Seminars in Pediatric Surgery
Volume 21, Issue 1 , Pages 15-20, February 2012

Wilms tumor: recent advances in clinical care and biology

  • Thomas E. Hamilton, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests and correspondence: Thomas E. Hamilton, MD, Department of Surgery, Children's Hospital Boston, Harvard Medical School, Fegan 3, 300 Longwood Ave., Boston, MA 02115
    • ,
  • Robert C. Shamberger, MD

Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts

Article Outline

Wilms tumor is the most common renal malignancy that occurs in childhood. The remarkable evolution of treatment for this malignancy has served as a paradigm for multimodal cancer treatment. A rich database has accrued over time from well-controlled clinical trials. Translational research has directly affected patient care by allowing risk-based therapy. This article will summarize advances in our knowledge of the biology of Wilms tumor and describe the impact on clinical treatment of Wilms tumor.

Keywords:  Wilms tumor , Adjuvant therapy , Molecular biology

 

Wilms tumor is the first solid malignancy in which the value of adjuvant chemotherapy was clearly recognized. The addition of radiotherapy to surgery and chemotherapy dramatically improved survival from 30% to 80%. Currently survival is 90% overall for children with Wilms tumor, but outcomes remain poor for those children with relapse or rhabdoid and anaplastic tumors. Current treatment protocols in North America and Europe are determined on the basis of risk assignment to minimize toxicity for low-risk children and improve outcomes for children with high-risk disease. Scientific advances have come from detailed analysis of treatment-based outcomes, tumor genetics, and biology. In this review, we summarize both advances in clinical care and biology.

Well-known associations with Wilms tumor and congenital anomalies, such as aniridia, Beckwith-Wiedmann, and hemihypertrophy, have directed investigators to candidate genetic loci, and several genes have been identified and studied. Huff1 has recently published an excellent detailed review on genetic alterations in Wilms tumors. Genes mutated in Wilms tumor include TP53, a classic tumor suppressor gene; CTNNB1 (encoding β-catenin), a classic oncogene; WTX, a tumor suppressor gene based on increasing data; and Wilms tumor 1 (WT1). WT1 has an important role in regulating normal differentiation in various organs. Loss or overexpression results in differing phenotypic consequences depending on the status of cellular differentiation as does its oncogenic or tumor suppressor effect. Understanding how cells respond to the loss or alteration of WT1 in various stages of differentiation and in the presence of other gene mutations in variable microenvironments are the target for future study to best understand the malignancy.1

Treatment of Wilms tumor has been advanced primarily by 2 large cooperative multinational trials: The National Wilms Tumor Study Group (NWTSG) merged with 3 other groups to form the Children's Oncology Group (COG) and the International Society of Pediatric Oncology (SIOP). Fundamental differences exist in the treatment of Wilms tumor between these 2 groups: primary surgery in NWTSG/COG versus initial or neoadjuvant chemotherapy in SIOP. Clinical outcomes are excellent in both groups, and productive debate continues on the merits of each approach. Abundant clinical data from protocols by both groups have permitted advances in treatment and our understanding of the molecular biology of this tumor.

In initial NWTSG studies, researchers identified the importance of histology and recognized the synergy of vincristine and dactinomycin.2 In subsequent NWTSG studies, authors discovered increased relapse-free survival for greater stage tumors when doxorubicin was added to treatment, and radiation was eliminated for stage I and II patients and decreased to 1000 cGy for children with stage III tumors.2 An increased incidence of local recurrence occurred in children who did not have lymph nodes sampled for staging and in whom spill occurred during the resection, 2 factors for which surgeons are responsible. On current protocols of COG, the need for lymph node sampling is stressed, and all children with tumor rupture, even if “contained,” are treated as stage III with more intensive therapy.3

The SIOP's strategy for upfront chemotherapy has produced abundant histologic data to guide postoperative therapy.4 It focuses more on how the tumors respond to chemotherapy than clinical stage at diagnosis. Blastemal predominant tumors after chemotherapy in particular had poor response, ie, 31%, in SIOP 9.4 Godzinski et al5 recently reviewed more than 1450 patients from SIOP 9301 retrospectively in an attempt to address the question of whether the extent of tumor volume decrease with chemotherapy was an accurate predictor of lymph node status at surgery. No predictive value was identified; however, larger initial tumor volume was associated with a greater risk of lymph node invasion.

