Wilms tumor studies for which focality was known 80 (4%)were bilateral and 250 (13%) were unilateral multicentricWT.18 More than half of the children with unilateral andmulticentric WT usually present with “grossly visible sub-capsular tumorlets,”2 which may be detected on imagingbefore surgery.5 Therefore, the present prevalence of unilat-eral multiple solid renal tumors seems realistic.

The constant association we found between hyperplastic andneoplastic NRs suggests that subjects with hyperplastic mul-ticentric NRs have a high risk of WT either at presentation orsubsequently. In addition to our 3 patients, we collected 20cases from the literature.8–14 Mean patient age at diagnosiswas 18.3 months and the male-to-female ratio was 0.9:1. Of23 collected cases with multifocal hyperplastic nephroblasto-matosis diagnosed by preoperative imaging or during opera-tion 20 (86%) presented initially or subsequently with histo-logical proven WT. The high risk of WT in children withhyperplastic nephroblastomatosis suggests that initial che-motherapy may be better than a “wait and see” policy, whichhas been previously advised.3, 8, 12

Metachronous WT developed in our case 1. Interestingly, ofthe 20 collected cases of multifocal hyperplastic nephroblas-tomatosis associated with WT 14 presented with bilateralWT (synchronous 11 and metachronous 3) and 6 with unilat-eral WT. These clinical data, even if in part due to selection,support the concept that hyperplastic nephroblastomatosisportends a higher risk of WT in both kidneys in comparisonwith the risk previously reported in children with micro-scopic nephroblastomatosis.4 Beckwith first advised NSS forWT from hyperplastic NRs based on the concept that NRs,reflecting processes involved in renal embryogenesis, areusually found in both kidneys.3 However, whether hyperplas-tic nephroblastomatosis portends a significant higher risk ofmetachronous bilateral WT has not been investigated. Asignificant higher incidence of metachronous bilateral WTwas found in girls compared with boys and in infants youngerthan 1 year who also had NRs.4 Therefore, the NWTS grouprecommended NSS only for a “very selected group of infantswith NRs demonstrated pre- or intraoperatively.”4 All chil-dren older than 1 year should be treated with nephrectomywithout preoperative chemotherapy, considering that “inju-dicious attempts are dangerous” and that “no data are avail-able on the benefit of NSS.”4

The safety of NSS in our small series of select patients(stage I nonanaplastic WT) cannot justify a conservativesurgical approach in all children with unilateral WT andmultiple solid renal masses on imaging. The SIOP studygroup has decided to collect data on the results obtained withpreoperative chemotherapy and NSS (performed with thesame guidelines for bilateral WT) in all children with WTassociated with hyperplastic nephroblastomatosis (SIOP2001). When this study is completed, more information willbe available on the advantages and risks of such a conserva-tive approach.

CONCLUSIONS

About 6% of children with unilateral WT present withhyperplastic and multicentric nephroblastomatosis, detect-able on imaging. Hyperplastic NRs seem to portend a highrisk of WT in both kidneys. In select children with unilateralWT associated with hyperplastic nephroblastomatosis preop-erative chemotherapy and NSS may be reasonable alterna-tives to nephrectomy.

REFERENCES

1. Beckwith, J. B., Kiviat, N. B. and Bonadio, J. F.: Nephrogenicrests, nephroblastomatosis, and the pathogenesis of Wilms’tumor. Pediatr Pathol, 10: 1, 1990

2. Bove, K. E. and McAdams, A. J.: Multifocal nephroblastic neo-plasia. J Natl Cancer Inst, 61: 285, 1978

3. Beckwith, J. B.: Precursor lesions of Wilms tumor: clinical andbiological implications. Med Pediatr Oncol, 21: 158, 1993

4. Coppes, M. J., Arnold, M., Beckwith, J. B., Ritchey, M. L.,D’Angio, G. J., Green, D. M. et al: Factors affecting the risk ofcontralateral Wilms tumor development: a report from theNational Wilms Tumor Study Group. Cancer, 85: 1616, 1999

