (the negative isoform is equally tumor suppressing for WT). This explains why Frasier patients do not develop WT.
Beckwith-wiedemann syndrome
Beckwith-Wiedemann syndrome (BWS) is a classic although rare genetic overgrowth syndrome. The syndrome has an estimated prevalence of approximately 1 per 10,000 live births. Although varying diagnostic criteria make generalizations difficult, patients mostly present in early childhood with macrosomia, macroglossia, and often abdominal wall defects, such as omphalocele or umbilical hernia, and visceromegaly. Patients with BWS are at high risk of developing multifocal WTs, with approximately 10% of children experiencing either a WT or a hepatoblastoma. Other nephrourologic complications are common, with 30% to 60% of patients having some anomaly (cysts and nephrocalcinosis top the list of non-WT complications). Not all patients with BWS present with all of the classic findings. Consensus recommendations now call for genetic testing in unclear cases. Classic abnormalities at 11p15.5– 11p15.4 are diagnostic. From a nephrologic standpoint, patients with BWS should be screened for both nephrocalcinosis/hypercalcuria and for WT. Given the doubling time of WT as 11 to 13 days, renal ultrasound is recommended every 3 months until age 7 years. After age 7 years, imaging may be spaced at greater intervals. Patients with certain molecular markers (IC1 Gain of Methylation [GOM] and segmental upd(11)pat molecular subgroups) are at highest risk for WT. Given the frequent screening for WT, patients with BWS are often discovered much earlier than in the general population. As such, their tumors are more often smaller and less likely anaplastic or metastatic at diagnosis. Treatment is usually partial nephrectomy with or without chemotherapy.
Wagr syndrome
WT in association with aniridia, genitourinary abnormalities, and mental retardation has been dubbed the WAGR syndrome. This rare genetic condition involves deletion of 11p13 and is therefore associated with WTs. The aniridia (and probably the mental deficiencies) is caused by additional deletion of the neighboring PAX6 ocular development gene.
Clinically, infants with WAGR usually present with sporadic aniridia. Such infants should always undergo screening for WAGR, because the presence of external genital abnormalities is not universal. Genetic testing for the characteristic 11p13 deletion can confirm diagnosis. A recent review of 54 cases of WAGR in patients ranging from 7 months to 42 years revealed that more than half (57%) had WT. Other genitourinary anomalies included cryptorchidism (60% of males), bicornuate uterus (17% of females), and ambiguous genitalia (10%).
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