SIOP now classifies tumors with complete necrosis as low risk and tumors with diffuse anaplasia and blastemal predominance after chemotherapy as high risk. Intermediate risk includes all other postchemotherapy histologies.4 The ongoing SIOP (2001) study treats patients with stage I low-risk postchemotherapy nephrectomy without additional chemotherapy; intermediate-risk stage I tumors receive actinomycin D and vincristine. One of the primary study objectives is whether stage II and III intermediate-risk tumors can be safely treated without doxorubicin. Patients with stage II or greater-risk tumors receive intensified postoperative chemotherapy with cyclophosphamide, carboplatin, etoposide, and doxorubicin.6

Preliminary data from NWTS-4 suggested that loss of heterozygosity (LOH) at chromosomes 1p and 16q predicted an adverse outcome for children with Wilms tumor.7 NWTS-5 was the first protocol by this organization that did not involve randomized therapy. The entire thrust of the study was to prospectively confirm or refute this finding. The combined LOH at both chromosomes 1p and 16q was shown to be an adverse prognostic indicator for all stages of Wilms tumor.7 This study was the gateway for the use of molecular findings to guide risk-based therapy by NWTSG.

Stage I favorable histology tumors (FH) with a specimen weight <550 g in children younger than 24 months (very-low-risk Wilms tumors) were treated on NWTS-5 by resection alone. This arm of the study was stopped early when the rate of relapse exceeded the stringent criteria of the protocol. These criteria were established on an expected salvage rate of 50% for children who relapsed, based on previous experience. The goal of the study was to achieve at least a 95% overall survival rate for this cohort of children.8 After this arm of the study was closed, children were subsequently treated with the standard therapy of actinomycin-D and vincristine (EE4A). A long-term analysis of this cohort of children revealed a much greater-than-anticipated salvage rate for the chemotherapy naive patients who relapsed. Although the relapse rate for the children treated with surgery alone was greater (84%) than for the children treated with chemotherapy (97%), the overall survivals were not different, ie, 98% vs 99%, respectively.9

A component of the current COG study of renal tumors is again recommending therapy of surgery only for this cohort of children. It is hoped that the group will confirm these results and thereby avoid the use of adjuvant chemotherapy and its potential toxicity, primarily sinusoidal obstruction syndrome, in this young group of children. To be eligible for this study, infants must have lymph nodes sampled to confirm their stage I status. Genetic analyses of subsets of the very low-risk tumors have demonstrated distinctive gene expression, histologic and clinical features.10 This study used global gene expression analysis with immunohistochemistry and tissue microarray from tumors of children treated in the NWTS-5 study. Two subsets of children comprising 56% of the very-low-risk Wilms tumors that have pathogenetic and molecular differences also demonstrate an apparent risk for relapse. One cluster included 9 tumors with tubular differentiated histology, paucity of nephrogenic rests, and lack of LOH for 1p, 16q, and 11p; absence of relapse; and a unique gene expression profile consistent with arrest after mesenchymal to epithelial transition. The second cluster included 13 tumors with mixed histology, intralobar rests, and decreased expression of WT1 3 of 6 relapses occurred in this cluster. Perlman and colleagues11 subsequently demonstrated in 2011 that WT1 mutation and 11p15 LOH were associated with relapse in patients with very-low-risk Wilms tumors who do not receive chemotherapy. These exciting translational findings may provide meaningful biomarkers to further identify appropriate patients for reduced chemotherapy. Tumors from the very-low-risk Wilms tumors cohort show an increased frequency of the WT1 mutation and 11p15 imprinting patterns than reported in Wilms tumors of all ages. These data provide fertile genetic substrate for understanding the cellular mechanisms for metastasis.

Gene expression analysis in greater-risk FH Wilms tumors12 demonstrated the feasibility and modest accuracy of predicting relapse (sensitivity of 47% and specificity of 70%) by stratifying local stage III FH Wilms tumors patients using a classifier of <50 genes. Existing markers for relapse currently used for stratification (1p and 16q LOH) have a sensitivity of 8% and specificity of 96%.7 This analysis of genes differentially expressed identified apoptosis, Wnt signaling, insulin-like growth factor pathway, and epigenetic modifications to be important in relapse. It also identifies potential therapeutic targets FRAP/MTOR and CD40.12

Anaplasia remains a powerful predictor of relapse and survival. NWTS-5 included single-arm therapeutic studies to evaluate the efficacy of a more intensive regimen for anaplastic histology Wilms tumor (AH).13 Patients with stage I AH were treated with vincristine and dactinomycin for 18 weeks. Patients with stages II to IV diffuse AH were treated with vincristine, doxorubicin, cyclophosphamide, and etoposide for 24 weeks plus flank irradiation.

