ENUCLEATION OF STAGE I NEPHROBLASTOMA 1791

performed in an avascular plane between the pseudocapsule a d normal parenchyma with a low incidence of bleeding. Therefore, it is technically less challenging than partial ne- phrectomy. The main disadvantage concerns the possible presence of residual tumor after enucleation.

However, in adults with low stage renal cell carcinoma enucleation compared to partial nephrectomy has led to no significant differences in survival and recurrence rates.13~ 14

In children with unilateral nephroblastoma the potential risk of residual microscopic disease after tumor enucleation may be further minimized by chemotherapy. “he efficacy of che- motherapy is supported by the fact that residual disease at the resection margins following nephron sparing surgery does not seem to influence relapse and survival rates in children with bilateral nephroblastoma.17.18 In the present pilot study chemotherapy, as for stage II nephroblastoma (negative lymph nodes), after enucleative surgery was con- sidered a reasonable price to preserve a good percent of functioning kidney. For the next eligible patients we plan to administer adjuvant chemotherapy after enucleation, as for stage I disease, when multiple microscopic sections of tumor pseudocapsule may exclude local invasion. Chemotherapy, as for stage I1 disease, may be reserved for cases in which positive margins become negative after excision of a further slice of surrounding parenchyma.

“he other concern regarding enucleative surgery is the presence of anaplastic cells inside the tumor. We believe that the selection of patients with stage I nephroblastoma should cover this potential risk. In the small group of children with stage I anaplastic nephroblastoma treated with nephrectomy the survival rate is comparable to that of patients with stage I favorable histology nephroblastoma.1, 19 Furthermore, ana- plastic and nonanaplastic tumors have a similar manner of local spread by penetration of the renal capsule or invasion of the renal vein.19 Therefore, enucleation of stage I anaplastic or nonanaplastic nephroblastoma should not cause a differ- ent risk of relapse.

In our opinion uncertainty concerning enucleative surgery due to the presence of nephrogenic rest in the spared renal parenchyma is not justified. In adults the potential risk of multifocal renal cell carcinoma may be an argument for or against conservative surgery, because it is not yet known whether multifocality is a unilateral or bilateral kidney dis- order. In children with unilateral nephroblastoma nephro- genic rests are associated with a higher risk of subsequent tumor formation in the remaining kidney, since more than 90% of those with metachronous bilateral nephroblastoma had nephrogenic rests in the initial nephrectomy specimen.20 In accordance with these data multifocality in children with nephroblastoma appears to be a bilateral kidney disorder. Thus, enucleative surgery associated with chemotherapy is advisable for unilateral nephroblastoma with nephrogenic rests.

CONCLUSIONS

The results of our series suggest that the approach as described may provide a valid option for select patients with unilateral nephroblastoma. However, additional data and longer followup are necessary to define better the role of enucleative surgery in the treatment of stage I nephroblas- toma with a normal contralateral kidney.

REFERENCES

1. D’Angio, G. J., Breslow, N., Beckwith, J. B., Evans, A., Baum, E., dehrimier, A., Fernbach, D., Hrabovsky, E., Jones, B., Kelalis, P., Othersen, B., Tern, M. and Thomas, R. M.: Treat- ment of Wilms’ tumor. Results of the Third National Wilms’ Tumor Study. Cancer, &4: 349, 1989.

2. Tournade, M. F., Com-NouguB, C., VoQte, P. A., Lemerle, J., de Kraker, J., Delemarre, J. F., Burgers, M., Habrand, J. L.,

Moorman, C. G., Biirger, D., Rey, A., Zucker, J. M., Carli, M., Jereb, B., Bey, P., Gauthier, F. and Sandstedt, B.: Results of the Sixth International Society of Pediatric Oncology Wilms’ Tumor Trial and Study: a risk-adapted therapeutic approach in Wilms’ tumor. J. Clin. Oncol., 11: 1014, 1993.

3. Barrera, M., Roy, P. and Stevens, M.: Long-term follow-up after unilateral nephrectomy and radiotherapy for Wilms’ tumor. Ped. Nephrol., 3 430, 1989.

4. Welch, T. R. and McAdams, A. J.: Focal glomerulosclerosis as a late sequela of W i h s tumor. J. Ped., 10s. 105, 1986.

