Wilms’ Tumor

Wilms’ tumor accounts for the majority (85%) of pediatric renal tumors with 500 new cases per year in the United States (Figure 59-1). The more aggressive anaplastic histologic subtype of Wilms’ makes up about 8% of all pediatric renal tumors. The mean age at presentation is 3 to 4 years for unilateral disease, and the majority of patients are younger than 10 years old at diagnosis. Patients with bilateral disease account for 5% of all Wilms’ cases and present younger than those for unilateral disease at 2 to 2.5 years of age.

Figure 59-1 Nephroblastoma (Wilms’ tumor).

Wilms’ tumor is an embryonic solid tumor derived from undifferentiated nephroblasts in the kidney. Thus, the persistence of embryonic renal tissue (nephrogenic rests) is often seen in kidneys resected for Wilms’ tumor. The presence of multiple, diffuse nephrogenic rests is known as nephroblastomatosis, a premalignant condition prone to transforming into Wilms’ tumor. Not all nephrogenic rests transform into Wilms’ tumor; they may also regress or differentiate into mature kidney tissue. Therefore, children with diffuse nephroblastomatosis or a genetic predisposition for Wilms’ are at highest risk of nephrogenic rests progressing to malignant Wilms’ tumor.

Certain genetic syndromes are associated with the development of Wilms’ tumor. Examples include overgrowth syndromes such as Beckwith-Wiedemann (organomegaly, neonatal hypoglycemia, macroglossia, and omphalocele; also associated with hepatoblastoma) and Perlman’s (distinct facial features, macrosomia, genitourinary abnormalities and polyhydramnios), Denys-Drash (genital anomalies and nephropathy), and WAGR (Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation) syndromes. These patients have germline genetic abnormalities, specifically at chromosome 11, that alter the genes responsible for growth and renal genesis.

The 11p locus has been shown to play an important role in Wilms’ tumor pathogenesis. The WT1 gene, thought to be a tumor suppressor gene, is located at 11p13. Deletions of this region are associated with WAGR syndrome, and mutations of this gene are associated with Denys-Drash syndrome. Loss of heterozygosity or loss of imprinting at the WT2 gene, located at chromosome 11p15, has also been identified in patients with overgrowth syndromes such as Beckwith-Wiedemann and Perlman syndromes.

Specific genetic abnormalities that are exclusive to the tumor alone seem to be associated with a more aggressive form of Wilms’ tumor. The combined loss of heterozygosity of chromosomes 16q and 1p in Wilms’ tumors has been associated with a poorer prognosis in lower stage tumors. More recently, an X chromosome gene mutation, WTX, seen in one-third of sporadic Wilms’ tumors, has been described.

Although most Wilms’ tumors fall into the category of favorable histology, a subset of tumors can be categorized as diffusely “anaplastic,” having irregular mitoses and hyperchromatic cells with large nuclei throughout, which carries a poorer prognosis. No specific genetic abnormalities have been determined thus far for this aggressive subtype of Wilms’ tumor.

Rare Renal Tumors

Clear cell sarcoma of the kidney (CCSK) is the second most common malignant kidney tumor of childhood and accounts for about 2% to 4% of primary pediatric renal tumors. The majority of patients are younger than 5 years old at the time of diagnosis, and classic pathology shows nests of cells separated by septae. The majority of tumors also demonstrate variant patterns, which may resemble Wilms’ tumor and make it difficult to differentiate CCSK from other renal tumors.

Rhabdoid tumor of the kidney (RTK) is a very aggressive renal tumor that is most often detected in infants but is not exclusive to infancy. RTK, like its central nervous system homologue, atypical teratoid rhabdoid tumor (ATRT) of the brain, carries a specific deletion of the INI1 gene located at 22q11-2 that is a germline mutation in 20% of cases and can be used to confirm the diagnosis.

Renal cell carcinoma (RCC) is the most common form of adult renal cancer; however, pediatric RCC accounts for only 1% of all RCC and 5% to 6% of all pediatric renal tumors. Pediatric RCC seem to have a distinct tumor from adult RCC, with a genetic translocation involving chromosome Xp11. Interestingly, RCC has been described in a number of patients with a history of neuroblastoma. Renal medullary carcinoma (RMC), a subset of RCC, is extremely rare and is seen almost exclusively in young adolescent patients with sickle cell trait; the etiology and rationale for the association is unclear. Patients with RMC generally present in the second to third decade of life with advanced disease and have a very poor prognosis.

Cystic nephroma, on the other hand, is a rare and benign tumor of the kidney that is associated with a very favorable prognosis after surgical resection alone.