The outcomes for patients with stage I AH (4-year event-free survival [EFS]: 69%, 95% confidence interval [95% CI] 46.9-84.0 and overall survival [OS]: 82.6%, 95% CI 63.1–92.40) is worse than stage I FH (4-year EFS 92.4%, 95% CI 89.5-94.5 and OS 98.3%, 95% CI 96.4–99.2). The 4-year EFS for patients who underwent immediate nephrectomy with stages II (23 patients), III (43), and IV (15) diffuse AH were 82.6% (95% CI 89.5–94.5), 64.7 (95% CI 48.3-77.7), and 33% (95% CI 12.2–56.4), respectively. OS was similar to EFS for these groups, demonstrating that salvage after relapse in patients with anaplastic tumors is quite low. For stage V bilateral AH, EFS and OS were 43.8% (95% CI 24.2–61.8) and 55.2% (95% CI 34.8-71.7), respectively. Novel treatment strategies are needed to improve the survival for AH tumors especially with stage III and IV disease. Current trials with more intensive therapy have encountered significant toxicity.

An international collaborative effort describing the molecular profile of anaplastic tumors was recently reported by Williams and co-authors in Genes, Chromosomes and Cancer 2011. The results demonstrate frequent gain of MYCN and anaplasia specific loss of 4q and 14q in Wilms tumor. These results support a model where anaplasia, rather than forming an entirely distinct molecular entity, arises from a general continuum of Wilms tumor by the acquisition of additional genomic changes at multiple loci.14

Relapse occurs in approximately 15% of children with Wilms tumor, but if it occurs, it is a very adverse predictor of outcome with long-term survival <30%.15, 16 Treatment in patients with Wilms tumor who relapsed after the initial treatment with vincristine and actinomycin-D was reported by Green and co-authors17 from the NWTS-5 study. In this study, a uniform treatment for patients with relapse was used. Seventy-two patients relapsed after immediate nephrectomy, initialchemotherapy with vincristine and actinomycin-D and no radiation. Relapse treatment included surgical excision when feasible, radiation therapy, and alternating courses of vincristine, doxorubicin and cyclophosphamide, and etoposide and cyclophosphamide.

The lung was the solitary site of relapse in 31 patients. EFS and OS at 4 years after relapse were 71.4% and 81.8% for all patients and 67.8% and 81% for those who relapsed only to their lungs, respectively. The most frequent toxicity was hematological. These data demonstrate that a significant proportion of children with Wilms tumor who relapse after initial treatment with vincristine and actinomycin-D can be successfully salvaged.18

A corollary study was published in 2008. Treatment in patients with Wilms tumor who relapsed after the initial treatment with vincristine, actinomycin-D, and doxorubicin and radiation therapy in NWTS-5 was reported by Malogolowkin and associates.18 Alternating cycles of cyclophosphamide/etoposide and carboplatin/ etoposide were used in 60 patients; the lung was the only site of relapse for 33, and other sites included the operative bed,7 the abdomen,6 and the liver.6 Four-year EFS and OS were 42.3% and 48% for all patients and 48.9% and 52.8% for patients with only pulmonary relapse, respectively. Thrombocytopenia was the most prevalent toxicity. Therefore, approximately one-half of the children with unilateral WT who relapse after initial vincristine, actinomycin-D, and doxorubicin and radiation can be successfully treated.

In several recent studies researchers have addressed the management of patients with tumors that extend beyond the kidney by extension or metastasis. Grundy et al (personal communication) analyzed the outcome of patients from NWTS-4 and 5 with metastatic lung lesions. In previous NWTS studies, authors used only plain chest radiographs (CXR) to guide treatment. The advent of computed tomography (CT) scanning led to detection of smaller lesions and questions of how best to treat patients who had lesions detected only by CT. Review of the 231 patients with lung lesions detected by CXR and 186 by CT only was performed. Of the CT only patients, 37 received 2 drugs (vincristine/actinomycin-D), and the remainder received 3 drugs (vincristine/actinomycin-D/doxorubicin), as was suggested by the protocol for patients with pulmonary metastases shown by CXR. A total of 101 patients did not receive lung irradiation.

Five-year EFS was significantly greater for CT-only patients receiving 3 drugs with or without radiation compared with 2 drugs (80% vs 56%; P < 0.004). There was, however, no difference in 5-year OS between the 2- and 3-drug subsets (87% vs 86%; P = 0.91). There was also no significant differences in EFS (82% vs 72%, P = 0.13) or OS (91% vs 83%; P = 0.46) for CT-only patients whether or not they received lung irradiation. These results suggest that CT-only patients with lung lesion have improved EFS but not OS from the addition of doxorubicin to treatment but receive no obvious benefit from pulmonary radiation.

