Etiology: Genetics and Molecular Biology

Wilms tumor is an embryonal malignancy of the kidney. Most cases are sporadic, although 1-2% of patients have a familial predisposition to Wilms tumor. Familial cases of Wilms tumor are inherited in an autosomal dominant manner with variable penetrance; they are associated with an earlier age at diagnosis and increased frequency of bilateral disease. Models of Wilms tumor development propose that a genetic mutation predisposes to nephrogenic rests. These are benign foci of embryonal kidney cells that persist abnormally into postnatal life in approximately 1% of newborn kidneys and usually regress or differentiate by early childhood. The nephrogenic rests that persist may sustain additional mutations and transform into Wilms tumor. Nephrogenic rests may be intralobar, as in Wilms tumor aniridia genitourinary abnormalities and mental retardation (WAGR) and Denys-Drash syndrome, or perilobar and often multiple, as in Beckwith-Wiedemann syndrome (BWS).

Wilms tumor is genetically heterogeneous (Table 493-2). Familial Wilms tumors have been linked to FWT1 gene at chromosome 17q and FWT2 gene at chromosome 19q13. However, some families carry neither of these mutations, suggesting that additional Wilms tumor loci exist.

Table 493-2 SYNDROMES ASSOCIATED WITH WILMS TUMOR

So far the best characterized Wilms tumor gene is WT1, located at 11p13. The WT1 gene encodes a zinc finger transcription factor that is critical to normal development of the kidneys and gonads. WAGR is caused by deletion at chromosome 11p13 that includes both PAX6 and WT1 loci. Aniridia arises from the deletion of PAX6 gene that lies telomeric to the WT1 gene. Individuals with WAGR are diagnosed with Wilms tumor at an earlier age and generally have a favorable histology; their tumors respond well to treatment but are associated with increased risk of end-stage renal disease (ESRD) as they approach adulthood. Individuals with intragenic WT1 germline mutation display the same Wilms tumor predisposition and range of genitourinary anomalies as patients with WAGR. Individuals with specific WT1 missense mutations additionally have early-onset renal failure (Denys-Drash syndrome). WT1 is homozygously inactivated in 10-20% of Wilms tumors, by either somatic alterations or a combination of germline and somatic WT1 alterations.

WT2 is a localized to a cluster of imprinted genes at 11p15. Altered expression of one or more of these genes due to duplication or loss of imprinting is observed in BWS. Loss of heterozygosity (LOH) or loss of imprinting (LOI) at 11p15 is observed in approximately 70% of Wilms tumors. Candidate genes in this region include IGF2, H19, CDKN1/p57kip, and KCNQ1OT1/LIT1. Uniparental isodisomy of 11p15 and hypermethylation of H19 are associated with development of Wilms tumor only, whereas alterations in KCNQ1OT1 are associated with other tumors, macrosomia, and abdominal wall defects in addition to Wilms tumor. Identification of inherited microdeletions within the H19/IGF2 imprinting control region (ICR) in BWS and BWS/Wilms tumor further strengthen the association between aberrant expressions of IGF2 and Wilms tumor development. WTX at X11.1 has now been reported to be somatically mutated in 20-30% of Wilms tumors. CTNNB1, located at 3p22.1, encodes β-catenin and is also somatically mutated in about 15% of Wilms tumors. The WNT signaling pathway seems to be commonly involved in Wilms tumorigenesis. In addition to these genes, loci at 1p, 7p, 16q, and 17p (p53 tumor suppressor gene) are also believed to harbor genes involved in the biology of Wilms tumor.

Epidemiology

The incidence of Wilms tumor is approximately 8 cases/million children <15 yr of age with about 500 new cases in North America per year. It accounts for nearly 6% of pediatric malignancies and is the second most common malignant abdominal tumor in childhood. Although peak incidence is between 2 and 5 yr of age, Wilms tumor has also been encountered in neonates, adolescents, and adults. It can arise in one or both kidneys. The incidence of bilateral Wilms tumors is 7%, and individuals with horseshoe kidney are at twice the risk for development of Wilms tumor as the general population. Wilms tumor may be associated with hemihypertrophy, aniridia, genitourinary anomalies, and a variety of rare syndromes (see Table 493-2), including BWS and Denys Drash syndrome.