5. Ritchey, M. L., Green, D. M., Thomas, P. R. M., Smith, G. R., Haase, G., Shochat, S., Moksness, J. and Breslow, N. E.: Renal failure in Wilms’ tumor patients: a report from the National Wilms’ Tumor Study Group. Med. Ped. Oncol., 2& 75, 1996.

6. Gruner, M., Chaouachi, B., Bitker, M. and Boccon Gibbod, L.: La place de la chirurgie conservatrice dans le traitement des nkphroblastomes. J. d’Urol., 88: 223, 1982.

7. Hanna, M. K and Samowitz, H. R.: The rationale for partial nephrectomy in selected cases of unilateral Wilms’ tumor. Dial. Ped. Urol., 14 (11): 3, 1991.

8. McLorie, G. A., McKenna, P. H., Greenberg, M., Babyn, P., Thorner, P., Churchill, B. M., Weitzman, S., Filler, R. and Khoury, A. E.: Reduction in tumor burden allowing partial nephredomy following preoperative chemotherapy in biopsy proved Wilms tumor. J. Urol., 146: 509, 1991.

9. Moorman-Voestermans, C. G. M., Staalman, C. R. and Delemarre, J . F. M.: Partial nephrectomy in unilateral Wilms’ tumor is feasible without local recurrence. Med. Ped. Oncol.. 2 3 218,1994.

10. Verea. G. and Paritzi. G. B.: Partial neDhrectomv for Wilms’ timor. J. Urol., 156: 981, 1986.

11. Urban, Ch. E.,HOllwarth, M. E., Sauer,H.,Klos, I., Lackner, H., Schwinger, W. and Ring, E.: Heminephrectomy in unilateral stage I Wilms’ tumor. Presented at the Meeting of the British Association of Paediatric Surgeons, Rotterdam, The Nether- lands, June 28-July 1,1994.

12. Herr, H. W.: Partial nephrectomy for renal cell carcinoma with a normal opposite kidney. Cancer, 7 3 160, 1994.

13. Morgan, W. R. and Zincke, H.: Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. J. Urol., 144.852,1990.

14. Stephens, R. and Graham, S. D., Jr.: Enucleation of tumor ver- sus partial nephrectomy as conservative treatment of renal cell carcinoma. Cancer, 65: 2663, 1990.

15. Licht, M. R. and Novick, A. C.: Nephron sparing surgery for renal cell carcinoma. J . Urol., 1 4 9 1, 1993.

16. Wilimas, J. A., Magill, L., Parham, D. M., Kumar, M. and Douglass, E. C.: The potential for renal salvage in nonmeta- static unilateral Wilms’ tumor. Amer. J . Ped. Hematol. Oncol., 1 3 342,1991.

17. Alfer, W., Jr., de Camargo, B. and do Carmo Assuncao, M.: Management of synchronous bilateral Wilms tumor: Brazilian Wilms Tumor Study Group experience with 14 cases. J. Urol., 150: 1456, 1993.

18. Shaul, D. B., Srikanth, M. M., Ortega, J . A. and Mahour, G. H.: Treatment of bilateral Wilms’ tumor: comparison of initial biopsy and chemotherapy to initial surgical resection in the preservation of renal mass and function. J. Ped. Surg., 27: 1009,1992.

19. Bonadio, J. F., Storer, B., Norkool, P., Farewell, V. T., Beckwith, J. B. and DAngio, G. J.: Anaplastic Wilms’ tumor: clinical and pathological studies. J. Clin. Oncol., 3 513, 1985.

20. Beckwith, J. B., Kiviat, N. B. and Bonadio, J . F.: Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Ped. Path., 1 0 1, 1990.

EDITORIAL COMMENT

The authors report parenchymal sparing procedures in 3 patients with unilateral Wilms tumor and a normal contralateral kidney. They summarized the published experience with this approach, al- though at most other centers partial nephredomy rather than enu- cleation of the tumor has been performed. The authors’ management of unilateral Wilms tumor is controversial and i t has not been adopted by the major pediatric oncology cooperative groups in the United States.

