Wilms tumor is rare in adulthood. The prognosis is poor when compared with children. Adults more frequently present with advanced disease stages, and chemotherapy has a moderate effect. The various protocols of chemotherapy and indications for surgery and radiotherapy are not yet precisely defined, mainly due to the rarity of the disease. The Society of Pediatric Oncology (SIOP) guidelines suggest that both pediatric and adult patients should have initial chemotherapy followed by surgery. However, the National Wilms Tumor Stage Group (NWTSG) recommends surgery followed by chemotherapy. The authors present 2 cases of adult nephroblastoma that were highly resistant to presurgical chemotherapy. Nephrectomy was not completed because of rapid disease progression. The poor response of these 2 patients indicates that the alternate NTWSG approach of initial surgery followed by systemic treatment might have better results for this population. The authors review related reports and discuss the diagnosis and management of adult Wilms tumor.
KEYWORDS: Adult Wilms tumor; Prognostic factors; Management.
CORRESPONDENCE: Samia Arifi, MD, Department of Medical Oncology, Hassan II University Hospital, Route Sidi Harazem, Fez, Morocco ().
CITATION: Urotoday Int J. 2010 Jun;3(3). doi:10.3834/uij.1944-5784.2010.06.04
ABBREVIATIONS AND ACRONYMS: AWT, adult Wilms tumor; CT, computed tomography; NWTSG, National Wilms Tumor Stage Group; OS, overall survival; PNET, primitive neuroendocrine tumors; PWT, pediatric Wilms tumor; SIOP, Society of Pediatric Oncology; VOD, venoocclusive disease.
Wilms tumor is the most common pediatric renal neoplasm, but its occurrence in adults is very rare. There is no morphological difference between adult Wilms tumor (AWT) and pediatric Wilms tumor (PWT), but the pathogenesis may be different . The prognosis of AWT is poorer when compared PWT, in part because adults more frequently present with advanced disease stages.
Clinical presentation of AWT is often indistinguishable from other more common adult renal tumors. Staging and treatment guidelines for adults are still lacking. Currently, the staging of both AWT and PWT is done in the same way, according to the National Wilms Tumor Stage Group (NWTSG) or the Society of Pediatric Oncology (SIOP) [2,3].
A multimodal approach is used for treatment of both PWT and AWT. Management involves chemotherapy, radiotherapy, and surgery. Chemotherapeutic regimens use vincristine, dactinomycin, and doxorubicin (Adriamycin; Bedford Laboratories, Bedford, OH, USA) [2,3]. Etoposide, carboplatinum, and ifosfamide are particularly successful at the time of relapse [4,5]. Radiation is added for the more advanced or histologically aggressive tumors [2,3].
The present authors report 2 cases of AWT that are unique because of their high resistance to chemotherapy and rapid disease progression. They discuss the difficulties in determining the patient's diagnosis and prognosis, and compare existing treatment plans.
A 17-year-old male complained of intermittent pain in the right flank. Abdominal ultrasound and computed tomography (CT) scan revealed a right renal mass. The mass had a tumor thrombus that extended through the renal vein and into the inferior vena cava, with lymph node metastases (Figure 1). The CT scan showed multiple liver and lung metastases (Figure 2). A true-cut biopsy was performed, and a final diagnosis of adult Wilms tumor was made after a second review of the histopathology by a pediatric pathologist (Figure 3). Chemotherapy was conducted for 6 weeks, with vincristine 2 mg per week and doxorubicin 50 mg/m2 (d1=d28). A radical nephrectomy was proposed, but the renal mass was unresectable (Figure 4). The patient received a second line of chemotherapy that consisted of etoposide 200 mg/m2 for 3 days and cisplatin 100 mg/m2 (d1=d21). After 3 cycles, a CT scan showed no response (Figure 5). The patient showed a sudden drop in performance status and died of hepatic failure 3 weeks after the last cycle.
