Journal of Pediatric Urology (2009) 5, 56e65

EDUCATIONAL ARTICLE

Current management of Wilms tumor in children

Edmund Y. Ko, Michael L. Ritchey*
Mayo Clinic College of Medicine, Phoenix, AZ, USA Received 3 August 2008; accepted 18 August 2008 Available online 9 October 2008

KEYWORDS
Nephroblastoma; Wilms tumor; Chemotherapy

Abstract Purpose: Wilms tumor is the most common renal tumor in children. Outcomes have improved dramatically over the past few decades, but important treatment questions remain. These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current treatment of Wilms tumor. Materials and methods: The medical literature and results of all cooperative group studies reporting treatment of children with Wilms tumor were reviewed. Results: Overall survival exceeds 90% for most patients with nephroblastoma. However, outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral tumors it continues to be dened. Conclusions: Current protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and mortality rates. 2008 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Wilms tumor (WT) or nephroblastoma is the most common primary malignant renal tumor in children. More than 90% of children are now expected to have an excellent outcome with current treatment modalities. Contemporary issues involve stratifying children to reduce morbidity and overtreatment of low-risk patients, and providing intensive treatment for high-risk patients for whom survival remains
* Corresponding author. 1920 E. Cambridge Avenue, Phoenix, AZ 85006, USA. Tel.: 1 602 279 1697; fax: 1 602 264 0461. E-mail address: michael.ritchey@gmail.com (M.L. Ritchey).

poor [1]. This article reviews the current thoughts on etiology, diagnosis and management recommendations for children with WT.

Epidemiology
In children under 15 years of age, the annual incidence rate of WT is about 7e10 cases per million, and this accounts for 6e7% of all childhood cancers [2]. More than 80% of cases are diagnosed before 5 years of age, with a median age of 3.5 years [3].

1477-5131/$34 2008 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2008.08.007

Wilms tumor in children A family history of WT is present in 1e2% of newly diagnosed patients, and has been localized to two familial WT genes (FWT1 at 17q12eq21 and FWT2 at 19q13.4) [4]. These patients usually have an earlier age of onset as well as an increased frequency of bilateral disease.

57 LOH at chromosome 16q occurs in 20% of WTs [19]. Similarly, 10% of cases have been found to have LOH at chromosome 1p [20]. These have been shown to be associated with an increased risk of tumor relapse and mortality. One of the major objectives of the National Wilms Tumor Study (NWTS)-5 was to conrm the utility of LOH at chromosome 16q and 1p to predict an adverse prognosis. Among patients with Stage IeII FH tumors, the relative risk of relapse and death was increased for LOH of either 1p or 16q in comparison with patients lacking LOH at either locus [20]. The risk of relapse and death for patients with Stage IIIeIV favorable histology (FH) tumors was increased only with LOH for both regions. In the current Childrens Oncology Group (COG) protocols, there is an intensication of treatment for children whose tumors demonstrate LOH for these chromosomal regions. Recently, a previously uncharacterized tumor suppressor gene otherwise known as the Wilms tumor gene on the X chromosome, or WTX, was found to be inactivated in up to one third of WT cases [21]. WTX is inactivated by a monoallelic, or single-hit event rather than by the classical biallelic two-hit Knudson model. It targets the single X chromosome in males and the active X chromosome in females with tumors, and occurs at comparable frequencies in both sexes. Tumors that are caused by WTX mutations lack WT1 mutations.

