Renal Tumors
Elizabeth Mullen
Approximately 550 children and adolescents are diagnosed with renal tumors in the United States each year. The vast majority of these (about 500 cases yearly) are nephroblastomas, also known as Wilms tumors (WT). Other types of renal tumors of childhood include rhabdoid tumor of the kidney (RTK), clear cell sarcoma (CCS), renal cell carcinoma (RCC), and congenital mesoblastic nephroma (CMN). Wilms tumors account for 95% of renal tumors of childhood, whereas adolescents over 15 years of age are more likely to be diagnosed with RCC than WT. A renal mass in an infant less than 3 months of age is likely to be a congenital mesoblastic nephroma. The overall incidence of each of these other renal tumors of childhood (CCS, RTK, CMN) is quite low. This chapter will focus primarily on WT as the major renal tumor of childhood. 
EPIDEMIOLOGY, ASSOCIATED SYNDROMES, AND POPULATIONS AT RISK
Pediatric renal tumors represent approximately 7% of all childhood cancers; 95% of these are Wilms tumors (WT).1 SEER data identify the peak of incidence of WT as the first 2 years of life, with steadily declining rates with increasing age after that time.2 The majority of WT occur prior to 5 years of age, and WT is very rare in children over 10 years of age. Bilateral tumors tend to present at younger age. Although SEER data from 1975 to 1995 overall showed a slight increased incidence in females and blacks, the more recent period within that of 1990 to 1995 shows no difference in race or sex. A lower incidence in Asian children has been observed both in North America and Europe.3,4
WT has been shown to occur with increased frequency in children with a number of well-described syndromes. These include WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and mental retardation), Denys-Drash, Frasier, Beckwith-Wiedermann, Simpson-Golabi-Behmel, Sotos, and Perlman.5,6 The frequency at which WT occurs in these syndromes ranges from 5% to 90%. A greater incidence of bilateral WT is observed in children with associated syndromes, and age of presentation is overall younger. Several, but not all, of the syndromes are classified as overgrowth syndromes, where macrosomia and often organomegaly are prominent features. A clear association of hemihypertrophy and WT is also seen. 
PATHOPHYSIOLOGY
The ontogeny of Wilms tumor (WT) is tightly interlaced with normal kidney development. In 1899, Max Wilms established the now classic description of WT as a mixed tumor, with his meticulous histologic description of the 3 defining components: epithelium, blastema, and stroma.7 He also contributed the important insight that the tumor developed from a common and macroscopically undifferentiated germ cell. The classic triphasic morphology of WT reflects phases of normal nephrogenesis, with the blastemal component resembling condensing nephrogenic mesenchyme and the epithelial portion resembling glomeruli. This link helps explain the correlation between WT and renal abnormalities, as well as the presence of persistent embryonic renal tissue (termed nephrogenic rests) in patients at risk for WT. The study of the genetics and biology of WT overlaps with investigation into normal renal organogenesis and has provided much insight into connections of tumorigenesis and normal development.6
GENETICS
The association of Wilms tumor (WT) and several known genetic syndromes has spurred much productive research into the genetics of WT. WT was one of the original tumors employed by Knudsen to develop the “two-hit hypothesis” of oncogenic transformation.8 He postulated that the development of WT required two independent, rate-limiting genetic events. Genetically susceptible children would carry a primary germline mutation, either inherited, or de novo. Tumorigenesis would occur when a second “hit” occurred. The young age of presentation of patients with WT, and the even younger age of presentation of children with bilateral WT and associated syndromes supported his hypothesis. The Knudson model has been confirmed by additional studies in a number of other tumors, which also demonstrate that the genetic loss of 2 alleles of a tumor suppressor gene can result in oncogenesis.
Years of additional study have revealed deeper complexity in the story of WT genetics. WT1 was the first gene mutation found in WT and was confirmed to be a tumor suppressor gene. WT1, found at 11p13, has been cloned and found to be a transcription factor of the zinc finger family.9 WT1 also has been found to serve an essential role in renal development in mice10 and is highly expressed in the developing kidney, gonads, spleen, and mesothelium. Variable WT1 mutations occur consistently in several of the WT-associated syndromes, notably in WAGR, Denys-Drash, and Frasier syndromes.11,12 WT1 mutations, however, are found in only 10% of sporadic tumors.
A second WT gene has been long postulated to occur at 11p15.13 Beckwith-Wiedermann syndrome maps to this location, and loss of heterozygosity (LOH) occurs at 11p15 in some cases of sporadic WT as well. Despite the promise of this region, no specific WT gene has yet been found at this location. A number of imprinted genes have been identified in this region, including IGF2, H19, and p57kip2. Fifteen percent of Wilms tumors have mutations in the B-catenin gene. 
It is an X chromosome gene and, therefore, can be inactivated by a single hit. The function of WTX is yet unknown, but high levels of expression have been identified in the developing lungs, brain, kidney, and spleen of mice.
