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Bast RC Jr, Kufe DW, Pollock RE, et al., editors. Holland-Frei Cancer Medicine. 5th edition. Hamilton (ON): BC Decker; 2000.

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Holland-Frei Cancer Medicine. 5th edition.

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Chapter 139BRenal Tumors of Childhood

, MD, , MD, , PhD, , MD, and , MB, BS.

Wilms’ tumor is the most common primary malignant renal tumor of childhood and the paradigm for multi-modal treatment of a pediatric malignant solid tumor. Developments in surgical techniques and postoperative care, recognition of the sensitivity of Wilms’ tumor to irradiation, and the availability of several active chemotherapeutic agents have led to a dramatic change in the prognosis for most patients with this once uniformly lethal malignancy.

Epidemiology

The annual incidence of Wilms’ tumor is 8.1 cases per million Caucasian children < 15 years of age.1 In 1991, Wilms’ tumor represented 5 to 6% of childhood cancers in the United States, where the total incidence was estimated at 460 cases per year.2 The incidence rate is higher for African Americans and lower for East Asians, relative to Caucasians.3

Wilms’ tumor in the United States is slightly less frequent in boys than in girls. The male-female ratio for those with a unilateral tumor is 0.92:1, and for those with bilateral tumors is 0.60:1.4 The tumor presents at an earlier age among males, with the mean age at diagnosis for those with unilateral tumors being 41.5 months and with bilateral tumors 29.5 months, compared with 46.9 months and 32.6 months, respectively, among females.4

Children with Wilms’ tumor may have associated anomalies, including aniridia, hemihypertrophy, cryptorchidism, and hypospadias.5,6 The constellation of Wilms’ tumor, aniridia, ambiguous genitalia, and mental retardation (WAGR syndrome) occurs in association with an interstitial deletion on chromosome 11 (del [11p 13]).7 Children with pseudohermaphroditism and/or renal disease (glomerulonephritis or nephrotic syndrome) who develop Wilms’ tumor may have the Denys-Drash or Frasier syndrome, which are associated with mutations in the WT1 gene at chromosome 11p13.8,9 Hemihypertrophy may occur as an isolated abnormality or as a component of Beckwith-Wiedemann syndrome (BWS), which includes macroglossia, omphalocele, visceromegaly, and a predisposition to embryonal tumors including Wilms’ tumor.10

The role of parental environmental exposures in the etiology of Wilms’ tumor is unknown. No consistent positive findings have emerged from a series of case-control studies.11–13

Molecular Biology and Genetics

Wilms’ tumor has become an important model for the study of fundamental mechanisms of tumorigenesis. Analysis of the epidemiologic and clinicopathologic features of Wilms’ tumor patients led National Wilms’ Tumor Study Group (NWTSG) investigators to suggest that some bilateral and multi-centric tumors may arise from somatic mosaicism rather than germline mutation14,15 in contrast to retinoblastoma. They also suggested that the disease comprises at least two pathogenic entities that are identifiable on the basis of distinct precursor lesions.16 The first evidence that a specific chromosomal locus was associated with Wilms’ tumor was the demonstration that patients with WAGR syndrome had a constitutional interstitial deletion encompassing chromosome 11 band p13.17 Subsequently, several laboratories reported that a third of sporadic Wilms’ tumors had undergone tumor-specific loss of heterozygosity (LOH) for DNA markers on 11p.18–21 The underlying tumor-suppressor gene, WT1, was isolated independently by three groups in 1990.22–24 WT1 appears to be a transcription factor that alters the expression of other genes, although its in vivo targets have not been conclusively identified.25,26 The normal function of WT1 is required for normal genitourinary development27 and is important for differentiation of the renal blastema.28 Constitutional mutations within the WT1 gene have now been identified in patients with Wilms’ tumor who have the rare Denys-Drash syndrome29 and in a few with bilateral Wilms’ tumor.30 However, mutations of WT1 have been found in only 10% or less of sporadic Wilms’ tumors.31

A second Wilms’ tumor locus (WT2) maps to chromosome 11p15.5, on the basis of tumor-specific LOH restricted to this region which does not include WT1.32,33 BWS also maps to this location,32 but it is not known whether a single gene or adjacent ones are involved in both the tumor and the syndrome.