Etiology
There are a number of recognized syndromes associated with an increased predisposition towards developing WT (Table 1). They can be divided into overgrowth and nonovergrowth syndromes. Common overgrowth syndromes include BeckwitheWiedemann syndrome (BWS) and isolated hemihypertrophy. The most recognized non-overgrowth syndromes include WAGR (WT, aniridia, genitourinary anomalies, mental retardation) syndrome and DenyseDrash syndrome (DDS) [5e8]. Aniridia is found in 1.1% of WT patients and is attributed to a PAX6 gene abnormality. This is located next to the WT1 gene on chromosome 11p13, which contains genes responsible for development of the kidney, genitourinary tract and eyes. WT1 identication and cloning is a result of the observations of heterozygous chromosomal deletions noted in those with WAGR syndrome [9,10]. WT1 encodes transcription factors involved with gene regulation during renal and gonadal development [11]. It is required for ureteric bud outgrowth and is important in nephrogenesis. Although WT1 mutations are present in a minority of WT cases (10e 15%), patients with WT1 abnormalities have a higher predisposition for developing nephroblastoma [6,12]. WT1 deletions in aniridia patients are associated with a 40% rate of WT development. Conversely, aniridia patients with normal WT1 appear to be at low-risk of developing nephroblastoma [7]. DDS is a syndrome associated with WT1 missense mutations. It is characterized by disorder of sexual development usually with a 46, XY karyotype, renal mesangial sclerosis and WT. Of patients with nephroblastoma 4.5% have genitourinary abnormalities, including renal fusion anomalies, cryptorchidism and hypospadias [13]. Although these disorders are commonly diagnosed in children, a prospective evaluation for WT is not necessary, unless DDS is suspected [14]. The WT2 gene located at 11p15 has been linked to BWS [15]. There is a 4e10% risk of developing WT in BWS children with hemihypertrophy [16e18]. This gene was identied as a result of nding loss of heterozygosity (LOH) at this location [15].

Presentation
Over 90% of children will present with an asymptomatic abdominal mass. Most WTs are solitary lesions, although 6% present with bilateral disease and 12% may present with multifocal disease within a single kidney [22]. Presenting symptoms can include abdominal pain that should alert the surgeon to the risk of preoperative rupture and bleeding. Gross hematuria may be a sign of tumor extension into the collecting system or ureter [23]. Atypical presentations occur in less than 10% of patients. They are a result of compression of surrounding organs or vascular invasion. Vascular extension into the renal vein or inferior vena cava occurs in up to 4% of WT patients [24]. Patients with vascular extension can present with ascites, congestive heart failure, hepatomegaly and varicocele [25]. Paraneoplastic syndromes can result from tumor production of hormonal substances, and include hypertension, hypercalcemia, erythrocytosis and von Willebrands disease [26,27].

Pathology
Table 1 Syndrome BeckwitheWiedemann DenyseDrash WAGR Bloom LieFraumeni Neurobromatosis SimpsoneGolabieBehmel Sotos Wilms tumor: syndromes and genetic loci Genes WT2 WT1 WT1 BLM p53 NF1 GPC3 NSD1 Locus IGF2, H19, p57, KIp2 11p13 11p13 15q26 17q13 17q11 Xq26 5q35

Histology is the most important prognostic indicator for WT. The majority of WT patients have tumors with FH. Several tumor types are associated with an increased risk of tumor recurrence, or resistance to standard WT chemotherapy. These include patients with anaplastic WT, which can be focal or diffuse. Two other renal tumors, rhabdoid tumor of the kidney and clear cell sarcoma of the kidney, were once considered to be WT. They were identied to have a higher risk of recurrence and therefore receive different therapy. Histologic classication has been very important for stratifying patients into treatment groups and protocols.

58 Classic WT includes three histological cell types in varying proportions: (1) blastemal; (2) epithelial; and (3) stromal components [28]. Tumors with predominantly epithelial differentiation have low aggressiveness and are mostly Stage I if diagnosed early. When diagnosed at an advanced stage, these tumors tend to be more resistant to therapy. Tumors with blastemal predominance are highly aggressive, although they are responsive to chemotherapy [29]. Anaplasia is a marker for chemoresistance representing up to 10% of unilateral WTs. Anaplasia may be focal or diffuse. The incidence of anaplasia in children less than 2 years old is about 2%, increasing signicantly to 13% in children diagnosed at ages greater than 5 years [29]. Although tumors with unfavorable histology carry a poor prognosis and are the greatest challenge to cure across all stages, when the anaplastic component is surgically removed in its entirety, the outcome is generally good [29e31]. Nephrogenic rests (NRs) are precursor lesions that are found in 25e40% of kidneys with WT [32e34]. They are found in 1% of infants at autopsy [35]. Most NRs do not develop into malignancy. Rather, they can undergo maturation, sclerosis, or disappear completely. An increased incidence of NRs is found in syndromic patients with BWS, DDS and sporadic aniridia [36]. There are two types of NR, intralobar (ILNR) and perilobar (PLNR) [32]. ILNRs are associated with the 11p13 WT locus, and are found with an increased incidence in children with aniridia and DDS. ILNR-associated tumors also have an earlier onset. PLNRs, developing later in renal embryogenesis, are associated with the 11p15 WT locus and are noted to have an increased incidence in children with BWS [36]. If NRs are present on one kidney they are also likely to be present on the contralateral kidney, and frequent surveillance of the contralateral kidney is recommended after surgery to monitor for metachronous tumors [37]. Children, less than 1 year of age, with WT and PLNRs have a markedly increased risk of developing metachronous tumors after undergoing nephrectomy [38]. Distinguishing hyperplastic, large NRs from a WT can be challenging. WT can be differentiated pathologically by observing an intrarenal pseudocapsule that is composed of compressed, atrophic renal tissue. NRs lack this capsule with the cells interfacing with the normal renal parenchyma.

