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.
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
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.
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.
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.
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.
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.
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.
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
Tumor limited to the kidney and completely resected
Intact renal capsule
No previous rupture or biopsy
Renal sinus vessels not involved
No evidence of tumor at or beyond margins of resection
Tumor completely resected
No evidence of tumor at or beyond the margins or resection1
Tumor extends beyond the kidney, as evidenced by one of the following:
Regional extension of the tumor (penetration through the renal capsule, or extensive invasion of the soft tissue of the renal sinus)
Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor
Residual nonhematogenous tumor confined to the abdomen is present after surgery, as evidenced by meeting any of the following criteria:
Lymph nodes within the abdomen or pelvis are involved with tumor (lymph node involvement in other extra-abdominal sites is criterion for Stage IV)
Tumor has penetrated through the peritoneal surface
Tumor implants are present on the peritoneal surface
Gross or microscopic tumor remains, postoperatively, including tumor present at the margin of the surgical resection
Tumor not completely resectable because of local infiltration into vital structures
Biopsy (of any type, including fine needle) of tumor prior to removal of kidney
Tumor treated with preoperative chemotherapy (with or without biopsy) prior to removal
Tumor spillage (of any degree or localization) occurring before or during surgery
Tumor is removed in greater than one piece
Hematogenous metastases (lung, liver, bone, brain, etc)
Lymph node metastases outside the abdominopelvic region1
Bilateral renal involvement at diagnosis2
From Perlman EJ. Pediatric renal tumors: practical updates for the pathologist. Pediatr Dev Pathol. 2005;8:320-338.
Surgical removal of primary tumor is the basis of cure in renal tumors. In WT, two schools of thought exist on the timing of primary nephrectomy. In North America, upfront nephrectomy is almost universally practiced, unless tumor is deemed inoperable at presentation. Advantages of this approach, advocated by NWTS and COG, include immediate removal of primary tumor burden and opportunity for complete initial pathologic and surgical staging. SIOP trials are based on preoperative chemotherapy, with nephrectomy done after 6 to 12 weeks of chemotherapy. Advantages include easier surgical resection if tumor has decreased in size with chemotherapy. Disadvantages include the risk of initiation of therapy without a confirmed pathologic diagnosis (and an accepted misdiagnosis rate of up to 5%)29,30 and loss of upfront biologic studies on tumor tissue.
Table 456-2. Revised Societe Internationale d’Oncologie Pediatrique (International Society of Pediatric Oncology, SIOP) Staging Criteria for Pediatric Renal Tumors
A number of chemotherapy drugs are known to be active in renal tumors. The NWTS and SIOP studies (as well as other cooperative studies) have refined regimens of combination chemotherapy appropriate to stage and histology. Those with lower-stage disease and more benign histology receive fewer agents for a shorter duration of time. Current COG studies are also using the biologic information of the presence of absence of LOH of 1p and 16q to assign therapy. Table 456-3 outlines current chemotherapy regimens for FH WT being studied in the first COG renal trials. As the overall cure rate of anaplastic Wilms tumors, rhabdoid tumors, and clear cell sarcoma are still unacceptably low, intensification of therapy with higher dosages and addition of different chemotherapy agents are being studied in those tumors.
Radiation therapy has been shown to be very effective against Wilms tumor (WT). This efficacy is balanced against the known risks of the acute and long-term toxicities of radiation therapy. Radiation therapy is reserved for higher-stage FH WT or anaplastic WT. The role of radiotherapy for patients with FH WT with pulmonary metastases is being investigated in the first COG trial for Higher Risk FH WT Patients. Patients with complete resolution of their pulmonary lesions after 6 weeks of chemotherapy will not receive radiation therapy but slow responders will. Current SIOP trials avoid the use of radiotherapy in FH WT patients with pulmonary disease with acceptable event-free survival (EFS), using doxorubicin-containing chemotherapy regimens.
A special subset of patients are those who present with bilateral tumors (approximately 7% of all WT patients) or whom are at known risk of developing bilateral tumors (those with certain associated syndromes) . In these patients, up-front surgery is avoided and partial nephrectomies are often performed in an effort to balance therapy with preservation of renal function. For this reason also, radiation therapy is avoided when possible in patients with bilateral disease.
Table 456-3. Children’s Oncology Group (COG) Treatment of Favorable Histology Wilms Tumor by Risk Stratification
COMPLICATIONS AND LATE EFFECTS
Almost all patients with a history of Wilms tumor (WT) will have a single kidney, or, in the case of patients with a history of bilateral WT, significant reduction in functioning renal tissue bilaterally. Therefore, precautions and follow-up appropriate to any child with a single kidney should be put in place. Consideration of restriction of activities with a high likelihood of damage to the remaining kidney is recommended. Blood pressure should be monitored at least yearly, and careful attention should be given to any evidence of hypertension.
Prognosis is dependent on histology and stage of tumor. Although overall survival of patients with pediatric renal tumors approaches 90%,32 patients with low-stage and FH WT are most likely to do well. The best prognosis is seen in patients with FH WT < 2 years of age with tumors < 550 grams. Ana-plastic histology confers a worse prognosis than FH WT, lymph node metastatic, renal capsular invasion, or renal vessel invasion; loss of heterozygosity of 1p and 16q all confer worse prognosis. Prognosis of survival after relapse is better for patients who did not receive either doxorubicin or radiation therapy for their initial tumor, relapsed distantly, and relapsed greater than 1 year after completion of therapy.33-35
PREVENTION AND CONTROL
Even in the absence of any physical findings, patients who have been identified as having genetic predisposition syndromes such as WAGR or BWS should undergo routine imaging because of their known risk of developing WT. A schedule of ultrasound every 3 to 4 months from birth to age 5 has been suggested for patients with WAGR, and up to age 7 or 8 in patients with associated overgrowth syndromes.36,37 Prophylactic nephrectomy in patients with Denys-Drasch has been suggested but is not universally recommended.
Although much has been learned about the genetics of Wilms tumor (WT), the underlying gene defect in the majority of WT has not been found. Active research in gene expression and expression profiling is underway, with the hope of using these techniques to further stratify patients. Such techniques may be useful in either identifying the patients who may do well with even less therapy than currently considered standard, and identifying those patients who, despite meeting all criteria to classify as standard or low risk, do not respond to current standard therapy.
The cure rates for anaplastic WT, rhabdoid tumor of the kidney, clear cell sarcoma, and some renal cell carcinoma remain unacceptably low. The study of both intensified chemotherapy regimens, and use of novel agents, including biologics, is underway for these patients.