It is now clear that WT2 is subject to genomic imprinting. There are several candidates for WT2, some of which are paternally imprinted (maternally active) and some maternally imprinted.34 LOH, which exclusively affects the maternal chromosome,33 has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes in this region has also been frequently observed and results in the same functional aberration.35,36

Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by LOH for these regions in 17% and 11% of Wilms’ tumors, respectively.37 The relevance of these alterations is underscored by the fact that in preliminary studies patients classified by tumor-specific loss of 16q had significantly worse relapse-free and overall survival rates.

Mutations of the p53 tumor-suppressor gene have also been reported in a few Wilms’ tumors.38 A striking association between p53 mutation and the anaplastic histology (86%), compared with favorable histology (0.8%), suggests that mutation of this gene may underlie the anaplastic phenotype.

Finally, linkage studies of rare, but large, Wilms’ tumor pedigrees have excluded linkage to 11p13 and 11p1539,40 and to 16q.41 Two familial loci have been identified by genetic linkage studies, FWT1 on chromosome 17q42 and FWT2 on chromosome 19q.43

In summary, the development of Wilms’ tumors may involve a number of genetic loci, although it is not clear how many are involved in each tumor. Rapid progress in uncovering both genetic and epigenetic (imprinting) alterations is facilitating a better understanding of the disease and may provide new tools for determining therapy.

Pathology

Aside from distortion of size and contour, there is little from the gross exam specific for Wilms’ tumor. Microscopically, all three cell types of the classic nephroblastoma are usually (but not necessarily) present: blastemal, shroud, and epithelial. The absence of anaplastic nuclear changes allows classification as “favorable histology”. Primordial tubules and glomeruli with associated supporting tissues can be recognized. 43a Anaplasia, which may be focal or diffuse is characterized by the presence of gigantic nuclei, which are polyploid. Their diameter is more than three times that of neighboring cells, and cells in mitosis are multipolar or obviously polyploid. Focal anaplasia is restricted to one region of the tumor. Diffuse anaplasia is considered to exist when anaplastic changes occur in two or more different sites of the tumor, or in any extrarenal site. Since anaplasia is reflected adversely in prognosis, meticulous documentation and photographs should be part of patholgic examination. 43a

Clear cell sarcoma of the kidney (CCSK) must enter the differential diagnosis, although not strictly a variant of Wilms’ tumor. this monomorphous neoplasm is more virulent, with a propensity for bone metastases, brain metastates, and early death. Although histologically quite distinctive, epithelial, myxoid and other variants can be confused with Wilms’ tumor. 43a

Rhabdoid tumor of the kidney (RTK) is another highly malignant tumor previously not distinguished from Wilms’ tumor. Its cells resemble myoblasts and their cytoplasm is prominently acidophilic. There are no ultra-structural features of skeletal muscle, however, and the cell of origin is unknown. Separate primary neuroectodermal tumors of the brain sometimes occur. 43a

Clinical Presentation

Most children with Wilms’ tumor come to medical attention because of abdominal swelling or because an abdominal mass is felt, often first by a family member. Abdominal pain, gross hematuria, hypertension, and fever are other frequent findings at diagnosis. Microscopic hematuria has been documented more often than gross hematuria (Table 139B.1).44

Table 139B.1. Presenting Signs and Symptoms of Wilms' Tumor.

Table 139B.1

Presenting Signs and Symptoms of Wilms' Tumor.

During the physical examination, it is important to note the location and size of the abdominal mass and its movement with respiration, to help differentiate Wilms’ tumor from splenomegaly or from neuroblastoma. A varicocele, particularly if persistent when supine, may be associated with the presence of a tumor thrombus in the renal vein or inferior vena cava. It is also important to note specifically any signs of Wilms’ tumor–associated syndromes marked by the presence of aniridia, partial or complete hemihypertrophy, and genitourinary abnormalities, such as hypospadias and cryptorchidism.