E.Y. Ko, M.L. Ritchey patient, but determination of inoperability must be at surgical exploration.

Screening
Syndromic patients with a known increased risk for WT undergo periodic screening renal US for early detection. The Wilms Tumor Surveillance Working Group from the UK recommended conducting screening when a condition has a WT incidence of greater than 5% [43]. US surveillance is performed from time of diagnosis until 5 years of age, with a frequency of every 3e4 months. Those that have BWS, SimpsoneGolabieBehmel and familial WT histories should continue to 7 years [43,44]. A CT or MRI should be performed if US demonstrates a suspicious lesion. The potential benets of WT screening are detecting lower stage tumors and thereby improving patient survival. Overall there is no compelling evidence that screening children at high-risk for WT has improved survival [46e47]. Two retrospective studies demonstrated a difference in stage distribution with unscreened children having more late-stage disease compared to unscreened cases [45,46]. Early detection can provide an opportunity for nephronsparing surgery (NSS), since these children are at an increased risk for bilateral disease [17]. The smaller tumors found on screening studies are more amenable to renal sparing surgery either before or after preoperative chemotherapy.

Staging
Stage and histopathology are the most important determinants of outcome in children with WT. There are currently two staging systems available reecting treatment differences (Tables 2 and 3). The current system used by the COG reects staging at primary surgery. Alternatively, the system used by the International Society of Paediatric Oncology (SIOP) is performed after preoperative chemotherapy. Tumors with favorable histology are more likely to

Table 2 System Stage I

Childrens Oncology Group Wilms Tumor Staging Tumor conned to kidney and completely resected; no capsular breach, tumor spillage or renal sinus extension Extracapsular penetration (including iatrogenic via biopsy prior to resection) or renal sinus extension with vascular involvement; complete resection with negative margins and no lymph node involvement Non-hematogenous spread beyond the kidney (abdominal lymph nodes, transected renal vein, IVC tumor thrombus); macroscopic/microscopic residual tumor after resection; peritoneal spillage during resection Hematogenous metastases (lung, liver, bone, brain) or extra-abdominal lymph node spread Bilateral renal involvement at diagnosis

Imaging
Ultrasound (US) is often the initial study obtained in children presenting with abdominal masses. Doppler studies can be used to evaluate the inferior vena cava (IVC) for patency and the presence of tumor extension, occurring in 4% of WT patients [24,39]. CT and MRI are also used to evaluate extent of the tumor, involvement of the contralateral kidney, venous involvement, invasion of surrounding structures, lymph node involvement, metastases to other organs, and treatment response [40]. CT of the chest is recommended to assess metastatic pulmonary disease [41]. The improved imaging has now obviated the need for exploration of the contralateral kidney [42]. However, one limitation of imaging is the ability to determine resectability. These are large lesions relative to the size of the

Stage II

Stage III

Stage IV Stage V

Wilms tumor in children

Table 3 International Society of Paediatric Oncology Staging System Stage I Tumor limited to kidney; brous pseudocapsule surrounds tumor if outside of contours of kidney; clear resection margins; no renal sinus vessel involvement Tumor extends beyond kidney into perirenal fat, renal sinus, adjacent organs or IVC; complete resection with clear margins Incomplete excision of tumor; positive abdominopelvic lymph nodes, tumor penetration through peritoneal surface, tumor thrombi at vascular resection margins Hematogenous metastases; extra-abdominopelvic lymph node metastases Bilateral tumors at diagnosis