Clinical Presentation

The most common initial clinical presentation for Wilms tumor is the incidental discovery of an asymptomatic abdominal mass by parents while bathing or clothing an affected child or by a physician during the course of a routine physical examination (Table 493-3). At presentation the mass can be quite large because retroperitoneal masses can grow unhampered by strict anatomic boundaries. Functional defects in paired organs like the kidney, with good functional reserve, are also unlikely to be detected early. Hypertension is detected in about 25% of tumors at presentation. Renin production by the tumor itself has been suggested as the cause. Elevated renin values are also attributed to renal ischemia caused by either pressure from the tumor directly on the renal artery or indirectly as a result of tumor compression within the renal capsule or by intrarenal arteriovenous fistula formation. But the etiology remains unknown in majority of the cases. Some patients present with abdominal pain. About 15- 25% of cases have hematuria, usually asymptomatic. Occasionally rapid abdominal enlargement and anemia occur as a result of bleeding into the renal parenchyma or pelvis. Wilms tumor thrombus extends into the inferior vena cava in 4-10% of patients, and rarely into the right atrium. Patients might also have microcytic anemia from iron deficiency or anemia of chronic disease, polycythemia, elevated platelet count, and acquired deficiency of von Willebrand factor or factor VII deficiency.

Diagnosis and Differential Diagnosis

An abdominal mass in a child should be considered malignant until diagnostic imaging, laboratory finding, and/or pathology can define its true nature (see Table 493-3). Imaging studies include abdominal flat plate radiography, abdominal ultrasonography (US), CT, and/or MRI of the abdomen to define the intrarenal origin of the mass and differentiate it from adrenal masses (e.g., neuroblastoma) and other masses in the abdomen. Abdominal US helps differentiate solid from cystic masses. Wilms tumor might show focal areas of necrosis or hemorrhage and hydronephrosis due to obstruction of the renal pelvis by the tumor. US with Doppler imaging of renal veins and the inferior vena cava is a useful first study that can not only look for Wilms tumor but also evaluate the collecting system and demonstrate tumor thrombi in the renal veins and/or inferior vena cava.

CT (Fig. 493-1) and/or MRI is useful to define the extent of the disease, integrity of the contralateral kidney, and metastasis. In bilateral cases, MRI may be a better guide to nephron-sparing surgery. If histologic diagnosis confirms clear cell sarcoma of the kidney, a bone scan is indicated. A brain MRI is indicated in case of rhabdoid tumor of the kidney, to look for metastasis. Chest CT is more sensitive than chest radiography to screen for and characterize pulmonary metastasis in Wilms tumor and other solid tumors.

Figure 493-1 Abdominal CT scan with Wilms tumor arising from left kidney. Because of their retroperitoneal location, such tumors can become very large (e.g., >10 cm) before clinical symptoms occur.

Wilms tumor lesions are metabolically active and concentrate fluorodeoxyglucose (FDG). Regional spread and metastatic lesions are often visualized on positron emission tomography (PET)/CT scanning, which is a useful modality to monitor response to therapy in or patients with relapsed Wilms tumor, in patients with regional lymph node involvement, pelvic soft tissue involvement, and liver metastasis, and in patients with recurrent disease.

Treatment

There are two major schools of thought in the management of Wilms tumor. The Children’s Oncology Group (COG), formerly National Wilms Tumor Study Group, advocates upfront surgery prior to initiating treatment. On the other hand, the International Society of Pediatric Oncology (SIOP) recommends preoperative chemotherapy. Each approach has advantages and limitations but they have similar outcomes. Early surgery has 100% accurate diagnosis and can facilitate risk-adapted therapy. Preoperative chemotherapy can make surgery easier and reduces the frequency of intraoperative tumor rupture and spillage.

Prognostic factors for risk-adapted therapy include age, stage, tumor weight, and loss of heterozygosity at chromosomes 1p and 16q (Table 493-4). Histology plays a major role in risk stratification of Wilms tumor. Absence of anaplasia is considered a favorable histologic finding. Presence of anaplasia is further classified as focal or diffuse, both of which are unfavorable histologic findings.

Table 493-4 STAGING OF WILMS TUMOR

Source: Children’s Oncology Group Protocol AREN 0532.