Preoperative Evaluation

The preoperative evaluation should include complete blood count and differential, liver and kidney function tests, serum calcium, urinalysis, and imaging studies. The main purpose of the imaging studies is to assist the physicians, primarily the surgeon, in planning management. They are therefore performed to (1) establish the presence of a renal tumor and a normally functioning contralateral kidney; (2) document the patency of the inferior vena cava; and (3) demonstrate the presence or absence of pulmonary metastases.

The initial study is often an abdominal ultrasound examination. Contrast-enhanced computed tomography (CT) of the abdomen will allow further evaluation of extension of the tumor into adjacent structures, such as the liver, spleen, or colon; however, the majority of children identified as having possible invasion of the liver on CT are found at surgical exploration to have hepatic compression rather than hepatic invasion.45 In addition, CT and ultrasonography (US) may demonstrate small lesions, which may be nephrogenic rests or Wilms’ tumor in the opposite kidney.46 It is important that the CT include a supine view of the abdomen following contrast injection because this view is necessary for planning and review of radiation therapy.

The patency of the inferior vena cava may be demonstrated relatively inexpensively using real-time US. When tumor is identified within that vessel, the proximal extent of the thrombus must be established prior to surgery because extension of the thrombus to the right atrium may not be suspected preoperatively, since there are few, if any, clinical signs.47 Sudden death has been reported at laparotomy following dislodgement and mobilization of tumor lying within the draining vessels.48

The results of the radiographic studies and real-time US provide sufficient information on which to make a decision for laparotomy in most children, although no imaging study unequivocally establishes the histologic diagnosis of Wilms’ tumor. A number of other neoplasms, benign and malignant, can mimic the clinical and radiographic findings of Wilms’ tumor. Data from the NWTSG show that 6.8% of children with suspected Wilms’ had other diagnoses,49 while the figure was 9.9% in an SIOP series.50 Neuroblastoma or benign renal cysts were the most common alternative diagnosis.

Plain chest radiographs should be obtained to determine whether pulmonary metastases are present. CT has been compared with conventional radiographic studies in Wilms’ tumor patients and is slightly more sensitive51,52 but identifies some lesions which are not metastases.53

A radionuclide bone scan and radiographic skeletal survey should be obtained postoperatively on all children with clear-cell sarcoma of the kidney (CCSK) and on all other children with pulmonary or hepatic metastases who have suggestive symptoms. Both studies are necessary because plain radiographs of the bones involved with CCSK can demonstrate lytic lesions that may not be seen on bone scan.54

Brain imaging by magnetic resonance imaging (MRI) or CT should be obtained on all children with CCSK or with malignant rhabdoid tumor of the kidney (RTK), since both are associated with intracranial metastases55,56 or second primary malignant brain tumors.57,58

Staging

The stage is determined by the results of the imaging studies and both the surgical and pathologic findings at nephrectomy. The staging system employed by the NWTSG is outlined below.

In stage I disease, the tumor is limited to the kidney and was completely resected. The renal capsule has an intact outer surface. The tumor was not ruptured or biopsied prior to removal (fine-needle aspiration biopsies are excluded from this restriction). The vessels of the renal sinus are not involved.

In stage II disease, the tumor extends beyond the kidney but was completely resected with no evidence of tumor at or beyond the margins of resection. The blood vessels outside the renal parenchyma, including those of the renal sinus, may contain tumor. The tumor may have been biopsied (except for fine-needle aspiration) or there was spillage of tumor before or during surgery that is confined to the flank and does not involve the peritoneal surface.

In stage III disease, residual tumor is present but confined to the abdomen: (1) Lymph nodes within the abdomen or pelvis are found to be involved by tumor. (2) The tumor has penetrated through the peritoneal surface. (3) Tumor implants are found on the peritoneal surface. (4) Gross or microscopic tumor remains postoperatively. (5) The tumor is not completely resectable because of local infiltration into vital structures. (6) Tumor spill not confined to the flank occurred either before or during surgery.

In stage IV disease, hematogenous metastases exist (e.g., lung, liver, bone, or brain), or lymph node metastases are present outside the abdominopelvic region.

In stage V disease, bilateral renal involvement is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease prior to biopsy.

