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Wilms' Tumor in Adults: Results of the Society of Pediatric Oncology (SIOP) 93-01/Society for Pediatric Oncology and Hematology (GPOH) Study

From the Department of Pediatric Oncology, Department of Radiotherapy, Department of Urology, University Hospital, Hombug/Saar; Department of Paidopathology, University Hospital, Kiel, Germany

Address reprint requests to Harald Reinhard, MD, Pediatric Oncology, University Hospital, Building 9, D-66421 Homburg/Saar, Germany; e-mail: harald.reinhard{at}uniklinik-saarland.de

	ABSTRACT

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PURPOSE: In the Society of Pediatric Oncology (SIOP) 93-01 study, 30 patients older than 16 years were found to have Wilms' tumor. They were treated according to the pediatric protocol and were analyzed for clinical presentation, stage distribution, and prognosis.

PATIENTS AND METHODS: Patient age ranged from 16 to 62 years (median, 25.4 years). Tumor stages were defined according to SIOP, and treatment was risk-adapted according to SIOP 93-01/Society for Pediatric Oncology and Hematology (GPOH) protocol. The patients were evaluated with regard to response, toxicity, and prognosis. Specimens of all tumors were centrally reviewed.

RESULTS: Ten patients (33%) had metastatic disease at the time of diagnosis (liver, four patients; lung, three patients; liver and lung, three patients). The local stage distribution showed a predominance of higher stages (stage I, eight patients; stage IIN–, three patients; stage IIN+, four patients; stage III, 15 patients). Histologic studies revealed intermediate-risk in 23 of 30 tumors; two tumors were classified as high-risk; and three tumors were clear-cell sarcomas. Two of 30 patients showed a nephroblastoma and a renal cell carcinoma simultaneously in the same kidney. A complete remission was achieved in 24 patients; four patients relapsed after complete remission; and three of them reached a second remission with further treatment. Event-free survival was 57%, with an overall survival of 83% (median observation time, 4 years).

CONCLUSION: Adults can be cured in a high percentage by a multimodal treatment according to pediatric protocols. Toxicity is higher than in children, but acceptable in view of the high remission rate.

	INTRODUCTION

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Wilms' tumor is the most common renal tumor in children. Dramatic improvement has occurred in the survival of children with this tumor entity in the previous decades.¹ This excellent outcome is attributed to effective chemotherapeutic agents, advances in radiation oncology, improved surgical and anesthetic techniques, and supportive care. The integration of the different treatment modalities is studied in several randomized trials conducted mainly by the Society of Pediatric Oncology (SIOP) in Europe and the National Wilms' Tumor Study in North America. The main objectives of these trials and studies are to treat patients according to well-defined risk groups, in an attempt to achieve the highest cure rates, to decrease the frequency and intensity of acute and late toxicity, and to minimize the cost of therapy.

In the SIOP studies, the diagnosis of Wilms' tumor in children aged between 6 months and 16 years is made by means of imaging studies alone, without histologic studies. Patients with localized disease receive a preoperative two-drug chemotherapy regimen (vincristine plus dactinomycin) for 4 weeks. Metastatic tumors are treated with additional adriamycin and receive a 6-week course of therapy before tumor resection. Additional treatment is given depending on tumor stage and histologic classification.^2,3

Wilms' tumor in adults is a rare disease. There are only a few reports of always small series of patients treated with different protocols.^4-8 Until recently, a standardized treatment for adults with Wilms' tumor is missing, and exact data on prognosis and late effects are not available. Primary radical nephrectomy followed by chemotherapy is the treatment strategy for patients older than 16 years. In this article, we report our experience of 30 adult patients with Wilms' tumor who were treated according to the SIOP 93-01/Society for Pediatric Oncology and Hematology (GPOH) protocol.

We assume that all patients older than 16 years living in Germany, Austria, and Switzerland were registered in our study. As approximately 3% of Wilms' tumor cases occur in adults⁸ the number of 30 of 962 registered patients confirms this assumption.