LOH of 1p and of 16q have been observed in WT. NWTS-5 prospectively analyzed incidence and clinical outcome of patients with these areas of LOH. LOH of 1p and 16q was found to occur together in about 5% of favorable histology WT and was correlated significantly with increased risk of relapse and death.17 This biologic marker is being used in the first Children’s Oncology Group (COG) renal protocols to stratify treatment for patients with WT. 
CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
The classic presentation of a child with Wilms tumor (WT) is the sudden discovery of a large abdominal mass by a parent while bathing or dressing the child. Children can also present with symptoms of constipation, including pain and distension. Hematuria, hypertension, and anemia are also occasional presenting symptoms. Rarely, spontaneous rupture of WT can occur and can result in presentation with sudden pain and severe anemia due to bleeding in and around the tumor. 
DIAGNOSTIC EVALUATION
History and Physical Exam
Patients with a suspected renal mass should be asked a thorough history, including any family history of cancer predisposition, congenital anomalies or urogenital defects, as well as birth and developmental history of the child. A physical exam should include notation of hypertension, any anomalous features, and careful plotting on a growth chart. Typical physical exam finding is of a palpable, firm, nontender, smooth abdominal mass that rarely crosses the midline, and usually does not move with respiration, helping to differentiate from splenomegaly or neuroblastoma.
Imaging
All patients with suspected renal tumors should undergo radiologic imaging. Abdominal radiographs can be obtained quickly and can often identify the presence of a mass. Calcifications, seen in some cases of neuroblastoma and germ cell tumor, can also be seen on plain films. Once the presence of a mass is confirmed, ultrasound (US) can be used for further characterization. Cystic lesions are very well defined by US, as is vascular involvement. Thorough examination of the renal vasculature and inferior vena cava (IVC) is important for the identification of presence and extent of intravascular tumor thrombus. The contralateral kidney can be examined for presence and function, evidence of bilateral tumor, or nephrogenic rests. 
Identification of a solid mass by ultrasound prompts further imaging by computerized tomography (CT). Both abdomen and lungs should be imaged by CT if a malignant process is suspected. Studies of pulmonary lesions in Wilms tumor (WT) that are not seen on chest x-ray, but are seen on CT (known as CT-only lung mets) have demonstrated the clinical importance of identifying these lesions. 
Magnetic resonance imaging (MRI) has been established as useful in some patients with WT.23 MRI can be critical in defining vascular involvement, particularly the level of involvement of tumor thrombus within the inferior vena cava. MRI is also being employed in patients with bilateral nephrogenic rests and WT. 
Laboratory Evaluation
Patients with a suspected renal mass should have a complete blood count and differential, a full electrolyte panel, kidney function testing (blood urea nitrogen and creatinine)25,26 and liver function tests. WT has been associated with acquired von Willebrand disease, and coagulation studies as well as a type and cross should be done prior to any planned surgical procedure. Urinalysis may reveal hematuria. Urine catecholamines will be negative in WT and positive in neuroblastoma, which can present similarly.
Histology
The classic description of Wilms tumor (WT) is of triphasic morphology, including blastemal, stromal, and epithelial elements, tremendous histologic diversity can be seen in these tumors. A variety of cell types and aggregation patterns that are seen in normal developing kidney can be found in WT samples, as well as tissues not normally present in the kidney, such as skeletal muscle, cartilage, and squamous epithelium. It is believed that these varied cell types may arise through the developmental potential of the primitive metanephric blastema. 
Grossly, tumors are often described as friable. Areas of tumor within the kidney are visualized as well-circumscribed or lobular masses, gray or variegated pink in color. Multiple nodules of variable size can often be found. Cystic changes, necrosis, and hemorrhage are commonly seen. 
WT is defined as favorable histology (FH) if no areas meeting the criteria of anaplasia are identified. Anaplasia can be focal or diffuse and is heralded by the presence of gigantic (> 3 × diameter of adjacent cells) hyperchromatic nuclei and polypoid or bizarre mitotic figures. 
STAGING
Different staging systems have been employed by NWTS (National Wilms Tumor Study) and SIOP (International Society of Pediatric Oncology), as the staging relates to timing of primary surgery. NWTS staging has been based on stage prior to chemotherapy.28 SIOP employs a staging system based on examination of the tumor after preoperative chemotherapy. COG has continued the use of the NWTS-5 staging system, with a few modifications based on the results of that trial. 
CT-only pulmonary lesions will be classified as Stage IV disease. Tables 456-1 and 456-2 describe the staging systems currently in use by COG and SIOP.
TREATMENT
Surgery, chemotherapy, and radiation therapy are all components of the multimodality therapy that has led to much improved cure rates for Wilms tumor (WT), as well as other renal tumors.
A subset of patients deemed very low risk (Stage I FHWT, age < 2 years, tumor weight < 550 gms) may have a good overall survival with surgery alone. All other patients with WT also receive adjuvant or neoadjuvant chemotherapy, with radiation therapy reserved for higher-risk patients.
Table 456-1. Children’s Oncology Group (COG) Staging of Pediatric Renal Tumors