Therapy

The treatment of children with renal tumors begins with the removal of the kidney and tumor and is determined by the stage and histology of the tumor. The histologic patterns of the renal tumors that occur in children include Wilms’ tumor with favorable histology, Wilms’ tumor with focal or diffuse anaplasia, CCSK, and RTK.59,60

Surgery

The transperitoneal approach to the tumor has become the standard procedure because it allows inspection of the regional lymph nodes, a very important criterion for staging.61,62 It also permits mobilization of the opposite kidney, which should be inspected on all surfaces for tumor or nephrogenic rests which may not be identified on preoperative imaging studies. Radical or modified radical nephrectomy is employed to remove the affected kidney. Heroic attempts to excise all or parts of adjoining organs that might be invaded are not warranted because such procedures are associated with an increased risk of surgical complications.63 Wedge resection of an infiltrated portion of the liver is advisable, however, if the lesion can be removed in toto, since this converts a stage III tumor to stage II.64

Attempts at primary surgical excision of the tumor with vena caval extension at or above the liver are associated with increased surgical morbidity.63 Preoperative chemotherapy should be administered to such patients,47 making the standard transabdominal approach subsequently feasible and avoiding thoracoabdominal incisions, cardiac bypass, and the other maneuvers necessary to extract the tumor from the heart.65 Preoperative chemotherapy may also be advisable in selected children but prevailing North American practice has been to perform an initial nephrectomy because treatments can best be modulated in their intensity according to accurate histopathologic and staging criteria, which are obscured when preoperative treatments are given.

Radiation Therapy

Radiation therapy is not required for children with stage I or II “favorable histology” Wilms’ tumor nor for stage I tumors with anaplasia. Abdominal radiation is used for stage III favorable histology, stage II and III anaplastic, and for stage IV favorable or anaplastic tumors, depending on the local stage of the primary. All CCSKs and RTKs at stages 1 to IV also require abdominal radiation. In any case, 1,080 cGy (180 cGy/d × 6) or 1,050 cGy (150 cGy/d × 7) is given, together with 1,080-cGy small-field supplements as required for areas of gross residual disease. Only the tumor bed and para-aortic lymph nodes are included in the treatment volume, if regional lymph node involvement is the only reason for designation as stage III. Larger fields are used for children with more extensive disease (e.g., the whole abdomen when massive tumor spillage has occurred). Pulmonary metastases are treated with 1,200 cGy (150 cGy/d × 8) to both lungs, regardless of the number and location of metastases. Bone lesions receive 3,060 cGy (180 cGy/d × 17) to the tumor plus a 3-cm margin. Brain metastases are given the same dose, but the whole brain is included. The liver is given 1,980 cGy (180 cGy/d × 11) except for anaplastic cases which are given 3,060 cGy (180 cGy × 17); local supplements of 540 to 1,080 cGy are permitted, depending on the amount of tumor and the volume of liver to be included.

Chemotherapy

Unilateral Favorable Histology

The standard chemotherapy regimens employed in NWTS-5 are detailed in Figs. 139B.1 and 139B.2. NWTS-4 demonstrated that the pulse-intensive regimens, which utilized single-dose dactinomycin and doxorubicin produce less hematologic toxicity than the previous standard regimens,66,67 can be administered at less cost68 and result in equivalent outcomes.69 NWTS-4 also demonstrated that approximately 6 months of chemotherapy resulted in equivalent outcomes as the previously standard 15 months of treatment.70

Figure 139B.1. Treatment regimens used on NWTS-5.

Figure 139B.1

Treatment regimens used on NWTS-5. A = Actinomycin D (1.35 mg/m2, max2.3 mg); V = Vincristine (1.5 mg/m2, max 2 mg); V* = Vincristine (2.0 mg/m2, max 2 mg); D = Doxorubicin (45 mg/m2); D* = Doxorubicin (30 mg/m2); C = Cyclophosphamide (440 mg/m2 /day (more...)

Figure 139B.2. Treatment algorithms by tumor histology and stage used on NWTS-5.

Figure 139B.2

Treatment algorithms by tumor histology and stage used on NWTS-5. IV* = stage IV patients receive abdominal RT, depending on the local stage of the abdominal primary.