	PATIENTS AND METHODS

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Between April 1994, and December 2001, 962 patients with Wilms' tumor were enrolled in the SIOP 93-01/GPOH trial and study. Tumors were classified as being of intermediate risk if they showed histological characteristics of blastemal, epithelial or stromal predominance, or mixed type without anaplasia. Tumors with focal or diffuse anaplasia were classified as being high-risk. Rhabdoid-type or clear-cell sarcomas of the kidney (CCSK) were treated according to high-risk. (Table 1). Thirty of these patients were older than 16 years, ranging from 16.4 to 62.4 years (median, 25.4 years). Characteristics of the patients are presented in Table 2. Diagnosis was confirmed by histologic classification before commencement of treatment in all of the 30 adult patients. Seventeen of them were male, and 13 were female; two had Down syndrome, and one patient had a horseshoe kidney. They were diagnosed and treated at 22 different centers. Initial radical nephrectomy was undertaken in 23 patients, whereas tumor histology was obtained via fine-needle or true-cut biopsy in seven patients. Four of the seven patients did receive preoperative chemotherapy. Patients with primary surgery did proceed directly to postoperative treatment. All tumor characteristics were reviewed by a central pathology panel to verify the diagnosis. Histologic classification was carried out according to the "Stockholm working classification of renal tumors of childhood and adolescence."⁹ The SIOP criteria were used for tumor staging. Clinical data, including syndromes and concomitant malignancies, surgical, pathological, and treatment data, as well as follow-up data were registered in the SIOP 93-01/GPOH database. Treatment toxicity was documented according to the National Cancer Institute Common Toxicity Criteria Version 2.0 toxicity score.¹⁰ Data analysis was performed using the statistical software package SPSS 11.5 for Windows.

	RESULTS

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In 28 patients, a kidney tumor was diagnosed, whereas two patients showed an extrarenal tumor mass. One of these tumors was located in the pelvis, and the other, in the mediastinum. Eighteen renal tumors were on the right, and 10 were on the left side. None of the patients presented with a bilateral nephroblastoma.

Stage Distribution
Twenty patients (66%) were diagnosed with localized disease, whereas a third of the patients (10 of 30) presented with metastatic disease (stage IV) at the time of diagnosis. Metastases were limited to the lungs in three patients, and to the liver in four patients. Three patients showed combined metastases (one lung and liver, one lung liver and mediastinum, and one liver and mediastinum).

Local stage I was diagnosed after surgery in eight patients (26%). Three patients were found to have stage II disease without lymph node involvement (II N–), and four patients, with positive lymph nodes (II N+). Fifteen patients (50%) had local stage III disease. In patients with metastatic disease, the local stage was II N– in one patient, II N+ in one patient, and stage III in eight patients. Tumor rupture occurred in none of the patients.

Pathology
Wilms' tumor or CCSK was diagnosed in 24 patients (80%) by local pathologists and confirmed by central review. In the remaining six patients who had a local diagnosis of primitive neuroectodermal tumor or renal cell carcinoma (RCC), the diagnosis of Wilms' tumor was established by reference pathology alone. The histological subtype was identical in 19 cases with regard to local and reference pathology, and underscored in five patients. The five cases reclassified as being high-risk after central pathological review and not of low or intermediate risk. Diagnosis of a nephroblastoma (blastemal predominant) and of an RCC in the same kidney was made by local and reference pathology in two cases.

Altogether, 25 tumors were of intermediate risk, two of high risk, and three were clear-cell sarcomas. The most frequent histological subtype was blastemal predominance, diagnosed in 15 tumors (50%); three had a mixed subtype; and five were of stromal or eptithelial predominance. Two of the high-risk tumors showed diffuse anaplasia, and none had a focal anaplasia according to the classification of Faria et al.¹¹ Two patients showed an RCC and a nephroblastoma (blastemal predominant) in the same kidney.

Treatment
Surgery. The majority of the patients (23 of 30) started treatment with radical nephrectomy. Three of the patients underwent primary tumor resection, though correct histologic diagnosis had been made by fine-needle biopsy. In four patients, surgery was done after preoperative chemotherapy according to SIOP 93-01/GPOH protocol. Response to chemotherapy was seen in three of the patients. Two tumors were found to be reduced in size, and one tumor remained stable. One patient was progressive under treatment. All of them had metastatic disease. Tumor resection was possible in 30 patients. Partial nephrectomy was never performed.