59 undergoing NSS had an 8% incidence of local recurrence [50]. Those with unilateral tumors and FH undergoing primary nephrectomy only had a 3% incidence of local recurrence [48]. The differences in local recurrence may be due to the increased aggressiveness in NSS technique for patients with bilateral disease to preserve renal function. The role of laparoscopic removal of renal tumors in children has been explored. Duarte et al. reported on eight patients with unilateral non-metastatic WT who underwent preoperative chemotherapy prior to nephrectomy [51]. In this small series, there were no conversions to open surgery, no tumor ruptures and no postoperative complications. Currently, the role of laparoscopy is limited to the removal of tumors that have been pretreated with chemotherapy. For the untreated tumor, this approach is likely not feasible due to concerns regarding removal of an intact tumor, risk of tumor spill and accurate surgical staging. Performing NSS in children with unilateral WT remains controversial [52]. Most tumors at the time of diagnosis are too large for NSS, thus making it difcult to obtain negative margins to decrease recurrence. Partial nephrectomy may be considered if the tumor involves one pole of the kidney, if there is no evidence of collecting system or vascular involvement, if clear margins exist between the tumor and surrounding structures, if there is a solitary kidney, and if the involved kidney demonstrates appreciable function. Less than 5% of patients with unilateral WT would be candidates for partial nephrectomy at diagnosis [53]. Preoperative chemotherapy can be used to decrease tumor burden to a size that is amenable to NSS [54,55]. It is unclear if this approach can decrease the incidence of renal failure, which is less than 1% in patients with unilateral WT undergoing nephrectomy [56]. More importantly, it will have to be shown that the benet of NSS outweighs the potential for increased local recurrence and mortality. Surgical removal of a large renal mass in a small child has inherent risks. The most common intraoperative complication is bleeding. Following surgery the most common complication is small bowel obstruction occurring in >5% of patients [57]. Chylous ascites is a less common but signicant event [58]. Tumor risk factors for surgical complications include tumor diameter >10 cm, and tumor or thrombus extension into the IVC or atrium. The overall surgical complication rate of nephrectomy for WT appears to have declined over time. In a comparison of the complication rates from NWTS-3 (1979e1987) to NWTS-4 (1986 and 1994), National Wilms Tumor Study Group (NWTSG) investigators found the complication rate decreased from 19.8% to 12.7% (P < 0.001) [59]. Preoperative chemotherapy may inuence surgical complication rates by producing tumor shrinkage. A report from SIOP, where nephrectomy was performed after 4 or 8 weeks of chemotherapy, showed an overall surgical complication rate of 5% [60]. A prospective comparison of complications (Table 4) in patients enrolled in the NWTS-5 and SIOP-93-01 trials demonstrated that the overall complication rate for the SIOP patients was 6.4% compared to 9.8% in NWTSG patients (P Z 0.12) [61]. There was a markedly decreased incidence of intraoperative tumor spill in the SIOP patients, 2.2%, compared to the NWSTG patients, 15.3% (P < 0.001). There was also a statistically

Stage II

Stage III

Stage IV Stage V

be of lower stages versus anaplastic tumors, which are twice as likely to have Stage IV disease [29].

Treatment
Surgery maintains an important role in treatment, although the improved prognosis for this malignancy during the 20th century is attributed primarily to advances in chemotherapy. Overall survival rates reach 90% with current treatment regimens. COG and SIOP treatment protocols are now focusing not only on maximizing cure, but also minimizing treatment side effects and associated morbidity [1].

Surgery
Transperitoneal radical nephrectomy is the standard operative procedure for unilateral WT. If preoperative CT or MRI demonstrates a normal contralateral kidney, exploration of the contralateral kidney is not needed [42]. During nephrectomy, careful dissection and surgical technique must be observed to ensure en-bloc resection of the tumor without contamination of the operative eld. Tumor spillage results in a six-fold increase in local abdominal recurrence. The risk factors for local tumor recurrence include unfavorable histology, incomplete removal of tumor, any tumor spillage and absence of lymph node sampling [48]. Although formal lymph node dissection is not needed, sampling of hilar and ipsilateral para-aortic or caval lymph nodes is mandatory. Absence of lymph nodes in the specimen will mandate treatment as Stage III disease. As noted above, many WTs look quite massive on preoperative imaging. Right-side tumors may appear to be invading the liver, particularly if only viewed on coronal CT views. Determination of resectability should be based on ndings at exploration. One exception is the diagnosis of extension into the IVC above the level of the hepatic veins [25]. A patient determined to have an inoperable tumor is considered Stage III and treated accordingly [49]. NSS is advocated for children with a solitary kidney and bilateral WT. The greatest concern is the increased risk of positive surgical margins and local tumor recurrence. NWTS-4 demonstrated that patients with bilateral WT