The main impetus for attempting parenchymal sparing proced~ree in patients with unilateral Wilms tumor is to reduce the f h q u e n q of

1792 ENUCLEATION OF STAGE I NEPHROBLASTOMA

the long-term complication of renal failure. Indeed, there have been reports of patients with Wilms tumor who have had renal failure but such reports have been infrequent. A recent review of National Wilms Tumor Study Group patients with unilateral Wilms tumor was performed to identify risk factors for renal insficiency (refer- ence 5 in article). A low incidence of renal failure was noted (0.25%) at a median followup of 6 years. Furthermore, most patients with a unilateral tumor in whom renal failure developed had the Denys- Drash syndrome and intrinsic renal disease, and generally presented with renal failure a t diagnosis or had inevitable progression to end stage renal disease. Another risk factor for renal failure is irradia- tion of the remaining kidney. Early protocols for the treatment of Wilms tumor included postoperative radiation for most children but currently few receive postoperative radiation and the dose has been markedly decreased. Therefore, the risk of renal failure following treatment for unilateral Wilms tumor appears low.

The authors state that the 1% incidence of metachronous Wilms tumor is another justification for parenchymal sparing procedures, because these patients are a t increased risk for renal failure. In fact, the incidence of metachronous Wilms tumor has decreased steadily with time (reference 5 in article) due to mandated exploration of the contralateral kidney at nephrectomy, and possibly to improved im- aging and detection of some small contralateral tumors preopera- tively . In earlier clinical trials children with metachronous Wilms tumor often presented with large lesions before the advent of effec- tive imaging to monitor for relapse of tumor in the contralateral kidney. Currently patients with nephrogenic rests, who are clearly the group at risk for metachronous Wilms tumor, are monitored with careful periodic imaging postoperatively,’ which theoretically allows earlier detection of small metachronous tumors to facilitate paren- chymal sparing surgery in the contralateral kidney. None of the 17 National Wilms Tumor Study-4 patients with metachronous Wilms tumor had renal failure (reference 5 in article).

The most important concerns regarding parenchymal sparing pro- cedures for patients with unilateral Wilms tumor are survival and treatment related morbidity. The authors identified 13 patients from a literature review who, they believe, were treated according to their criteria, stage I disease on imaging. However, these patients were treated at separate institutions with different surgical procedures (partial nephrectomy versus enucleation) and staging was based on preoperative imaging. It should be noted that to my knowledge no published prospective studies have correlated staging by imaging with surgicdpathological staging. The latter is the basis for the staging system of the National Wilms Tumor Study Group. Out- comes in terms of survival and risk of tumor relapse for patients with disease staged according to this system have been well defined (ref- erence 1 in article). Hundreds of cases managed in the manner defined by the authors must be studied before the risk of relapse and overall survival can be ascertained. An additional concern is that pathological staging after chemotherapy may be less accurate.2

There are other concerns regarding the protocol proposed by the authors, including performing tumor enucleation rather than partial nephrectomy. A recent review of patients with bilateral Wilms tumor indicated that the incidence of local recurrence was 7.5% after par- tial nephrectomy versus 14% after enucleation (not significant).3 Although overall survival in children with bilateral Wilms tumor is comparable to that of patients treated for unilateral Wilms tumor, a few points must be made. There were too few patients to perform a statistical comparison, particularly when matching by stage, histol- ogy and treatment regimens.3 A large percent of patients with bilat- eral tumors and residual disease receive added therapy t o maintain this excellent survival rate. As the authors report, all of their pa- tients were given epirubicin as part of the chemotherapy regimen. The use of anthracycline increases the risk of cardiotoxicity.4 Cur- rently only patients with stages 111 and IV disease entered in the National Wilms Tumor Study receive this drug. Children with stages I and I1 tumors only receive dactinomycin and vincrinstine. The presumption of the authors is that “CT stage I” is the same as National Wilms Tumor Study stage I. Therefore, many children eligible for parenchymal sparing procedures according to these cri- teria will receive anthracyclines unnecessarily. One must weigh the potential risk of cardiotoxicity versus the potential risk of renal insufficiency. Another point to consider is that select patients younger than 2 years with stage I tumors of less than 550 gm. who are entered in the current National Wilms Tumor Study-5 clinical trial will be considered for treatment with surgery alone. These patients will not receive chemotherapy and have the attendant risks.