Chemotherapy. Chemotherapy was given to all patients. Three of the patients were initially treated according to different protocols because of a wrong initial histologic finding. After central review of histology, all patients were treated according to the SIOP 93-01/GPOH protocol (Table 1). Nineteen of them received the intermediate risk chemotherapy, and 11 received the high-risk chemotherapy. Criteria for high-risk treatment were high-risk histology (five patients) or poor response to intermediate-risk chemotherapy (six patients). Three patients underwent high-dose chemotherapy with stem-cell rescue—two of them in first-line therapy and one in relapse. The decision for this treatment strategy was taken by the local treatment center because no general criteria were given for high-dose therapy in this protocol. One of these patients is still in complete remission, and the other two died of tumor progression (Table 3).

The average time from surgery to the initiation of chemotherapy was 4.7 weeks (range, 1 to 15 weeks). This interval was mainly attributable to delays in the verification of histology, or to transfer of the patients to a specialized center.

Twenty percent of patients (2 of 10) with metastatic disease were treated according to the intermediate-risk protocol, and 80% (8 of 10), according to the high-risk protocol. Complete remission of metastases occurred in three patients during chemotherapy alone (one with isolated lung metastases, one with isolated liver metastases, and one with combined metastases of liver and lungs). In two patients, all metastases could be removed after 8 weeks of the four-drug regimen. In the other five patients, the metastases remained inoperable; all of them succumbed to tumor progression.

Radiotherapy. Fourteen patients (46.7%) received local irradiation. Four of them had stage II N+, and 10 had stage III. The irradiation dose ranged from 15 to 35 Gy, which included a boost dose to residual tumor or to the region of involved lymph nodes in all patients. Complete abdominal irradiation because of peritoneal metastasis was undertaken in two patients. Radiotherapy could not be applied in five cases because of refusal of the patient (three cases) or due to tumor progression (two cases). In three patients, nonresectable metastatic sites were irradiated in addition to the tumor region (lung, two; mediastinum, one). Whole-lung irradiation was performed in two cases. Irradiation was not applied to metastatic sites when a complete remission was achieved by chemotherapy alone or in combination with surgery. In three patients with inoperable metastasis, irradiation was not applied because of tumor progression, severe toxicity of chemotherapy, or refusal of the patient.

Outcome
In 24 patients (80%), a complete remission could be achieved, whereas in six patients, the tumor did progress during treatment despite further intensification of therapy. Only one of these patients is alive, with a residual tumor burden. All six patients presented with metastatic disease at diagnosis, and all of them had stage III disease after surgery. Two of them showed anaplasia on histologic study. The median time of survival of the five patients who died was 14.4 months (range, 10 to 26 months). To date, the three patients with CCSK are in first complete remission; one of the two patients with anaplasia (both stage IV) did not reach complete remission and died 12 months after diagnosis. The two patients with nephroblastoma and RCC in the same kidney are in clinical complete remission 48 months after diagnosis.

The tumor did relapse in four patients. Mean time to relapse was 15 months after the end of treatment. Of these four patients, three achieved a second remission, and one patient is alive in partial remission. All four patients presented with distant metastases—one isolated to the lung, one to the lung and mediastinal lymph nodes, one to a single cervical lymph node, and one to a lymph node of the liver port. There were no local recurrences.

To date, the 19 patients who received a two- or three-drug regimen are all alive. The survival of the patients with advanced disease who received the four-drug regimen is poor. Five of the 11 patients died. Patients with metastatic disease did receive at least three drugs.

The overall survival (SUR) of the patients is 83%, with an disease-free survival (DFS) of 57%. Median follow-up is 4 years. Kaplan-Meier estimates of SUR and DFS for all patients and according to stage is shown in Figure 1. SUR with regard to localized and metastatic disease is shown in Figure 2.

View larger version (17K): [in this window] [in a new window]   Fig 1. Disease-free survival (DFS) and overall survival (SUR) of the 30 patients. Median follow-up time is 4 years.