60
Table 4 Comparison of complication rates from SIOP and NWTSG trials SIOP-93-01 NWTS-5 No. of patients Complication rate Intraoperative tumor spill Small bowel obstruction Stage III tumors Resection of other organs 360 6.4% 2.2% 1.1% 14.2% 6.9% 326 9.8% 15.3% 4.3% 30.4% 15.0% (P Z 0.12) (P < 0.001) (P Z 0.002) (P < 0.001) (P < 0.001)

E.Y. Ko, M.L. Ritchey ndings of the trial was that LOH for chromosomes 16q and 1p is predictive for increased risk of tumor relapse and death [20]. In NWTS-5, children less than 2 years of age with Stage I FH tumors weighing less than 550 g did not receive chemotherapy after nephrectomy. This portion of the study was closed when the number of tumor relapses exceeded the limit allowed by the design of the study [66]. However, the 2-year overall survival of this cohort was 100% due to the high rate of retrieval of the relapsed patients. The COG has assumed the role of the NWTSG in conducting WT clinical trials. The current studies are outlined in Table 5. This will also be a single-arm therapeutic trial comparing outcomes to historic controls. Patients are stratied into low-risk, standard risk and high-risk categories. The low-risk study will again evaluate the feasibility of omitting postoperative chemotherapy for infants with small Stage I tumors. Low-stage patients with LOH of 1p and 16q will be treated with more intensive treatment. Patients with pulmonary metastases will be monitored for response of the pulmonary lesions to chemotherapy. Patients with complete resolution of the pulmonary lesions after 6 weeks of chemotherapy will not receive pulmonary irradiation. A new chemotherapy regimen has been designed for treatment of patients with diffuse anaplastic WT and malignant rhabdoid tumor of the kidney.

signicantly decreased incidence of Stage III tumors in the SIOP group (14.2%) compared to NWST-5 (30.4%).

Chemotherapy
The clinical course of children with WT was altered in the 1960s with the application of the chemotherapeutic agents dactinomycin (AMD) and vincristine (VCR). Survival was dramatically improved even for patients with high-stage tumors compared to prior treatment with surgery and radiation therapy alone. The NWTSG, SIOP and others have conducted randomized clinical trials to determine the most effective combinations of treatment for these patients. The primary goals have been to improve overall survival but they are continually adjusting treatment protocols to prevent late effects from these treatments. Stratication of treatment is primarily based on stage and tumor histology, although the biologic features of the tumor are also a consideration. The difference between NWTSG and SIOP treatment protocols is that SIOP recommends treatment to begin with preoperative chemotherapy.

International Society of Paediatric Oncology (SIOP)

Beginning in 1971, the SIOP treatment protocols have examined the role of therapy prior to surgery. The SIOP protocols have the same goal of maximizing cure while minimizing toxicity. They have demonstrated that this approach is effective in reducing tumor volume in most patients and reduces the risk of tumor rupture [60,67]. The preoperative treatment also leads to a downstaging of the tumor. The SIOP trials report a higher percentage of Stage I tumors and a lower percentage of Stage III tumors compared to the NWTSG trials. This reects the inherent differences in staging a tumor after the effects of chemotherapy. Clearly, there are patients with extra-renal tumor extension that is eradicated by the preoperative chemotherapy and cannot be detected on pathology after the tumor is resected. In SIOP-6 (1980e1986), Stage II patients with negative lymph nodes that did not receive postoperative abdominal irradiation had a higher recurrence rate compared to those with radiation [68]. In SIOP-9 (1987e1993), they demonstrated that the relapse rate for Stage II patients with negative lymph nodes without radiation therapy was reduced with epirubicin. However, the addition of an anthracycline has increased the risk of late effects for these children [69,70]. This study also demonstrated that treatment with VCR and AMD for 4 weeks versus 8 weeks gave comparable rates of stage distribution and tumor shrinkage in patients with Stage IeIII disease. More recently, SIOP investigators have studied the usefulness of histologic changes in the tumor after preoperative therapy to guide postoperative treatment decisions [71,72]. This approach places more emphasis on the response of the tumor to chemotherapy than on the apparent aggressive behavior of the tumor as reected by

