Abstract: Wilms tumor is the most common childhood renal tumor accounting for about 6% of pediatric malignant disease. Most patients with Wilms tumor can be cured with treatment and subsequently lead normal life. The multidisciplinary management of Wilms tumor has resulted striking improvement in survival of more than 85% nowadays and has become a paradigm for successful cancer therapy. We describe the results of patients treated according to National Wilms Tumor studies (NWTS) 3-5, with surgical staging, Central pathology review and multimodality treatment. This is a historical cohort study on the all patients who had Wilms tumor. We used the existing files of all patients who had admitted to Ali Asghar Children’s hospital with Wilms tumor in the years of 1990-2003. The patients evaluated for age, sex, histologic type of cancer, metastasis, outlook of relapse and outcome after 5 years from diagnosis. We analyzed 175 files of Wilms tumor. They are 49.7% are male and 50.3% female. Mean age (±S.D.) of patients at diagnosis was 3.8±0.4 year. The 5-year survival rate of these patients was approximately 76±4%. History of cancer in first degree of relative was 11.5% and family marriage was 36.4%. Tumor involvement were 45.3% in right kidney, 51.5% in left kidney and both kidney involvement in 3.2%. Congenital anomalies in association with Wilms tumor were urologic problem (1.5%), hemihypertrophy (0.5%), sporadic aniridia (0.5%) and without abnormalities (97.5%). Histologic type of tumor were 32.6% favorable, 65.2% unfavorable and 2.2% intermediate. Stage II and III were the most common (35.4 and 32.4%, respectively). Tumor relapse were occurred in 25.4%.

INTRODUCTION

Wilms tumor (WT) is the second most common malignant retroperitoneal tumor. It is most common primary renal tumor of childhood (Reinhard et al., 2007). Wilms tumor consist 6% of all childhood cancer. Male to Female ratio in unilateral disease is 0.92 and 0.6 in bilateral disease (Petruzzi and Green, 1997). Seventy-eight percent of children are diagnosed at 1-5years of age, with a peak incidence occurring between 3 and 4 years of age. Median age of presentation is 44 months in unilateral disease, 32 months in bilateral disease (Zugor et al., 2007). The median age of presentation is 36.5 months for boys and 42.5 months for girls. WT is rare in adults (>16 years of age) (Seyed-Ahadi et al., 2007). Wilms tumor is usually sporadic. Congenital anomalies occur in 12-15% of cases (Abu-Gosh et al., 2002). Children with renal tumor most of which are favorable histology Wilms tumor, have an excellent 5 year survival rate (Petruzzi and Green, 1997; Zugor et al., 2007; Seyed-Ahadi et al., 2007; Abu-Gosh et al., 2002; Pastore et al., 2006). Modern therapy includes nephrectomy and combination chemo-therapy and for some, radiation therapy to the abdomen and/or lungs (Pastore et al., 2006; Mitchell et al., 2006; Dome and Coppes, 2002; Beckwith et al., 1996; Balaguer et al., 2006). The most frequent site of relapse is the lungs, while recurrence in the original tumor bed, at other intra-abdominal sites, brain and bone are less frequent. The percentage of event-free survival and overall survival at diagnosis are in relationship to the stage of disease and histology (Mitchell et al., 2006). Positive prognostic factors include the following: Stages I and II, Negative Para-aortic nodes, Absence of anaplastic or sarcomatous histology, Absence of tumor rupture, Site of metastases at relapse: lung better than liver, Time of relapse: Late better than early (>15 months from diagnosis). Initial treatment of children with Wilms tumor has been so successful (Dome and Coppes, 2002). We describe the results of patients treated according to National Wilms Tumor studies (NWTS) 3-4, with surgical staging, Central pathology review and multimodality treatment.

MATERIALS AND METHODS

Clinical characteristics: One hundred and seventy five patients with diagnosis of wilm’s tumor registered in this study. The clinical data, including treatment details and follow-up information, were gathered from retrospective review of patient charts. This is a historical cohort study on the all patients who had Wilms tumor. We used the existing files of all patients <14 years who had admitted to Ali Asghar Children’s hospital with Wilms tumor in the years of 1990-2000. All patients underwent an initial nephrectomy after completing a pre-operative assessment, which was to include radiographic imaging of the kidneys (abdominal CT scan), inferior vena cava and lungs, CBC, blood chemistries, coagulation factor and assessment of cardiac status. The surgical procedure was to performed through a transabdominal incision. The contalateral kidney was to be mobilized, all surface inspected and any lesion suspicious for Wilms tumor biopsied. A stage was according to surgical-pathological staging system (NWTSG).

Treatment protocol: Children received chemotherapy protocol according their stage of disease. We used NWTS 3-4 chemotherapy protocol. Radiation therapy was usually begun for stage III and IV shortly after chemotherapy to the tumor bed at a dose 1080 cGy.

Statistical analysis: Five year survival and Overall Survival (OS) were calculated from the time of diagnosis to the time of last followup. OS were estimated using the Kaplan-Meier and Log rank test by SPSS 11.5.

The patients evaluated for age, sex, histologic type of cancer, metastasis, outlook of relapse and outcome after 5 years from diagnosis.