View larger version (19K): [in this window] [in a new window]   Fig 2. Overall survival of the 30 patients according to stage. For localized disease (stage I to III), prognosis is significantly better than for metastatic disease (stage IV).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The most common kidney tumor in adults is RCC. Wilms' tumor in subjects who are older than 16 years is rare. Only 3% of Wilms' tumors are reported in adults, which explains the difficulties in diagnosis and treatment of this tumor entity in this age group.⁸ In the literature, there are mainly single case reports of adult patients,^12-14 and studies on larger patients series are rare.^4-8

The clinical presentation of adults with Wilms' tumor differs from that of children. The main symptom of adults is flank pain, and the majority of them have a history of weight loss and of a sudden drop in performance status. This observation is in accordance with other reports on symptoms of Wilms' tumor.^15,16 In children, tumors are mainly asymptomatic, or children present with a painless swollen abdomen.

There are no data in the literature about a correlation between Wilms' tumor and Down syndrome. Generally, patients with Down syndrome have a higher risk for malignancies, but cases of Wilms' tumor in those patients have not yet been described.

The prognosis of the disease was reported to be dismal, with an event-free survival of 20% to 30% in the 1980s.¹⁷ The first series showing an improved survival was presented by Arrigo et al for the National Wilms' Tumor Study in 1990.⁴ They reported on 27 adult patients in whom an event-free survival of 67% was achieved. Relapses occurring later than 2 years after diagnosis were not reported in this study. This is in concordance with the pediatric population. They recommend to treat risk-adapted adults depending on the tumor stage and histology.

In our series of 30 patients, SUR is even better, and reaches 83%. The stage distribution of our patients shows a predominance of high local tumor stages and a tendency for metastatic disease. This confirms the published data of the last 15 years.^5,7 The improvement of prognosis is due to central monitoring of the patients and to standardized treatment according to the pediatric protocol.

The high rate of irradiated patients in the adult group is explained by the stage distribution (Table 2). Additional to the local irradiation, 10% of our patients did receive radiotherapy of nonresectable metastatic regions.

In contrast to the pediatric population, in the SIOP studies, the majority (23 of 30) of the adult patients are operated primarily. It is not possible to achieve a safe diagnosis by imaging studies alone in this patient group.¹⁸ Even in the concept of the SIOP Wilms' tumor protocol, patients older than 16 years undergo primary surgery of the tumor.

A fine-needle or true-cut biopsy may facilitate histological diagnosis in cases of primarily inoperable tumors or stage IV disease. This approach was carried out in seven of the patients and helped to stratify further treatment. In four of the patients, preoperative chemotherapy could therefore be initiated. This resulted in a regression of the tumor, and in operability.

Molecular and genetic studies should be carried out in nephroblastoma to collect data about mutations and cytogenetics. A fine-needle or true-cut biopsy is not an impediment for these studies. A recent publication shows that cytogenetics can also be done if this method is employed to win tumor material.¹⁹

As Wilms' tumor is a rare entity in adults, its occurrence is hardly suspected by local pathologists. RCC is the most common tumor in this age group, and in some cases, histological differentiation of nephroblastoma and RCC is difficult. Additionally, defining the subgroup and regression rate of the tumor can be difficult for a local pathologist. In our series, five patients had to be upgraded to the high-risk group after central review, and in six patients, even the diagnosis of Wilms' tumor was established only after central review. The difficulties in correct diagnosis may lead to inappropriate or delayed treatment and may thus contribute to a poorer prognosis in these patients. Our study clearly shows that a central pathological review is necessary in order to diminish this risk. The presence of a RCC simultaneously with a Wilms' tumor does not necessarily worsen the prognosis of these patients. A localized RCC can be cured by operation alone and does not need further treatment.

A considerable lapse of time after primary surgery until the initiation of treatment is another problem concerning the pathological management. Other authors describe a poorer prognosis in patients with delay of treatment.²⁰ We saw no impact of treatment delay in our series, but this might be due to the small number of patients.

Histological subtypes do not differ from pediatric tumors. There is no higher rate of high-risk tumors. The biology of the tumors seems to be identical to those in children. The tumors tend to respond to the preoperative treatment protocol and to have a good prognosis if they are treated in the same manner. In conclusion, adults do not need a more aggressive treatment for Wilms' tumor than children.

All of our patients received chemotherapy according to the SIOP 93-01/GPOH regimen. This included vincristine in a large number of the patients. To date, no data on toxicity of treatment in adults have been published. With the improved prognosis of the patients, toxicity and late effects are becoming increasingly important. The main toxicity in our patients was grade 3 and 4 neuropathy due to vincristine. This lead to treatment delay and even refusal to take the medication in a significant number of the patients. In most of them, neuropathy was at least partially reversible.