National Wilms Tumor Study Group (NWTSG) and Childrens Oncology Group (COG)
The early NWTSG studies showed that the combination of VCR and AMD was more effective than the use of either drug alone. The addition of doxorubicin (DOX) resulted in improved survival for Stage III and IV patients. Postoperative ank irradiation was eliminated for Stage I and II patients and the dose for Stage III patients decreased to 1000 cGy [62,63]. A major accomplishment was identication of prognostic factors that allowed stratication of patients into high-risk and low-risk treatment groups. Patients with positive lymph nodes and tumor spill have an increased risk of abdominal relapse and are therefore considered Stage III and given abdominal irradiation. One of the most important ndings of the NWTSG was the identication of unfavorable histologic features that have a very adverse impact on survival [63]. These patients continue to be a challenge as standard WT chemotherapy is ineffective for patients with high-stage anaplastic tumors or rhabdoid tumor [64,30]. Children with clear cell sarcoma of the kidney have a good outcome if treated with DOX and postoperative radiation [65]. Overall, the 4-year survival for patients with all stages of FH WT now exceeds 90%. The last NWTS trial (NWTS-5 1995e2001) was a singlearm therapeutic trial. As noted above, one of the major

Wilms tumor in children

Table 5 protocols Recommended therapy according to COG Radiotherapy None None None None Yes Yes Yes Yes Chemotherapy None Regimen EE-4A Regimen EE-4A Regimen DD-4A Regimen DD-4A Regimen DD-4A Regimen DD-4A Regimen M

61 this tumor type to the preoperative chemotherapy. However, patients with blastemal predominant tumors after chemotherapy had a 31% relapse rate in SIOP-9 [71]. In SIOP-9, approximately 10% of all tumors resected after preoperative chemotherapy were completely necrotic (with <1% of viable tumor) [72]. Of these patients, 98% had no evidence of disease at 5 years (one non-tumor death). The SIOP now classies tumors with complete tumor necrosis following preoperative chemotherapy as low-risk, and tumors with diffuse anaplasia and blastemal predominance after chemotherapy (because of the high rate of recurrence in these patients) as high-risk. SIOP intermediate-risk tumors comprise all other histologies [71]. In the most recently concluded study, SIOP 93-01, as well as in the current SIOP 2001 study, children with Stage I low-risk tumors following post-chemotherapy nephrectomy receive no further chemotherapy [73]. The ongoing SIOP 2001 study treats patients with Stage I intermediate risk-tumors with AMD and VCR. The most important study question of this trial is whether patients with Stage II and III intermediate-risk tumors can be safely treated without DOX. Patients with Stage II or higher high-risk tumors will receive intensied postoperative chemotherapy with a combination of cyclophosphamide, carboplatin, etoposide and DOX.

Stage/histology Stage I FHWT <2 years, <550 g Stage 1 FHWT, >2 years or >550 g Stage II FHWT Stage I, II, FHWT and LOH 1p, 16q Stage III FHWT no LOH 1p, 16q Stage IeIII focal AHWT Stage I diffuse AHWT Stage III, IV FHWT and LOH 1p, 16q Stage IV FHWT pulmonary metastases Lesions resected at diagnosis Lesions resolve after 6 weeks chemo Lesions persist after 6 weeks chemo Stage IV FHWT nonpulmonary metastases Stage IIeIII diffuse AHWT Stage IV diffuse AHWT (no measurable disease) Stage IV focal AHWT Stage I CCSK Stage IIeIII CCSK Stage IV CCSK Stage IeIII MRT Stage IV MRT Stage IV AHWT (measurable disease)