The COG has very specific drug dose and schedule recommendations for risk-adapted treatment of Wilms tumor. Therapy is generally performed in the outpatient clinic. Patients <2 yr of age and with a tumor weight <550 g are classified as having very low risk and are treated with nephrectomy only followed by close observation. Patients with stage I and II disease receive two drugs, vincristine and actinomycin D, a regimen (EE-4A) that takes 18 weeks. Actinomycin D (also called dactinomycin) is given every 3 weeks. Vincristine is given weekly for 10 weeks, and then every 3 weeks until week 18. Vincristine doses are adapted for age and weight in order to avoid neurotoxicity; children rarely have alopecia from the vincristine and dactinomycin regimen.

Doxorubicin is used in higher-risk patients and results in alopecia. Currently in North America, doxorubicin is alternated every 3 weeks with dactinomycin for a total of 24 weeks (regimen DD4A) if LOH is present at both 1p and 16q in patients with stage I and II disease. Patients with stage III disease receive intensive chemotherapy with three drugs and radiation therapy. Patients with presence of LOH at 1p and 16q are treated as being at high risk along with patients with stage IV and favorable histology; these two groups receive two cycles of three drug regimen followed by nephrectomy and then irradiation. Wilms tumors with focal and anaplastic histology have been treated with multiple regimens that included irinotecan, carboplatin and ifosfamide in addition to the standard agents, vincristine, doxorubicin, and actinomycin D.

Recurrent Disease

Patients with recurrent Wilms tumor who previously received only actinomycin D and vincristine had a 4 year recurrence-free survival (RFS) of about 70%, whereas those who previously received the 3-drug regimen of vincristine, actinomycin D, and doxorubicin had an RFS of only 40%. Patients with metachronous relapse (i.e., new disease in the other kidney) are treated with kidney-sparing surgery and chemotherapy in order to try to avoid chronic renal failure. Other agents used to treat recurrent Wilms tumor have included doxorubicin, carboplatin, ifosfamide, topotecan, irinotecan, docetaxel, and etoposide.

Prognosis

Despite some adverse risk factors that decrease prognosis (metastases, unfavorable histology, recurrent disease, and loss of heterozygosity of both 1p and 16q), most children with Wilms tumor have a very favorable prognosis. Overall the survival of children with Wilms tumor approaches 90%, with some risk factors (low stage, favorable histology, young age, low tumor weight) conferring even better outcomes. Thus, Wilms tumor is at the top of the list for best outcome of the common pediatric solid tumors.

Late Effects

Current strategies are successful with relatively few long-term effects of therapy. Rare late effects in survivors have included secondary malignant neoplasms, cardiac toxicity, pulmonary disease, and renal failure.

Mesoblastic Nephroma

The most likely diagnosis of a solid renal tumor in a neonate is congenital mesoblastic nephroma. Many cases are diagnosed with prenatal ultrasound and can manifest as polyhydramnios, hydrops, and premature delivery. Most of the patients are diagnosed before 3 mo of age. Wilms tumor is rarely diagnosed before 6 mo of age. Ninety-five percent of mesoblastic nephromas are benign. Radical nephrectomy is the treatment of choice and may be sufficient by itself. Although rare, malignant variants do occur, marked by metastases to the lung, liver, heart, and brain.

Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney (CCSK) is a rare pediatric tumor with around 20 cases per year diagnosed in North America. Peak incidence is between 1 and 4 years of age, usually presenting as an abdominal mass. CCSK has a high metastatic potential with predilection to involve the bone. Therefore, it is important to get a bone scan in CCSK patients. Early stage disease has excellent prognosis, especially with the addition of doxorubicin.

Rhabdoid Tumor of the Kidney

Malignant rhabdoid tumor of the kidney (RTK) has rhabdomyoblast-like morphology. It is a rare but aggressive cancer. Hematuria is a common presenting feature. Both rhabdoid tumor of the kidney and CNS atypical teratoid rhabdoid tumors (ATRT) have deletions and mutations of the hSNF5/INI1 gene and are considered to be related. Prognosis is poor with current therapeutic protocols.

Renal Cell Carcinoma

Renal call carcinoma (RCC) is rare in children, accounting for <5% of all renal tumors of childhood. Patients may present with frank hematuria, flank pain, and/or a palpable mass, although RCC can be asymptomatic and detected incidentally. It has propensity to metastasize to the lungs, bone, liver, and brain. RCC can be associated with von Hippel–Lindau disease. Unlike in adult RCC, local lymph node involvement is not a poor prognostic indicator in pediatric RCC. Nephrectomy alone may be adequate for early-stage RCC.