UPDATE ON WILMS TUMOR IN CHILDREN

Transcription

1 UROLOGY FOR THE PRACTITIONER UPDATE ON WILMS TUMOR IN CHILDREN Anthony COOK, Walid FARHAT, Antoine KHOURY Cook A, Farhat W, Khoury A. Update on Wilms tumor in children. Leb Med J 2005 ; 53 (2) : ABSTRACT : Although rare, Wilms tumor is the most common primary renal malignancy in children and is associated with a number of congenital anomalies and documented syndromes. Appropriate laboratory, radiologic and pathologic investigations are necessary components of the evaluation of children with suspected Wilms tumor. This provides accurate diagnosis and subsequent staging ; information which is essential to generate a multidisciplinary treatment plan utilizing surgery, chemotherapy and radiotherapy. Patients treated for Wilms tumor as children must continue to be monitored for possible long-term sequelae as adults including secondary malignancies as well as treatment-related toxicity. INTRODUCTION Wilms tumor is the most common primary renal malignancy of childhood and accounts for approximately 6-7% of all pediatric cancers [1]. It represents one of the few malignancies in which, over the past several decades, advances in biomedical technology have led to significant improvements in patient survival. By employing a multidisciplinary approach incorporating surgery, radiotherapy and chemotherapy, the management of Wilms tumor represents an ideal model of cancer therapy. However, as these advances have better defined high-risk patients who obviously benefit from intensified treatment regimens, ongoing investigations are attempting to delineate those patients with low-risk disease whom could be spared the possible long-term sequelae of more intensive treatment without compromising cure rates. We present an update on Wilms tumor in childhood including its epidemiology, biology, pathology, clinical presentation and diagnosis, as well as the current treatment of all stages of the disease. EPIDEMIOLOGY Division of Urology, The Hospital for Sick Children, University of Toronto, Canada. Correspondence : Dr Antoine Khoury. Division of Urology. The Hospital for Sick Children. 555 University Avenue 3. Toronto. Ontario M5G 1X8. Canada. Phone : (1) Fax : (1) tony.khoury@sickkids.ca The incidence of Wilms tumor ranges from 8-10 cases per million population [2-3]. The median age at presentation is 3.5 years although bilateral disease and those with associated syndromes tend to present at an earlier age. Wilms tumor accounts for over 80% of genitourinary malignancies in children less than 15 years of age and 90% of children are diagnosed before age 7. Frequently, Wilms tumor is associated with a number of congenital anomalies or documented syndromes. A number of these syndromes share somatic overgrowth as a key feature and include the Beckwith-Wiedemann syndrome (BWS) and hemihypertrophy. BWS is characterized by excess cellular growth leading to macroglossia, nephromegaly, hepatomegaly and hemihypertrophy [4]. Overall, the risk of tumor development including Wilms, adrenal cortical carcinoma and hepatoblastoma is 10-20% in patients with BWS while the risk of Wilms tumor alone is estimated to be 4-10% [5]. Nephromegaly appears to be the most significant risk factor for the subsequent development of Wilms in patients with BWS [6]. A number of other overgrowth syndromes have also been identified which appear to impart an increased risk of the development of Wilms tumor including Soto, Simpson-Golabi-Behmel and Perlman syndromes [7-8]. Other associations include the WAGR and Denys- Drash syndromes. WAGR consists of Wilms, aniridia, genitourinary anomalies, and mental retardation while the Denys-Drash syndrome is characterized by male pseudohermaphroditism, renal mesangial sclerosis and Wilms tumor [9-10]. Currently, it is recommended that children with syndromes known to be associated with an increased risk of Wilms tumor undergo semiannual screening abdominal ultrasonography. Finally, approximately 4.5% of patients with Wilms tumor also present with other genitourinary abnormalities not otherwise specified by a specific syndrome including hypospadias, cryptorchidism, and renal fusion anomalies including horseshoe kidneys [11]. BIOLOGY OF WILMS TUMOR Wilms tumor was one of the original examples of the Knudson two-hit hypothesis of tumorigenesis where two separate genetic alterations are necessary for tumor formation [12]. Initially, susceptible individuals carry a germline mutation either from parental inheritance or from a de novo mutation. Thereafter, only one somatic mutation is necessary to induce malignant change. Alternatively, individuals without an initial germline mutation (sporadic disease) require two relatively rare, separate genetic mutations in the same cell in order for tumorigenesis to occur. The fact that some patients with Wilms tumor presented at an earlier age and had asso- Lebanese Medical Journal 2005 Volume 53 (2) 85