Anaplastic Histology

Children with stage I focal or diffuse anaplasia receive the same chemotherapy regimen, EE4A, as those with stage I favorable histology disease. NWTS-3 and -4 demonstrated that the addition of cyclophosphamide to the DD regimen resulted in significantly better relapse-free and overall survival for diffuse, but not focal, anaplastic tumors.71 Thus, although tumors with focal anaplasia may be treated with regimen DD4A (see Figure 139B.2), the therapy for diffusely anaplastic tumors should include cyclophosphamide. In NWTS-5, this group is being treated on an experimental regimen (I) to determine whether the substitution of etoposide for dactinomycin and an increase in the dose intensity of cyclophosphamide result in further improvement in outcome for this group of patients.

Clear-Cell Sarcoma of the Kidney

The prognosis of children with CCSK in NWTS-3 was not improved by the addition of cyclophosphamide, in the dose and schedule employed in NWTS-3.72 In NWTS-5, this group will receive an experimental regimen (I) identical to that for tumors with diffuse anaplastic histology (see Figure 139B.2).

Rhabdoid Tumor of the Kidney

The outcome for children with RTK treated according to the regimens evaluated in NWTS-1, -2, and -3,56 utilizing treatment with vincristine, dactinomycin, and doxorubicin, has been very poor.72 The available histologic and histochemical data suggest that this tumor may be of neurogenic origin.56,73,74 Since agents such as cyclophosphamide, etoposide, and cisplatin have been employed for the treatment of infants and young children with primitive neurogenic tumors, a modification of this regimen (RTK) will be evaluated in NWTS-5 to provide phase II response data (see Fig. 139B.2).

Bilateral Wilms’ Tumor

Approximately 7% of children with Wilms’ tumor present with simultaneous bilateral tumors. Most children with bilateral Wilms’ tumor are not diagnosed on the basis of the physical examination, and approximately 10% of those found at laparotomy to have bilateral renal disease are not even identified using CT,46 emphasizing the importance of contralateral renal exploration at the time of laparotomy.

The treatment of children with bilateral Wilms’ tumor must be individualized. The goal of therapy is to eradicate all tumor and to preserve as much normal renal tissue as possible, with the hope of decreasing the risk of chronic renal failure among these children.75 The approach presently recommended is initial bilateral renal biopsy with staging of each kidney. Initial treatment is with regimen EE4A (see Fig. 139B.2), if the renal tumors are of favorable histology and not more extensive than stage II. Those with more extensive favorable histology disease would receive doxorubicin in addition (regimen DD4A), and those with anaplastic histology would also receive cyclophosphamide (regimen I). A re-evaluation is performed at about week 6 to determine whether there has been sufficient response of the tumors to allow tumor resection with preservation of a substantial amount of normal renal tissue. Additional chemotherapeutic agents, such as doxorubicin, with or without radiation therapy, may be necessary for the management of children whose tumors respond poorly to the combination of vincristine and dactinomycin.

Inoperable Wilms’ Tumor

There are occasional patients with massive tumors and/or intravascular extension that are judged to pose too great a risk for surgical removal.63 Past experience in the NWTSG and the studies conducted by the International Society of Pediatric Oncology (SIOP)76 have shown that pretreatment with chemotherapy almost always reduces the bulk of the tumor and renders it resectable, thus reducing the frequency of surgical complications.47 However, this method does not result in improved survival rates and does result in the loss of important staging information.77

Nearly all such patients should undergo initial exploration to establish the diagnosis by biopsy and to assess operability. If suspicious lymph nodes or other metastatic deposits are found, these should be biopsied to document tumor involvement since patients who are staged by imaging studies alone are at risk of being both under- and overstaged. If one chooses to give preoperative therapy for inoperable tumors on the basis of needle biopsy alone, the treatment should be as for a stage III tumor of favorable or anaplastic histology (see Fig. 139B.2).

Definitive resection should be completed once there is an adequate reduction in the size of the tumor to facilitate nephrectomy, usually at week 6. Failure of the tumor to shrink could be due to predominance of skeletal muscle or benign elements, and a second-look procedure to confirm persistent tumor may be necessary.78 Patients who fail to respond can be considered for preoperative irradiation (180 cGy × 7), as this may produce enough shrinkage to permit nephrectomy.