Yes None Yes Yes Yes Yes

Regimen DD-4A Regimen DD-4A Regimen M Regimen M Regimen UH-1 Regimen UH-1

Bilateral Wilms tumor

Synchronous bilateral WT (BWT) occurs in 4e6% of patients with WT [50]. Children with BWT should not undergo initial radical nephrectomy. Rather, these children should receive preoperative chemotherapy with the goal of tumor shrinkage and renal preservation. This is important because the risk of renal failure in patients with BWT approaches 15% at 15 years post treatment [74]. The proposed COG protocol for patients with BWT recommends 6 weeks of chemotherapy prior to surgery. Tumor response is evaluated with CT or MR after 6 weeks. Patients with tumors amenable to renal sparing procedures can proceed with surgery. If there has not been a good response, biopsy of the tumor(s) is recommended to determine the histology. SIOP has reported that patients with unilateral tumors not responding to chemotherapy have a worse prognosis [75]. Additional chemotherapy is then given, but all patients should proceed to surgical resection within 12 weeks of starting therapy. Continuing treatment beyond 12 weeks will not likely provide any additional reduction in tumor burden. Partial nephrectomy or wedge excision of the tumor is preferred, but only if it will not compromise tumor resection and negative margins can be obtained. The kidney with the lower tumor burden is addressed rst. If complete excision of tumor from this kidney can be performed leaving a viable and functioning kidney, then radical nephrectomy of the contralateral kidney with more extensive tumor involvement is done. Tumor enucleation may be considered in lieu of a formal partial nephrectomy. This will usually be considered for large centrally located tumors where removal of a margin of renal tissue would compromise the vascular supply to the kidney. Even when large bilateral masses remain after initial chemotherapy, a high percentage of children can be successfully managed

Yes None Yes Yes Yes Yes Yes

Regimen Regimen Regimen Regimen Regimen Regimen Regimen

UH-1 I I UH-1 UH-1 UH-2 UH-2

Regimen EE-4A: Pulse-intensive AMD plus VCR (18 weeks). Regimen DD-4A: Pulse-intensive AMD, VCR and DOX (24 weeks). Regimen M: VCR, AMD, DOX, alternating with CYCLO and ETOP (24 weeks). Regimen UH-1: CYCLO, Carboplatin, ETOP alternating with VCR, DOX, CYCLO (30 weeks). Regimen I: VCR, DOX, CYCLO alternating with CYCLO, ETOP (24 weeks). Regimen UH2: VCR, DOX, CYCLO alternating with CYCLO, Carboplatin, ETOP and VCR, Irinotecan (30 weeks). FHWT, favorable histology Wilms tumor; AHWT, anaplastic histology Wilms tumor; CCSK, clear-cell sarcoma of the kidney; MRT, malignant rhabdoid tumor of the kidney; AMD, dactinomycin; VCR, vincristine; DOX, doxorubicin; CYCLO, cyclophosphamide; ETOP, etoposide.

the tumors clinical stage at diagnosis. The relative proportions of histologic subtypes of WT differ following preoperative chemotherapy when compared to those reported following primary surgical resection [71,72]. Stromal and epithelial predominant tumors are found more often after chemotherapy. These histologic subtypes may demonstrate a poor clinical response to therapy but have an excellent prognosis if the tumor is completely excised [71]. The proportion of blastemal predominant tumors is decreased after chemotherapy, indicating some response of

62 with renal sparing surgery [76]. It is easy to underestimate the amount of renal parenchyma that can be salvaged due to compression by the tumor, therefore NSS should be entertained in all patients.

E.Y. Ko, M.L. Ritchey cancer, hepatocellular carcinoma, lymphoma, gastrointestinal tract tumors, melanoma and leukemias [90,91]. Children who are exposed to radiation during their primary treatment are at the greatest risk of developing subsequent secondary malignancies. Despite the potential late effects from treatment for WT, the success rate is in excess of 80% with long-term survival. Along with this, less than 20% experience serious morbidity at 20 years from diagnosis [92]. The increased risk of late effects is in direct correlation to the aggressiveness of therapy for high-stage disease. Current treatment protocols focus on reducing the aggressive nature of treatment while decreasing morbidity especially for lowstage disease [93]. There is concern about late occurrence of renal dysfunction after unilateral nephrectomy. Some studies have noted proteinuria and a decrease in creatinine clearance, but other investigators have failed to conrm these ndings. The incidence of renal failure following treatment for unilateral WT is low. Only 0.25% of NWTSG patients have developed renal failure after nephrectomy for unilateral tumors [56]. Most of those were children with DDS who have intrinsic renal disease and often progress to end-stage renal disease. Patients with the WAGR syndrome are at increased risk of renal failure: 38% at a median of 14 years from diagnosis [94]. NWTSG investigators have noted an increased risk of renal failure in children presenting with genitourinary anomalies and WT. The renal dysfunction in these patients may be due to mutation of WT1 which is necessary for normal renal development. As noted above, the children with the highest rate of renal failure are those with bilateral tumors [56].