2 ciated congenital anomalies led to the hypothesis that genetic alterations consistent with the two-hit model were, in part, contributing to tumor development in these patients. However, subsequent investigations have determined that multiple genetic loci and several biological events are involved in this complex disease process [13]. Individuals with the WAGR syndrome were the first to be identified with an abnormality at a specific genetic locus, termed WT1 isolated on chromosome 11p13, which ultimately results in Wilms tumor formation [14]. WT1 normally encodes a transcription factor and acts as a classic tumor suppressor gene which is involved in normal renal and gonadal development [15]. WT1 mutations have also been identified in individuals with the Denys-Drash syndrome [16]. Although the development of Wilms tumor in patients with WAGR or Denys- Drash is clearly affected by WT1 mutations, very few patients with sporadic Wilms tumor carry mutations either in the germline (< 5%) or in tumor tissue (6-18% [15], thus indicating that other genes are involved in tumorigenesis. A second locus, termed WT2 was mapped on chromosome 11p15 and, similar to the relationship between WT1 and WAGR syndrome, it is associated with the BWS [17]. Genetic linkage studies have identified that the BWS gene maps to the same area on chromosome 11p15 as WT2 and likely involves a region of 11p15 where loss of heterozygosity (LOH) has been associated with Wilms tumor [18]. Other candidate genetic loci have also been identified on chromosomes 17q and 19q [15] and, although their roles remain as of yet undefined, future studies will undoubtedly further clarify the underlying genetic basis for Wilms tumorigenesis. PATHOLOGY OF WILMS TUMOR FIGURE 1. Classic triphasic Wilms tumor consisting of blastemal, stromal, and epithelial elements. Most pediatric renal tumors were previously classified as either favorable or unfavorable Wilms tumors ; however, the National Wilms Tumor Study Group (NWTSG), a North American multicenter collaborative research consortium, identified that some tumors initially classified as unfavorable variants were in fact separate malignancies [19]. Subsequent trials from the NWTSG excluded both clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RTK) from further evaluation. The present NWTSG-5 has separate treatment protocols for both CCSK and RTK (see below). Grossly, Wilms tumor tends to be soft and friable, compresses adjacent normal renal parenchyma, and is usually associated with central hemorrhagic necrosis. Microscopically, it classically contains a triphasic pattern of cell types including blastema, epithelium and stroma (Figure 1). Occasionally, biphasic or even monophasic Wilms is identified. Due to its embryonic nature, heterologous tissue is frequently encountered including skeletal muscle, squamous epithelium, cartilage, bone and fat [20]. The most clinically significant histopathological finding is that of unfavorable histology (defined as enlarged, polyploid nuclei) which, although present in only 10% of tumor specimens, was associated with almost 50% of the deaths in the early NWTSG results [21]. Furthermore, anaplasia is known to confer an increased resistance to chemotherapy and, although rare in the first two years of life, its incidence increases to 13% in older children [22]. Anaplasia has been further characterized as either focal or diffuse and, depending on tumor stage, alters NWTSG-5 present treatment protocols. For many years the presence of precursor lesions, termed nephrogenic rests have been identified in as many as one-third of kidneys resected for Wilms tumor [23]. Nephrogenic