The current COG study is designed to further address these issues in children with pulmonary metastasis. Data from 201 patients with Wilms tumor and primary lung metastases from the collaborative multicenter trials SIOP 93-01/German Society for Pediatric Oncology and SIOP (2001)/German Society for Pediatric Oncology of the German Society of Pediatric Oncology and Hematology was recently reported by Warmann and co-authors19 in Annals of Surgery 2011. Five-year OS was 83.3% and 5-year EFS was 72.3% for all children. Survival was significantly worse in children with high-risk primary histology (OS 44.4%) compared with low-risk (OS 100.0%) and intermediate-risk histology (OS 89.2%, P < 0.001). Within the high-risk group the blastemal subtype (OS 56.6%) was associated with significantly better outcome than the diffuse anaplasia (OS 22.2%, P < 0.02) subgroup. Further, prognostic markers were lacking response to chemotherapy (P = 0.011), persistence of metastases after local treatment (P = 0.007), and viability of metastases (P = 0.01). Thus, the prognosis of children with Wilms tumor and lung metastases mainly depends on the biology of the primary tumor and metastases and is excellent with adequate treatment.19

The value of surgery in directing therapy for patients with Wilms tumor with pulmonary disease was described by Ehrlich and colleagues.20 On the basis of a review of patients treated on NWTS-5, CT-only lesions were not invariably shown to be the result of tumor. There were 16 patients with isolated lung lesions and 26 with multiple lesions, average size 5.8 ± 0.5 mm. Eighty-two percent of the patients with isolated lesions and 69% of the patients with multiple lesions had tumor on biopsy. Of the 24 who received radiation therapy, 8 had a negative biopsy. Five of 6 treated with just 2 drugs may have been undertreated and 9 of 12 patients treated with 3 drugs had tumor on biopsy. Biopsy of lung lesions remains critical to definitively confirm metastatic disease in lesions seen only on CT scan and should be considered in patients in whom the lesions do not resolve with initial chemotherapy prior to use of x-ray therapy or more intensive chemotherapy.

Szavay et al21 reported a SIOP series of children with primary hepatic metastasis in nephroblastoma suggesting that initial surgical resection improved survival. However, in a subsequent analysis of children treated on NWTS-4 and 5, Ehrlich et al22 did not support consideration for initial “up-front” hepatic resection. Ureteral extension in Wilms tumor was identified in 45 children (2% of children treated in NWTS-5).23 This diagnosis should be suspected in patients with gross hematuria, hydronephrosis, or nonfunctioning kidney. Cystoscopy with retrograde ureterogram may aid in a preoperative diagnosis. Complete resection of the involved portion of the ureter at the time of nephrectomy can avoid spillage of tumor and residual disease and the need for more intensive chemotherapy and radiation therapy.

Bilateral Wilms tumor (BWT) poses a unique clinical challenge because of the competing priorities of maximizing preservation of renal parenchyma to prevent renal failure and complete surgical resection to cure the malignancy. In previous studies, patients were treated as followed only with guidelines given, but they were not enrolled on a specific protocol. For the first time, COG now has an open protocol. Recently the NWTS-4 experience with 188 synchronous BWT patients was reported by Hamilton and coauthors.24 Guidelines for the 188 BWTs included initial biopsy followed by chemotherapy. One hundred ninety-five kidneys in 123 patients had initial open biopsy; 44 kidneys in 31 patients had needle biopsies. Although preresection chemotherapy was recommended, 87 kidneys in 83 patients were managed by primary resection. Complete nephrectomy was obtained in 48, 31 had partial wedge nephrectomies, and 8 had enucleations. No initial surgery was performed in 45 kidneys. Relapse or progression of disease occurred in 54 children. End-stage renal failure occurred in 23 children; 6 had bilateral nephrectomies. The 8-year EFS for BWT FH was 74% and OS was 89%; for BWT unfavorable-histology EFS was 40%, OS was 45%. Anaplasia was diagnosed after completion of initial chemotherapy in 14 patients. The average interval from the start of chemotherapy to diagnosis of anaplasia was 390 days (range, 44-1925 days).