RESULTS

The mean (±S.D.) age at diagnosis was 3.8±0.4 year (range 8 months -13 years). There is 49.7% (87 patients) male and 50.3% (88 patients) female. Positive family history of cancer in first degree of relative was 11.5%. History of family marriage was positive in 36.4%. Initial signs and symptoms, in order of frequency, are listed in Table 1. Tumor involvements were 45.3% in right kidney, 51.5% in left kidney and both kidney involvement in 3.2%. Congenital anomalies in association with wilm’s tumor were urologic problem (1.5%), hemihypertrophy (0.5%), sporadic aniridia (0.5%) and without abnormalities (97.5%). Histologic type of tumor were 32.6% favorable, 65.2% unfavorable and 2.2% intermediate. A stage frequency according to surgical-pathological staging system (NWTSG) was I (23.3%), II(35.4%), III(32.4%), IV(5.1%) and V (3.8%) (Table 2).

Table 1:	Initial signs and symptoms of Wilm’s Tumor in order of frequency

Table 2:	Relation of 5-year survival with age, stage and sex

Fig. 1:	Survival analysis of Wilm's tumor

The overall relative 5 year survival rate for children with wilm’s tumor was approximately 76±4% (Fig. 1). Males with wilm’s tumor had better survival rate than females with significant difference (85±4 vs. 64±7% P = 0.01) (Table 2). The 5-year survival rate was better in for patients under 1 years compare to others, respectively (90±9% vs. 73±4%, P = 0.85) (Table 2). Renal function test in all patients was normal except in 2 patients with bilateral wilm’s tumor report increase BUN. Relapse had occurred in 25.4% of patients. The most common site of relapse is primary site (52.7%), lung (33.3%) and mixed (14%). The tumor relapse rate among patients with stage I, II, III and IV disease was 0, 15, 18 and 55%, respectively. The time of relapse is 56.2% during treatment (1-9 months) and 43.7% after treatment (1 month -1 years).

DISCUSSION

Childhood Wilm's tumor or nephroblastoma represents one of the challenges for pediatric oncologists in developing countries (Beckwith et al., 1996; Balaguer et al., 2006; Green et al., 1997; Metzger and Dome, 2005; Hartman and Maclennan, 2005; Zils et al., 2008; Pession et al., 2008). Wilms tumor is one of the commonest childhood solid tumors which has an excellent outlook in the developed world with 5 year overall survival exceeding 90% (Balaguer et al., 2006; D’Angio, 2003; Uba and Chirdan, 2007; Abuidris et al., 2008). We review the clinical characteristics and outcome of management of childhood nephroblastoma. In our study overall relative 5 year survival rate for children with wilm’s tumor was approximately 76±4% (Green et al., 1997). A highly significant improved 5 year overall survival rate was found for relapsed patients with consultation (65 vs. 10%) in SIOP 2001 trial (Van den Heuvel-Eibrink et al., 2008). In another were 32 children (M: F=1.9:1) with histologically confirmed nephroblastoma seen over the 7 year period. Their median (range) age was 4 (3-15) years. The patients invariably presented with a palpable abdominal mass, but hematuria was exceptional (Metzger and Dome, 2005; Hartman and Maclennan, 2005; Zils et al., 2008; Pession et al., 2008). At presentation, 1 (3.1%) patient was in stage I, 8 (25%) stage II, 11 (34.4%) stage III and 12 (37.5%) stage IV. About 72% of the patients presented with stage III-IV disease same as our study (Pession et al., 2008; D’Angio, 2003). Overall, only 43.8% were alive between 1 and 9 months (median: 6 months) of follow-up period, but there was no survivor at 2 years after treatment. Childhood nephroblastoma has a high mortality rate in poor developing country because of late clinical presentation with advanced disease, poor availability of cytotoxic drugs and frequent interruptions in treatment and inadequate follow-up but in Iran we had good result (Uba and Chirdan, 2007; Abuidris et al., 2008). In another study 5 years event-free survival (EFS) was 80% and overall survival (OS) 86% (Zils et al., 2008; Pession et al., 2008). Renal tumors diagnosed in the first 7 months of life generally have an excellent prognosis though histology is an important prognostic factor same as our study. In the SIOP 93-01/GPOH trial and study 1 020 patients with a newly diagnosed renal tumor, the stage distribution of the tumors was stage I in 315 (61%), stage II N- in 126 (24%), stage II N+ in 25 (5%) and stage III in 36 (7%) patients against our study (D’Angio, 2003). The event free survival (EFS) after 5 years was 91% for all patients with unilateral Wilms tumor without distant metastasis (Uba and Chirdan, 2007). Today the results of the treatment of Wilms tumors are very good. In the NWTS-3 the 4 year relapse-free survival rate in stage 1 with favorable and with anaplastic histology was 92%, in stage 2 with favorable histology 88%, in stage 3 with favorable histology 79%, in stage 4 and in stage 2, 3 and 4 with unfavorable histology 71% (Abuidris et al., 2008; Van den Heuvel-Eibrink et al., 2008). The Italian group has obtained less impressive results in the 80%, but similar results in the first stage with the 92% (Merguerian, 2003; Slovis, 2008). Finally wilm’s tumor are good prognosis, today we know the optimal treatment for most children diagnosed with wilm’s tumor. Work continues on trying to identify effective treatment for children with unfavorable histologies.

CONCLUSION

Although, excellent survival has been maintained, many patients receive less therapy today than patients with similar characteristic did a decade ago. Today we know the optimal treatment for most children diagnosed with Wilms tumor. Work continues on trying to identify effective treatment for children with unfavorable histology. Better understanding of biological processes that leads to this childhood cancer will allow further improvements in its management.