rests have been identified in approximately 1% of infant postmortem examinations [24]. These lesions consist of postnatally persistent embryonal cells which may undergo subsequent maturation, sclerosis, and involution or, in a minority, malignant degeneration. The presence of multiple nephrogenic rests is termed nephroblastomatosis and is associated with increased risk of bilaterality and recurrent disease and requires close radiographic and clinical follow-up [23]. CLINICAL PRESENTATION AND DIAGNOSIS Wilms tumor most commonly presents in childhood as an asymptomatic abdominal mass (Figure 2). Other signs and symptoms include abdominal pain, hematuria and fever. Approximately 25% of patients present with hypertension attributable to elevated plasma renin activity while up to 10% have an identifiable coagulopathy secondary to acquired Von Willebrand s disease [25]. Intracaval extension of Wilms is found in 4-10% and presents with varicocele, peripheral edema, hepatic congestion, ascites or even overt heart failure [26]. Rarely, children can present with an acute abdomen and evidence of hemodynamic compromise secondary to hemorrhage within a Wilms tumor or even from intrabdominal rupture. Following a careful history and physical examination (including a search for stigmata of Wilms associated 86 Lebanese Medical Journal 2005 Volume 53 (2) A. COOK et al. Update on Wilms Tumor in Children

3 FIGURE 2. CT scan of a 4-year-old male with Wilms tumor who presented with an asymptomatic abdominal mass. syndromes or other anomalies), the initial evaluation of a child with an abdominal mass is a complete abdominal ultrasound. This non-invasive test will determine if the lesion is of renal origin, cystic or solid, and associated with other intra-abdominal lesions such as adenopathy. Other differential diagnoses to consider include hydronephrosis, multicystic dysplastic kidney, polycystic kidney disease, neuroblastoma, and various other visceral lesions such as splenomegaly and gastrointestinal duplication anomalies (Figure 3). Fortunately, the abdominal ultrasound will elucidate the underlying origin for many of these masses and, if the lesion is found to be of renal origin, subsequent investigations are directed toward its diagnosis and staging. Cross sectional imaging, either CT or MRI, is the next most appropriate radiologic investigation as it not only evaluates the extent of the primary lesion including extrarenal extension, contiguous organ invasion, intracaval invasion, and locoregional metastases, but, with the use of intravenous contrast agents, also determines the presence of a functioning contralateral kidney. Furthermore, CT or MRI can accurately identify bilateral Wilms tumor, identified synchronously in 5% of patients, which (as will be described) requires a significantly altered approach to management [27]. Further radiographic staging includes either plain film chest x-rays or, more commonly, chest CT. Other imaging studies are reserved for specific clinical situations including radionuclide bone scan and skeletal survey for all children diagnosed with clear cell sarcoma as well as brain CT or MRI for those with either clear cell sarcoma or rhabdoid tumor as both are associated with intracranial metastases [28-29]. Laboratory investigations for children with suspected Wilms tumor include a complete blood count, electrolytes, renal function, liver enzymes, serum calcium Figure 3. Abdominal ultrasound of a 6-month-old female with a left multicystic dysplastic kidney who initially presented with a palpable left abdominal mass. Note the compensatory hypertrophy of the contralateral ultrasonographically normal right kidney. and urinalysis. Following the completion of all radiologic and laboratory investigations, usually within 2-3 days, a multidisciplinary team approach including pediatric urology or surgery, hematology/oncology, social work, and nursing is utilized to provide the patient, and their family, the optimal therapeutic regimen. Staging The most common staging system used for Wilms tumor is from the NWTSG and is based on the anatomical extent of disease. STAGE I Tumor confined to the kidney, without evidence of capsular penetration or positive margins, and completely excised. The renal hilar vessels are not involved and the tumor was not biopsied prior to removal (small fine-needle aspiration biopsies are excluded). STAGE II Tumor extends beyond the kidney but is completely excised without evidence of margin positivity or nodal involvement. There is evidence of capsular penetration, invasion of renal hilar vessels, and local flank spillage during resection, or previous biopsy of the tumor. A. COOK et al. Update on Wilms Tumor in Children Lebanese Medical Journal 2005 Volume 53 (2) 87