A 25-year-old male presented with pain in the left flank and gross hematuria. He had a history of weight loss and drop in performance status. Abdominal ultrasound and CT imaging revealed a left renal mass with retroperitoneal lymphadenopathy and multiple liver metastases. A renal true-cut biopsy was done. Pathological examination, reviewed by 2 pathologists, confirmed the diagnosis of nephroblastoma. The chest scan showed multiple lung and parietal pleura metastases. The patient received 6 weeks of chemotherapy with dactinomycin 45 ug/kg for 15 days, vincristin 2 mg per week, and doxorubicin 50 mg/m2 for 4 weeks. A follow-up CT scan showed stable disease. A second line of chemotherapy was started, consisting of etoposide 150 mg/m2 for 3 days and carboplatin area under curve (AUC) 5. The mass remained inoperable after 3 cycles of this second line of chemotherapy. The patient died 3 months after the last cycle of chemotherapy.
Wilms tumor is an embryonal malignancy that arises from remnants of an immature kidney. Only 3% of Wilms tumors are diagnosed in adult patients . Results from the California Cancer Registry  showed that AWT represents 30% of primary renal cancer in the second decade of life and that patients have a mean age of 13.9 years.
Because AWT is rare, its diagnosis is infrequently suspected in adult patients. Tumor symptoms are unspecific (eg, flank pain, abdominal mass, hematuria), and it is not possible to achieve a safe diagnosis by imaging studies alone. Imaging only confirms the presence of a renal mass. Usually, the diagnosis is established after primary nephrectomy . A fine-needle or true-cut biopsy may be a plausible approach in cases of primarily inoperable tumors or metastatic disease.
Histologically, AWT does not differ from PWT. The tumors are composed of blastemal, stromal, and epithelial cells that recapitulate normal kidney development. The proportions of the 3 cell components vary greatly [2,3]. Both of the present patients had a biphasic nephroblastoma composed of blastemal and stromal contingents Figure 3.
In some cases diagnosis is difficult by morphology alone, especially in adults. Diagnosis of nephroblastoma is retained after exclusion of other disorders that are more common to this age, such as renal cell carcinoma (RCC), renal sarcoma, and primitive neuroendocrine tumors (PNET) [6,8]. Some markers may be used such as CD99, FLI-1 (relatively specific for PNET), and WT-1 for Wilms tumors .
A central review of the histological feature of AWT is mandatory. This is exemplified in the SIOP 93-01/Society for Pediatric Oncology and Hematology (GPOH) study of 30 patients with Wilms tumor . Central review was needed to establish the diagnosis in 6 patients, and to upgrade the status to high risk in 5 patients.
AWT often shows anaplasia, which is associated with a more aggressive clinical behavior. Patients with anaplasia have a 5-year overall survival (OS) rate of 37%; patients without anaplasia have a corresponding OS rate of 65% . The prognosis of AWT is poor when compared with children. Approximately 33% to 50% of adult patients have metastatic diseases at the time of diagnosis, and adults often have weight loss or a decline in their performance status that is not typically seen in children [2,6]. These previously reported findings are in accordance with the observations of the present authors.
Because of the rarity of AWT, exact prognostic factors are not available. Izawa et al  reviewed data from all reports of AWT published between 1973 and 2006. The authors summarized information from 128 patients that included age, sex, favorable or unfavorable histopathology, the absence or presence of anaplasia, clinical stage (according to the NWTSG), and chemotherapy and radiotherapy received. The data were analyzed to determine factors that predict outcomes for patients with AWT. Favorable histopathology significantly predicted superior OS and disease-specific survival (DSS) (both P < .001). Higher clinical stage significantly predicted inferior OS and DSS (both P < .001); the tumor relapse rate among patients with stage I, II, III, and IV disease was 0%, 13%, 17%, and 50%, respectively. The variables of age, sex, and therapy with external beam radiation were not associated with any survival outcomes.
The present authors describe 2 rare cases of advanced AWT with very poor prognostic features, judging by their survival. Both patients had pathology ratings of stage IV and showed predominance of blastemal components and anaplasia on histological study. All of these factors are associated with a more aggressive clinical behavior [3,9]. Furthermore, these cases were refractory to 2 lines of chemotherapy. Both tumors had a poor, transient response to systemic treatment, in spite of receiving the multiagent chemotherapy that is typically effective in patients with PWT. This poor response could be secondary to a lack of effectiveness of classic combination drugs in patients with AWT, and might suggest the need for alternative drugs for adults. Additional pathologic and biologic data are needed to explain this chemoresistance. Recently, several markers have been identified as poor prognostic indicators, such as loss of heterozygosity (LOH) at chromosomes 1p and 16q and telomerase expression level . These factors should be investigated in patients with AWT. Molecular studies and gene expression profiling should be carried out to identify new prognostic factors and incorporate them into treatment decisions.