A kidney tumor noted on prenatal ultrasonography or in the first 6 months of life is almost always a congenital mesoblastic nephroma (CMN). CMN occurs in one in 27,500 live births and is the most common benign renal tumor of infancy. Because of the differential diagnosis of an infant renal tumor including malignant Wilms’ tumor and RTK, a nephrectomy is often performed to diagnose the lesion. The cellular variant of CMN is more aggressive with a 20% chance of local recurrence and shares the t(12;15)(p13;q26) gene fusion product ETV6-NTRK3 that is also found in infantile fibrosarcoma.

Wilms’ Tumor

Patients with Wilms’ tumor are often well appearing and asymptomatic and present only with a palpable abdominal mass. Often, patients come to medical attention after a caretaker feels an abdominal mass while bathing the toddler or a health care provider detects an abdominal mass on routine physical examination. Hypertension and hematuria may also be present because of tumor mass effects on the renal vessels. The most common site for metastatic disease is the lungs, which is often asymptomatic. Metastases may also involve regional or distant lymph nodes, liver, and rarely brain or bone. Patients with a propensity for bilateral disease may have synchronous tumors at the time of diagnosis or may present with unilateral disease and develop a contralateral tumor at a later time point (metachronous disease).

Rare Renal Tumors

Wilms’ Tumor

In addition to the dedicated renal imaging as described above, diagnostic evaluation for Wilms’ tumor should include a CT scan of the chest to rule out metastasis.

Treatment for Wilms’ tumor depends on the tumor stage and histology. The clinical stage of a Wilms’ tumor is based on the amount of residual disease left behind after the diagnostic surgery (most often nephrectomy), whether lymph nodes are involved, and the absence or presence of metastatic disease. Surgery and chemotherapy are always part of the treatment, and patients may receive radiation to the abdomen and lungs based on the stage of the disease. Patients who have low-stage (I or II) favorable histology tumors are treated with nephrectomy followed by chemotherapy with vincristine and dactinomycin. Those with higher stage III (gross residual disease or nodal involvement) or IV (metastatic) disease receive the same surgery and chemotherapy as lower stage patients with the addition of doxorubicin and local abdominal (stage III) or metastatic site radiation. Based on data from International Society of Pediatric Oncology clinical trials for Wilms’ tumor, newer study protocols are sparing lung radiation in stage IV patients whose lung metastases clear with 6 weeks of induction chemotherapy.

Anaplastic Wilms’ tumor is associated with greater chemotherapy resistance, and despite the stage, it is more difficult to cure than the more common favorable histology variant. After upfront nephrectomy, chemotherapy for patients with anaplastic Wilms’ tumor includes vincristine, cyclophosphamide, doxorubicin, and etoposide. Despite receiving more intensive chemotherapy as well as abdominal radiation, survival for patients with this variant remains poor.

Treatment for bilateral Wilms’ tumor differs from that of unilateral disease because bilateral nephrectomy is not a treatment option. Furthermore, patients with certain genetic syndromes who have unilateral disease are predisposed to renal failure genetically or from their potential to develop metachronous Wilms’ tumors in the unaffected kidney. Therefore, the focus of management for this subset of patients is to preserve as much normal kidney tissue while still curing the patient of the cancer with local surgical resection, called nephron-sparing surgery. Most often, a urologist will perform this procedure because it requires intimate knowledge of renal anatomy. The goal is to obtain tumor-free margins while preserving renal parenchyma and function. Chemotherapy for patients with bilateral disease is based on the staging of the most involved kidney and is often given preoperatively to shrink the tumors to ensure adequate margins and maximal sparing of normal kidney tissue. Other patients for whom preoperative chemotherapy is recommended include patients with a solitary kidney; vascular extension of tumor into the inferior vena cava; and those with very large, unresectable tumors at diagnosis. Preoperative chemotherapy is a common therapeutic approach in Europe but remains controversial in American oncology study groups because patients are upstaged to receive abdominal radiation and doxorubicin if the tumor is not taken out before the initiation of chemotherapy.

Management of patients with Wilms’ tumor predisposition syndromes or nephroblastomatosis is unique as well, both before and after development of a tumor. Screening for renal tumors in this unique group should begin early and continue until 7 to 8 years of age because this is the time period during which they are most likely to develop a tumor. Recommended screening includes renal ultrasonography every 3 months followed by CT scan if a mass is detected. Historically, there has been no standard therapy for these patients. Treatment with chemotherapy and nephron-sparing surgery when nephroblastomatosis is detected in the unaffected kidney has been described at a number of centers.

The prognosis for Wilms’ tumor is excellent with overall survival greater than 90% for patients with non-metastatic, favorable histology disease. National Wilms’ Tumor Study Group data also show that patients with stage IV (metastatic) favorable histology Wilms’ tumor or favorable histology bilateral disease have a 10-year overall survival rate between 70 and 80%.

Rare Renal Tumors