4 STAGE III Residual non-hematogenous tumor confined to the abdomen remains following surgery including gross or microscopic resection margins, positive abdominal lymph nodes, peritoneal penetration or tumor implants, transected tumor thrombus, or gross tumor spillage involving peritoneal surfaces. STAGE IV Hematogenous metastases or lymph node metastases outside the abdominopelvic region are present (eg. lung, liver, brain, bone). STAGE V Bilateral Wilms tumors. Accurate staging allows comparisons between various treatment regimens and enables large scale studies to further improve patient survival. Although presently still investigational, genetic markers are expected to be included in staging and guide therapy in the future. For example, one study demonstrated that LOH on a portion of chromosomes 16q and 1p imparted a poorer 2-year relapse-free and overall survival than those without LOH [30]. TREATMENT Following appropriate laboratory and radiographic staging investigations, complete surgical resection remains the standard initial therapy in North America. NWTSG- 5 recommends a transperitoneal approach in order to adequately stage the locoregional extent of disease, including inspection of the contralateral kidney to exclude bilaterality prior to nephrectomy [31]. Suspicious lymph nodes are sampled, however, formal lymph node dissection is neither recommended nor beneficial. Care must be taken to avoid tumor spillage as this results in upstaging (from stage II to III), and necessitate postoperative radiotherapy. Tumors deemed unresectable at the time of initial exploration are biopsied and the patient is treated with appropriate chemotherapy ; surgical resection is then undertaken following downsizing of the mass. Other NWTSG-5 indications for preoperative chemotherapy include vascular invasion and bilaterality. Controversy remains regarding partial nephrectomy for primary lesions and is not presently recommended in the routine treatment of unilateral Wilms tumor. Longterm follow-up has demonstrated that the majority of patients do not progress to end stage renal disease [32]. Furthermore, at the time of initial presentation, only a small number of patients could be considered for partial nephrectomy due to the large size and central location of most Wilms tumors [33]. Nephron-sparing surgery is reserved for those patients with solitary kidneys, intrinsic renal disease or those with, or at risk for, bilateral disease. Adjuvant chemotherapy ± radiotherapy is then undertaken depending on tumor stage and histology. Treatment regimens presently recommended by NWTSG-5 are outlined in table I. One of the primary goals of NWTSG-5 is to reduce treatment for those patients with favorable histology without compromising cure rates while continuing to maximize therapy for those with high-risk disease. An alternative treatment approach, employed by the Société internationale d oncologie pédiatrique (SIOP) involves preoperative chemotherapy followed by surgical resection and histopathological confirmation. Patients undergo initial staging investigations and subsequently embark on a course of chemotherapy without histological diagnosis. Thereafter, repeat imaging is performed, and surgery planned accordingly. Proponents state that this approach facilitates subsequent surgery and may allow partial nephrectomy to be performed [34]. Furthermore it reduces the risk of tumor rupture and evaluates tumor responsiveness to chemotherapy which allows early modifications to postoperative chemotherapy in those who do not respond to neoadjuvant therapy [35]. However, the approach advocated by the SIOP must be weighed against the risks of chemotherapy without tissue diagnosis as chemotherapy is initiated without pathological confirmation of disease. Bilateral Wilms Tumor As previously mentioned, the presence