The authors briefly discuss the issue of anaplasia and suggest that

it would not be a concern in their patients, citing the excellent survival rate of those with stage I anaplasia. This is true for patients who undergo complete tumor resection but when any residual dis- ease remains after partial nephrectomy or enucleation in a patient with anaplasia, the outcome will be markedly different. Anaplasia is resistant to conventional ~hemotherapy.~ Therefore, it would not be prudent to consider this type of approach in such patients.

In conclusion, parenchymal sparing procedures for patients with unilateral Wilms tumor is controversial. The members of the Na- tional Wilms Tumor Study Group do not believe that the benefits of this procedure in children with unilateral Wilms tumor outweigh the potential risks as described. The current recommendation of the National Wilms Tumor Study Group is to consider partial nephrec- tomy for patients with bilateral Wilms tumor, solitary kidney and renal insuficiency. Also, patients known to have an increased inci- dence of nephrogenic rests (for example the Beckwith-Wiedemann syndrome, hemihypertrophy and aniridia) are a t increased risk for a metachronous tumor and they should be considered for parenchymal sparing procedures. The National Wilms Tumor Study Group will continue to monitor the more than 6,000 patients registered to date for late effects, particularly renal insufficiency. Much remains to be learned about partial nephrectomy for Wilms tumor and its role in the treatment of these children.

Michael L. Ritchey Division of Pediatric Surgery University of Texas Health Center Houston, Texas

1. D’Angio, G. J., Rosenberg, H., Sharples, K., Kelalis, P., Breslow, N. and Green, D. M.: Position paper: imaging methods for primary renal tumors of childhood: costs versus benefits. Med. Ped. Oncol., 21: 205, 1993.

2. Green, D. M., Breslow, N. E. and DAngio, G. J.: The treatment of children with unilateral Wilms’ tumor. J. Clin. Oncol., 11: 1009, 1993.

3. Horwitz, J., Ritchey, M. L. and Moksness, J.: Renal salvage procedures in patients with synchronous bilateral Wilms tu- mors: a report of the NWTSG. J . Ped. Surg., in press.

4. Green, D. M., Breslow, N. E., Moksness, J. and DAngio, G. J.: Congestive failure following initial therapy for Wilms tumor. A report from the National Wilms Tumor Study. Ped. Res., 35: 161A, 1994.

5. Green, D. M., Beckwith, J. B., Breslow, N. E., Faria, P., Moksness, J., Finklestein, J. Z., Grundy, P., Thomas, P. R., Kim, T., Shochat, S., Haase, G., Ritchey, M., Kelalis, P. and D’Angio, G. J.: Treatment of children with stages I1 to IV anaplastic Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J. Clin. Oncol., 12: 2126, 1994.

REPLY BY AUTHORS

The low incidence of renal failure (defined as persistent serum creatinine of greater than 2.5 mg./dl.) in children and adolescents following nephrectomy for unilateral nephroblastoma (reference 5 in article) does not rule out the presence of renal damage due to hyper- filtration. In fact, glomerular hyperfiltration is expected to manifest during adulthood and it is usually preceded by proteinuria. Signifi- cant microalbuminuria and decrease in glomerular filtration rate have been noted in 47% of adults born with unilateral renal agenesis or who underwent nephrectomy in childhood because of hydrone- phrosis.1 Therefore, the evaluation of renal function after nephrec- tomy should include 24-hour urinary protein determination in addi- tion to serum creatinine level and glomerular filtration rate. Age dependent impairment of renal function due to glomerular hyperfil- tration is a major concern in children with a solitary kidney because they have a greater life expectancy than adults with a solitary kidney and, therefore, are at greater risk for progressive renal damage.

The risk of local recurrence following nephron sparing surgery in 700 patients with bilateral renal cell carcinoma or renal cell carci- noma involving a solitary functioning kidney is approximately 7% (reference 15 in article). The risk of local recurrence after nephron sparing surgery in 241 patients with renal cell carcinoma and a normal contralateral kidney is less than 1%. These data on the incidence of local recurrence following nephron sparing surgery con- firm those in children with bilateral nephroblastoma (reference 3 in Comment) or stage I nephroblastoma and a normal contralateral kidney, as described in our article. The higher rate of local recur- rence in patients with bilateral tumors probably represents multifo-