For the present patients, the authors created the treatment plan in accordance with a pediatric oncologist, who recommend the use of at least 3 drugs (vincristin, dactinomycin, doxorubicin) followed by nephrectomy and radiotherapy for metastatic disease. Dactinomycin was not available for the first case. Because of the poor response to the first line of chemotherapy, both patients received etoposide and platinum as a second line. The tumors remained inoperable and neither patient completed surgery before succumbing to the tumor progression.
The poor outcomes of the present patients after following the typical SIOP protocol of presurgical chemotherapy suggests that the alternate accepted NWTSG approach may be preferable. This approach consists of initial surgery followed by systemic treatment, even for metastatic disease. Tumor debulking and removal of the primary tumor might carry an advantage over initial systemic therapy for patients with AWT, because standard chemotherapy used for patients with PWT is expected to be less effective in adults.
Until recently, a standardized treatment for AWT was missing from the literature. There were only a few reports of a small series of patients with AWT. These patients were treated with different protocols involving chemotherapy, surgery, and radiotherapy. The results of these early studies are somewhat contradictory. Fortunately, the more current guidelines proposed by the NWTSG and SIOP have helped to direct physicians.
In 1982, the NWTSG reported a series of 31 patients with AWT who were treated between 1968 and 1979 . A total of 51.7% had stage III and stage IV disease. The 3-year survival rate was 24%, compared with 74% for patients with PWT. These results indicated a need for new therapeutic approaches for patients with AWT. In 1990, Arrigo et al  from the NWTSG studied 27 adult patients who were treated between 1979 and 1987. Their results demonstrated a survival rate of 67% at 3 years, which was a significant improvement over the previous report. Moreover, patients registered in NWTSG-4 with favorable histologic type AWT who were treated according to NWTSG protocols had good survival . The 5-year relapse-free survival, overall survival, and disease-specific survival rates were 77.3%, 82.6%, and 95.7%, respectively. The survival rates for those with stage I, II, III, and IV disease were 100%, 92%, 70%, and 73%, respectively. In the SIOP 93-10/GPOH study , 30 patients older than 16 years were treated between 1994 and 2001. Of the total N, 66% were diagnosed with localized disease, 33% were metastatic at the time of diagnosis (2 patients showed anaplasia on histologic study). The OS was 83% and the event-free survival was 57% at 4 years. Note that in the SIOP study, in contrast to the protocols for the pediatric population, the majority of the adult patients had primary surgery; only 4 out of 30 patients received preoperative chemotherapy. Five of the 10 patients with metastatic tumors progressed during treatment, 4 showed a complete remission, and 1 had a residual tumor burden . Finally, Terenziani et al  reported their institutional experience regarding AWT. Between 1983 and 2001, 17 patients with AWT who were older than 16 years were treated according to PWT guidelines. In this series, the OS was 62.4% at 5 years.
In summary, previous reports suggest that Wilms tumor in adults may be curable if treated according to pediatric strategy, including chemotherapy, radiotherapy, and surgery. However, the reported OS rates range from 24% to 67% at 3 years, 83% at 4 years, and 70-100% at 5 years, depending on the stage of the disease and the study reporting the data.
An additional factor is proposed by Kalapurakal et al . These authors suggest that the unfavorable outcome of patients with AWT may be the result of hepatic venoocclusive disease (VOD). The incidence of hepatic VOD ranges from 8% to 13% among patients who receive chemotherapy for AWT. The authors propose that oncologists specializing in adult patients, who are not routinely accustomed to treating AWT, are not familiar with VOD as a potential complication. This lack of familiarity may contribute to delayed recognition and early fatality in these patients [12,14].
In the absence of randomized controlled data, central reporting of cases of AWT may help improve their management. Further study should increase the present understanding of the disease pathogenesis, direct the development of new agents, and potentially lead to revised treatment protocols to improve outcomes for these patients.
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