of bilateral disease mandates a significantly altered treatment regimen. Fortunately, the resolution of modern CT or MRI allows the preoperative identification of bilaterality in TABLE I NWTSG-5 TREATMENT REGIMENS STAGE Histology Radiotherapy Chemotherapy regimen Duration (weeks) I-II Favorable No EE4A 18 I Anaplastic No EE4A 18 III-IV Favorable Yes DD4A 24 II-IV Focal anaplasia Yes DD4A 24 II-IV Anaplastic Yes 1 24 I-IV CCSK Yes 1 24 I-IV RTK Yes RTK* 24 EE4A : vincristine + pulse-intensive dactinomycin DD4A : vincristine + pulse-intensive dactinomycin & doxorubicin 1 : vincristine, doxorubicin, cyclophosphamide, & etoposide RTK : rhabdoid tumor of the kidney CCSK : clear cell sarcoma of the kidney RTK* : carboplatin, etoposide, & cyclophosphamide 88 Lebanese Medical Journal 2005 Volume 53 (2) A. COOK et al. Update on Wilms Tumor in Children

5 the vast majority of cases [36]. A nephron-sparing approach is initially undertaken and both kidneys undergo either incisional or needle biopsy only. However, complete resection is appropriate only if an entire lesion can be excised without significant compromise to the remaining normal renal parenchyma. Following 6-8 weeks of chemotherapy, the patient is reassessed and complete resection is then undertaken if deemed technically feasible. This second-look procedure is then followed by adjuvant chemotherapy and, if necessary, radiotherapy. Long-term Effects of Treatment Patients treated for Wilms tumor as children must continue to be monitored for possible long-term sequelae as adults. Musculoskeletal abnormalities (such as scoliosis), hypogonadism and ovarian failure have all been described following abdominal radiation [37-38]. Cardiotoxicity secondary to doxorubicin therapy may result in congestive heart failure in as many as 4% of patients and secondary malignancies have been documented in 1% of long-term Wilms tumor survivors. Lifelong follow-up of these patients is essential in order to identify and treat these potential complications [39-40]. CONCLUSION Wilms tumor is the most common primary renal malignancy in childhood. Fortunately, with a multidisciplinary approach to its management as well as ongoing genetic and molecular advances, over 85% of children with Wilms tumor can be expected to be long-term survivors. As large scale cooperative studies mature (such as NWTSG-5), further refinements in treatment will undoubtedly limit adjuvant therapy, and consequently treatment related morbidity, in those considered low risk, while still maximizing therapy, and cure rates, in those with high-risk disease. REFERENCES 1. Breslow N, Olshan A, Beckwith JB, Green DM. Epidemiology of Wilms tumor. Med Pediatr Oncol 1993 ; 21 (3) : Gurney JG, Severson RK, Davis S, Robinson LL. Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 1995 ; 75 (8) : Breslow N, Olshan A, Beckwith JB et al. Ethnic variation in the incidence, diagnosis, prognosis, and follow-up of children with Wilms tumor. J Natl Cancer Inst 1994 ; 86 (1) : Beckwith JB. Macroglossia, omphalocele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly. Birth Defects : Original Article Series 1969 ; 5 : Beckwith JB. Certain conditions have an increased incidence of Wilms Tumor. Am J Roentgenol 1996 ; 164 : DeBaun MR, Siegel MJ, Choyke PL. Nephromegaly in infancy and early childhood : a risk factor for Wilms tumor in Beckwith-Wiedemann syndrome.[see comment]. J Pediatr 1998 ; 132 (3 Pt 1) : Neri G, Gurrieri F, Zanni G, Lin A. Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome [see comment]. Am J Med Genet 1998 ; 79 (4) : Perlman M, Levin M, Wittels B. Syndrome of fetal gigantism, renal hamartomas, and nephroblastomatosis with Wilms tumor. Cancer 1975 ; 35 (4) : Drash A, Sherman F, Hartmann WH, Blizzard RM. A syndrome of pseudohermaphroditism, Wilms tumor, hypertension, and degenerative renal disease. J Pediatr 1970 ; 76 (4) : Hittner HM, Riccardi VM, Ferrel RE et al. Genetic heterogeneity of aniridia : negative linkage data. Metab Pediatr Ophthalmol 1980 ; 4 (4) : Breslow NE, Beckwith JB. Epidemiological features of Wilms tumor : results of the National Wilms Tumor Study. J Natl Cancer Inst 1982 ; 68 (3) : Knudson AG Jr, Strong LC. Mutation and cancer : a model for Wilms tumor of the kidney. J Natl Cancer Inst 1972 ; 48 (2) : Dome JS, Coppes MJ, Recent advances in Wilms tumor genetics. Curr Opin Pediatr 2002 ; 14 (1) : Call KM, Glaser T, Ito CY et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms tumor locus. Cell 1990 ; 60 (3) : Coppes MJ, Pritchard-Jones K. Principles of Wilms tumor biology. Urol Clin North Am 2000 ; 27 (3) : Little MH, Williamson KA, Mannens M et al. Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum Mol Genet 1993 ; 2 (3) : Koufos A, Grundy P, Morgan et al. Familial Wiedemann- Beckwith syndrome and a second Wilms tumor locus both map to 11p15. Am J Hum Genet 1989 ; 44 (5) : Ping AJ, Reeve AE, Law DJ et al. Genetic linkage of Beckwith-Wiedemann syndrome to 11p15. Am J Hum Genet 1989 ; 44 (5) : Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors : results from the First National Wilms Tumor Study. Cancer 1978 ; 41 (5) : Beckwith JB. Wilms tumor and other renal tumors of childhood : a selective review from the National Wilms Tumor Study Pathology Center. Hum Pathol 1983 ; 14 (6) : Breslow N, Churchill G, Beckwith JB et al. Prognosis for Wilms tumor patients with nonmetastatic disease at diagnosis - results of the second National Wilms Tumor Study. J Clin Oncol 1985 ; 3 (4) : Bonadio JF, Storer B, Norkool P et al. Anaplastic Wilms tumor : clinical and pathologic studies. J Clin Oncol 1985 ; 3 (4) : Beckwith JB, Kiviat NB, Bonadio J. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms tumor. Pediatr Pathol 1990 ; 10 (1-2) : Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor : developmental and clinical considerations. Am J Med Genet 1998 ; 79 (4) : Coppes MJ. Serum biological markers and paraneoplastic syndromes in Wilms tumor. Med Pediatr Oncol 1993 ; 21 : Ritchey ML, Kelalis PP, Breslow N et al. Intracaval and atrial involvement with nephroblastoma : review of Na- A. COOK et al. Update on Wilms Tumor in Children Lebanese Medical Journal 2005 Volume 53 (2) 89

6 tional Wilms Tumor Study-3. J Urol 1988 ; 140 (5 Pt 2) : Blute ML, Kelalis PP, Offord KP et al. Bilateral Wilms tumor. J Urol 1987 ; 138 (4 Pt 2) : Feusner JH, Beckwith JB, D Angio GJ. Clear cell sarcoma of the kidney : accuracy of imaging methods for detecting bone metastases. Report from the National Wilms Tumor Study. Med Pediatr Oncol 1990 ; 18 (3) : Weeks DA, Beckwith JB, Mierau GW et al. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms Tumor Study Pathology Center. Am J Surg Pathol 1989 ; 13 (6) : Grundy PE, Telzerow PE, Breslow N et al. Loss of heterozygosity for chromosomes 16q and 1p in Wilms tumors predicts an adverse outcome. Cancer Res 1994 ; 54 (9) : Blakely ML, Ritchey ML. Controversies in the management of Wilm ' tumor. Semin Pediatr Surg 2001 ; 10 (3) : Ritchey ML, Green DM, Thomas PR et al. Renal failure in Wilms tumor patients : a report from the National Wilms Tumor Study Group [see comment]. Med Pediatr Oncol 1996 ; 26 (2) : Wilimas JA, Magill L, Parham DM et al. The potential for renal salvage in nonmetastatic unilateral Wilms tumor. Am J Pediatr Hematol Oncol 1991 ; 13 (3) : McLorie GA, McKenna PH, Greenberg M et al. Reduction in tumor burden allowing partial nephrectomy following preoperative chemotherapy in biopsy proved Wilms tumor [see comment]. J Urol 1991 ; 146 (2 Pt 2) : Tournade MF, Com-Nougue C, Voute PA et al. Results of the Sixth International Society of Pediatric Oncology Wilms Tumor Trial and Study : a risk-adapted therapeutic approach in Wilms tumor [see comment]. J Clin Oncol 1993 ; 11 (6) : Farhat W, McLorie G, Capolicchio G. Wilms tumor. Surgical considerations and controversies. Urolo Clin North Am 2000 ; 27 (3) : Evans AE, Norkool P, Evans I et al. Late effects of treatment for Wilms tumor. A report from the National Wilms Tumor Study Group. Cancer 1991 ; 67 (2) : Kinsella TJ, Trivette G, Rowland J et al. Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin s disease. J Clin Oncol 1989 ; 7 (6) : Breslow NE, Norkool PA, Olshan A et al. Second malignant neoplasms in survivors of Wilms tumor : a report from the National Wilms Tumor Study. J Natl Cancer Inst 1988 ; 80 (8) : Green DM, Grigoriev YA, Nan B et al. Congestive heart failure after treatment for Wilms tumor : a report from the National Wilms Tumor Study group. J Clin Oncol 2001 ; 19 (7) : Lebanese Medical Journal 2005 Volume 53 (2) A. COOK et al. Update on Wilm s Tumor in Children