In summary, Wilms' tumor in adults is a curable disease if treated according to pediatric strategy, including chemotherapy, radiotherapy, and surgical standards. Although the tumor stages of the adult patients at diagnosis are higher than in childhood, they can be cured with this treatment approach. A central pathological review is mandatory. Toxicity has to be taken into account. Suggestions for a standardized treatment for patients older than 16 years still include early nephrectomy. The dosage and schedule of vincristine has to be adapted. We recommend that a prospective multicenter study for the treatment of Wilms' tumor in adults be established to confirm our findings.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by grant No. 70-1899 from the Deutsche Krebshilfe.

Presented in part at the meeting of the International Society of Pediatric Oncology (SIOP), Cairo, Egypt, October 8-11, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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3. Graf N, Tournade MF, de Kraaker J: The role of preoperative chemotherapy in the management of Wilms' tumor: The SIOP studies. Urol Clin North Am 27:443-450, 2000[CrossRef][Medline]

4. Arrigo S, Beckwith JB, Sharples K, et al: Better survival after combined modality care for adults with Wilm's tumor. Cancer 66:827-830, 1990[CrossRef][Medline]

5. Kattan J, Tournade MF, Culine S, et al: Adult Wilms' tumour: Review of 22 cases. Eur J Cancer 30A:1778-1782, 1994

6. Williams G, Colbeck RA, Gowing NFC: Adult Wilms' tumour: Review of 14 patients. Br J Urol 70:230-235, 1992[Medline]

7. Huser J, Grignon DJ, Ro JY, et al: Adult Wilms' tumor: A clinicopathologic study of 11 cases. Mod Pathol 3:321-326, 1990[Medline]

8. Gutjahr P, Neisius D, Bode U, et al: Therapie und Prognose bei 11 Erwachsenen mit Wilms-Tumoren (Nephroblastome). Aktuelle Urol 23:232-235, 1992

9. Vujanic GM, Sandstedt B, Harms D, et al: Revised International Society of Paediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 38:79-82, 2002[CrossRef][Medline]

10. National Cancer Institute: Common Toxicity Criteria (CTC) Version 2.0, 1999. http://ctep.cancer.gov/reporting/ctc.html

11. Faria P, Beckwith JB, Mishra K, et al: Focal versus diffuse anaplasia: New definitions with prognostic significance—A report from the National Wilms' Tumor Study Group. Am J Surg Pathol 20:909-920, 1996[CrossRef][Medline]

12. Mydlo JH, Horowitz M, delRosario C, et al: An unusual presentation of adult Wilms' tumor. Urol Int 57:104-107, 1996[Medline]

13. Lurie M, Sova I, Mecz Y, et al: Adult nephroblastoma. Cancer 61:2342-2347, 1988[Medline]

14. Bozeman G, Bissada NK, Abboud MR, et al: Adult Wilms' tumor: Prognostic and management considerations. Urology 45:1055-1058, 1995[Medline]

15. Weichert-Jacobsen K, Papadopoulos I, Skrezek C, et al: Adult Wilms' tumor: Case report, management, prognosis. Urol Int 54:99-103, 1995[Medline]

16. Knispel H, Dieckmann KP, Henze G, et al: Wilms-Tumor beim Erwachsenen. Urologe 29:226-229, 1990[Medline]

17. Byrd R, Evans E, D'Angio D: Adult Wilms tumor: Effect of combined therapy on survival. J Urol 127:648-651, 1982[Medline]

18. Meyer JS, Harty MP, Khademian Z: Imaging of neuroblastoma and Wilms' tumor. Magn Reson Imaging Clin N Am 10:275-302, 2002[CrossRef][Medline]

19. Li P, Perle MA, Scholes JV, et al: Wilms' tumor in adults: Aspiration cytology and cytogenetics. Diagn Cytopathol 26:99-103, 2002[Medline]

20. Spreafico F, Fossati-Bellani F, Collini P, et al: Wilms' tumor in adolescents and adults: What is required for a correct approach. Med Pediatr Oncol 41:267, 2003[CrossRef]

Submitted December 16, 2003; accepted August 30, 2004.

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