The analysis of NWTS-4 BWT demonstrated that preservation of renal parenchyma is possible after initial preoperative chemotherapy. The incidence of renal failure remained significantly greater (12%) than in unilateral patients (1%). The current COG BWT protocol includes upfront intensification of initial chemotherapy, requires second look surgery at 6 weeks for patients who do not respond (<50% reduction in size of the tumor) and definitive surgery or open biopsy at 12 weeks. Adjuvant chemotherapy after resection will be modified on the basis of histology. The goal of earlier surgery is to address possible under treatment of anaplastic tumors and obviate prolonged treatment for differentiated or necrotic tumors. BWT with anaplastic tumors were not identified by needle biopsy and discordance was present in 80% (20/24) on final tissue diagnosis. Davidoff et al25 recently published a single institution series where 10 patients with BWT all had successful nephron sparing surgery. Many of these children had very large tumors even after preoperative chemotherapy, this emphasizes that it is easy to underestimate the amount of renal parenchyma that can be salvaged when compressed by a large tumor. Parenchymal-sparing surgery is advocated with partial nephrectomy or wedge excision preferred if it will not compromise tumor resection and negative margins are established.

Late effects are an important element in the treatment of childhood malignancy. Green et al26 recently reported 25-year follow-up of childhood Wilms tumor survivors from the Childhood Cancer Survival Study. The cumulative incidence of all versus severe health conditions was 65.4% and 24.2% at 25 years. Hazard ratios (HRs) were 2.0, 95% CI 1.8-2.3 for grades 1-4 and 4.7%, 95% CI 3.6-6.1 for grades 3 and 4 compared with the sibling group. WT survivors reported more adverse general health status than sibling group prevalence ratio 1.7, 95% CI 1.2-2.4, but mental health status, socioeconomic status, and health care use were similar. The cumulative incidence of second malignant neoplasm (SMN) was 3.0% (95% CI 1.9%-4.0%) and mortality was 6.1% (95% CI 4.7%-7.4%). This finding excludes nonmelanoma skin cancer. The most common SMNs were soft-tissue sarcoma in 6, 5 confirmed breast cancers, one osteogenic sarcoma, and one Ewing sarcoma. Radiation exposure increased the likelihood of congestive heart failure in patients who received no doxorubicin (HR 6.6; 95% CI 1.6-28.3), in patients who received <250 mg m−2 doxorubicin (HR 13.0, 95% CI 1.9-89.7), and in those who received >250 doxorubicin (HR 18.3% 95% CI 3.8-88.2; SMN, standardized incidence ratio 9.0, 95% CI 3.9-17.7 with and 4.9, 95% CI 1.8-10.6 without doxorubicin) and death. Long-term survivors of WT treated between 1970 and 1986 are at increased risk of treatment related morbidity and mortality now 25 years from diagnosis.

End-stage renal disease (ESRD) in patients with Wilms tumor was assessed in a study by Breslow and associates27 from the NWTSG. The cumulative overall risk of ESRD at 20 years after diagnosis of unilateral WT was clearly determined by associated syndromic findings: 74% for 17 patients with Deny-Drash syndrome (DDS), 36% for 37 patients with WAGR syndrome, 7% for 125 male patients with hypospadias or cryptorchidism, and 0.6% for 5347 patients without these conditions. For patients with BWT the findings were similar: 50% with DDS (n = 6), 90% for WAGR (n = 10), 25% for those with a genitourinary (GU) anomaly (n = 25), and 12% for other patients (n = 409). ESRD for patients with WAGR syndrome or GU anomalies tended to occur relatively late, often during or after adolescence. The risk of ESRD is exceptionally low for the majority of WT patients. Those with WAGR, DDS or associated GU anomalies should be screened indefinitely to address impaired renal function.

The risk factors for ESRD in non-WT1-related syndromes were recently described by Lange and colleagues (personal communication). Cumulative incidence of ESRD attributable to chronic renal failure (CRF) 20 years after WT diagnosis was 0.7%; for ESRD attributable to progressive BWT it was 4% at 3 years after WT diagnosis in synchronous BWT and 19.3% in metachronous BWT. Metachronous BWT is associated with high rates of ESRD because of surgery for progressive WT. Characteristics associated with WT1 etiology (ie, stromal predominant histology HR 6.4% 95% CI P < 0.001, intralobar nephrogenic rests HR of 5.9 to no rests, 95% CI P = 0.001, and early-onset WT <24 months had an HR of 1.7 relative to appearance at 24-48 months and 2.8 relative to >48 months, P = 0.003 for trend) markedly increased the risk of ESRD as the result of CRF despite an overall low risk in non-WT1 syndromic patients.

Wilms tumor biology and treatment is evolving at a rapid pace and remains a paradigm for multimodal cancer therapy. Future efforts will focus on unlocking the cellular mechanisms of metastasis and clinical efforts will remain focused on minimizing toxicity and improving outcomes for patients with unfavorable histology tumors and recurrent disease.

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References 

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PII: S1055-8586(11)00089-8

doi:10.1053/j.sempedsurg.2011.10.002

Seminars in Pediatric Surgery
Volume 21, Issue 1 , Pages 15-20, February 2012

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