Following surgical resection, patients should continue on treatment until they have completed regimen DD-4A or regimen I. Postoperative radiation therapy is given to all such patients who did not receive preoperative radiation therapy. This recommendation is based on the results of the SIOP-6 nephroblastoma trial, where a significantly higher infradiaphragmatic relapse rate was reported in nonirradiated children given preoperative chemotherapy.76

Treatment of Recurrent Disease

Children with relapsed favorable histology Wilms’ tumor have a variable prognosis, depending on the site of relapse, the time from initial diagnosis to relapse, and their previous therapy. Favorable prognostic factors include no prior treatment with doxorubicin, relapse more than 12 months after diagnosis, and intra-abdominal relapse in a patient not previously treated with abdominal irradiation.79

Children in this more favorable group should be treated aggressively because they generally have a good response to retrieval therapy. Although surgical excision of pulmonary metastases does not improve outcome,80 surgical biopsy or excision should be performed to histologically confirm recurrent disease and, particularly in the case of intra-abdominal recurrence, reducing the tumor burden prior to the initiation of radiation therapy and combination chemotherapy.

The optimal chemotherapy regimen has not been defined but should include doxorubicin, if not used previously. The combination of etoposide and carboplatin81 is active against recurrent Wilms’ tumor with favorable histology and, although studied in few cases, probably with diffuse anaplasia and in CCSK. There are insufficient studies of this combination in patients with RTK.

The combination of etoposide and ifosfamide is also highly active in favorable histology Wilms’ tumor and CCSK82,83 although the nephrotoxicity of ifosfamide in children with Wilms’ tumor discourages its use in previously untreated children.83,84 The substitution of cyclophosphamide, using a dose intensity similar to that employed in the phase II trial of ifosfamide and etoposide, may also be effective85 and is currently under study in NWTS-5.

Patients who relapse after prior treatment with a regimen that included doxorubicin or who develop a recurrence in the abdomen (including liver) after previous irradiation have a poor prognosis. It has been suggested that high-dose chemotherapy with stem cell rescue should be employed in the management of those patients with adverse prognostic factors at the time of relapse,86,87 although the relative efficacy of this approach remains unproven. In general, these children should be referred to centers that are conducting research in the treatment of children with recurrent solid tumors.

Prognostic Factors

The distinction between favorable and anaplastic histology Wilms’ tumor has been identified as the most important determinant of prognosis. Recent analyses have also confirmed the importance of lymph node involvement, while the prognostic significance of previously identified factors, such as age and tumor size, has lessened as treatment efficacy has improved.88

The results of the NWTS-4 trials predict that the 4-year relapse-free and overall survival percentages that can be expected with use of the regimens, outlined in Fig. 139B.1, are (1) stage I favorable histology Wilms’ tumor, 92% and 98%; (2) stage II favorable histology Wilms’ tumor, 85% and 96%; (3) stage III favorable histology Wilms’ tumor, 90% and 95%; and (4) stage IV favorable histology Wilms’ tumor, 80% and 90%.69,70 Regimens for other histologies are new in NWTS-5, but using NWTS-3 and -4 regimens, the 4-year relapse-free and overall survival were (1) stages II to IV diffuse anaplasia, 82.5% and 81.8%; (2) stages I to IV CCSK, 70.6% and 74.8%; and (3) stages I to IV RTK, 23.1% and 25.4%.72,71

Present research is focused on identification of additional prognostic factors that could be employed for further stratification of therapy according to the risk of recurrence. Our findings that loss of heterozygosity for 16q, present in 17% Wilms’ tumors, and for chromosome 1p, present in 11%, may be associated with adverse outcome37 are being tested in NWTS-5.

Acknowledgment

The authors thank the investigators of the Pediatric Oncology Group and the Children’s Cancer Group and the many pathologists, surgeons, pediatricians, radiation oncologists, and other health professionals, who managed the children entered on the National Wilms’ Tumor Studies, and Gina Kennedy for preparation of the manuscript.

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