Late effects of Wilms tumor treatment

Normal tissues and organs are damaged as a consequence of the non-specic nature of WT anticancer therapy. This is a particular problem in the very young, in whom cytotoxic therapy can severely affect future growth and development. Clinicians must monitor these children as they mature and be aware of potential future problems. Studies demonstrate that at least 60% of young adult cancer survivors manifest chronic health problems [77,78]. The major sequelae in WT survivors are cardiotoxicity, musculoskeletal problems, reproductive issues and the development of secondary tumors. Anthracyclines, such as DOX, have been known to have preferential myocytic toxicity, which reduces myocardial mass and causes myobril dysfunction [69,70]. This results in reduced contractility and cardiomyopathy, with congestive heart failure as the presenting problem occurring acutely or many years after treatment [79]. A preliminary review of NWTS-1e4 by Green et al. demonstrated a heart failure frequency of 4.4% in patients who received DOX as a part of their initial chemotherapy [69,70]. Total cumulative dose is the most important risk factor associated with cardiac dysfunction, although any amount of DOX exposure can lead to myocardial injury [80]. Radiation treatment has detrimental consequences upon growing and developing tissues. Children receiving radiation therapy in early NWTSG trials had signicant musculoskeletal conditions, such as scoliosis [81]. Height reductions were noted to be dependent upon total radiation dose, age of treatment, fractionation and eld [82]. The current recommended radiation doses should not have clinically signicant height sequelae [83]. Fertility and pregnancy are two areas that can be detrimentally affected by WT treatment. Radiation to the testes can result in hypogonadism and temporary azoospermia in males [84]. Inadequate testosterone production can result in delayed sexual maturation. Females who have their ovaries or uterus located within the radiation eld are at a signicant risk of adverse fertility outcomes [85]. Postradiation females have been found to have small or absent ovaries, primary ovarian failure and even premature menopause. There is also a high incidence of infertility, spontaneous miscarriages and intrauterine growth retardation [86,87]. The offspring are at risk for premature birth, intrauterine growth retardation resulting in low birth weight, as well as congenital malformations. Children treated for WT have also been noted to have an increased risk of developing subsequent malignant tumors. Most of these occurred in children who received radiation, and most tumors occurred within the radiation eld. WT survivors have been noted to have a 1% cumulative incidence of developing second neoplasms 10 years after diagnosis with an increasing incidence thereafter [88]. The cumulative risk within 15 years of diagnosis reached 1.6% [89]. Second cancers include bone and soft-tissue sarcomas, breast

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65 Review of Wilms tumor e multiple choice questions 1. A 5-year-old boy presents with a solid abdominal mass noted on ultrasound. The child is found to have a palpable right-sided abdominal mass as well as an ipsilateral varicocele on physical examination. The next step in evaluation is: a. CT scan of abdomen and pelvis b. intravenous pyelogram c. MRI scan of abdomen and pelvis d. ultrasound of scrotum 2. A 6-year-old boy undergoes radical nephrectomy for an asymptomatic palpable abdominal mass conrmed to be a solid right renal mass on imaging. The worst prognostic indicator would be: a. diffuse anaplasia b. diffuse tumor spill c. pulmonary metastases d. positive surgical margins 3. A 1-year-old girl is found to have a left-sided renal mass consistent with Wilms tumor. The histologic nding associated with an increased risk for a metachronous tumor is: a. blastemal predominant pattern b. diffuse anaplasia c. nephrogenic rests d. renal sinus invasion 4. A 3-year-old boy is found to have bilateral Wilms tumor. The right kidney has >50% involvement with tumor and the left kidney has a 3.0 cm lower pole mass. The next step in management is: a. bilateral partial nephrectomy b. chemotherapy c. radiation d. right nephrectomy and left partial nephrectomy 5. A 4-year-old girl has been diagnosed with Stage III Wilms tumor. While undergoing chemotherapy, she develops dyspnea on exertion, orthopnea, as well as edema. The chemotherapeutic agent most likely responsible for these ndings is: a. dactinomycin b. doxorubicin c. etoposide d. vincristineAnswer Key

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