5. Gylys-Morin, V., Hoffer, F. A., Kozakewich, H. and Shamberger,R. C.: Wilms tumor and nephroblastomatosis: imaging char-acteristics at gadolinium-enhanced MR imaging. Radiology,188: 517, 1993

6. Lonergan, G. J., Martinez-Leon, M. I., Agrons, G. A.,Montemarano, H. and Suarez, E. S.: Nephrogenic rests,nephroblastomatosis, and associated lesions of the kidney.Radiographics, 18: 947, 1998

7. Rohrschneider, W. K., Weirich, A., Rieden, K., Darge, K., Troger,J. and Graf, N.: US, CT and MR imaging characteristics ofnephroblastomatosis. Pediatr Radiol, 28: 435, 1998

8. Antall, P. M., Myers, M. T., Dahms, B., Vogt, B. A. and Kodish,E.: Growth of a new intrarenal lesion in the remaining kidneyof a patient with bilateral nephroblastomatosis and a previousnephrectomy for Wilms tumor. Med Pediatr Oncol, 35: 66,2000

9. Fuchs, J., Wunsch, L., Flemming, P., Weinel, P. andMildenberger, H.: Nephron-sparing surgery in synchronousbilateral Wilms’ tumors. J Pediatr Surg, 34: 1505, 1999

10. Laberge, J. M.: Nephroblastomatosis update. Med Pediatr Oncol,41: 96, 2003

11. Plantaz, D., Drago, G., Vannier, J. P., Rubie, H., Lutz, P.,Brunat-Mentigny, M. et al: Nephroblastomatosis (NBM): as-sociation with Wilms tumor (WT). A retrospective multicenterstudy. Med Pediatr Oncol, 25: 312, 1995

12. Prasil, P., Laberge, J. M., Bond, M., Bernstein, M., Pippi-Salle,J. L., Bernard, C. et al: Management decisions in children withnephroblastomatosis. Med Pediatr Oncol, 35: 429, 2000

13. Regalado, J. J., Rodriguez, M. M. and Toledano, S.: Bilaterallymulticentric synchronous Wilms tumor: successful conserva-tive treatment despite persistence of nephrogenic rests. MedPediatr Oncol, 28: 420, 1997

14. Santiago, J., Bouvier, R., Pouillaude, J. M., Thiesse, P.,Bergeron, C., Chapuis, J. P. et al: Nephroblastomatose depresentation inhabituelle. Arch Pediatr, 5: 627, 1998

15. Cozzi, F., Schiavetti, A., Bonanni, M., Cozzi, D. A., Matrunola,M. and Castello, M. A.: Enucleative surgery for stage I nephro-blastoma with a normal contralateral kidney. J Urol, 156:1788, 1996

16. Cozzi, D. A., Schiavetti, A., Morini, F., Castello, M. A. and Cozzi,F.: Nephron-sparing surgery for unilateral primary renal tu-mor in children. J Pediatr Surg, 36: 362, 2001

17. Breslow, N., Beckwith, J. B., Ciol, M. and Sharples, K.: Agedistribution of Wilms’ tumor: report from the National Wilms’Tumor Study. Cancer Res, 48: 1653, 1988

18. Bonaiti-Pellie, C., Chompret, A., Tournade, M. F., Lemerle, J.,Voute, P. A. and Delemarre, J. F.: Excess of multifocal tumorsin nephroblastoma: implications for mechanisms of tumor de-velopment and genetic counseling. Hum Genet, 91: 373, 1993

EDITORIAL COMMENT

The authors suggest that children with unilateral multicentrictumors should be treated with nephron sparing surgery. Theypresent 3 cases but 1 had bilateral masses, which is the only casewith a “metachronous” tumor that could be viewed as relapse. Theother 2 patients had multiple masses on preoperative imaging stud-ies.

It is unclear how many children can be identified with unilateralmulticentric tumors on preoperative evaluation. The authors quotedata from the NWTS group stating that 13% of unilateral Wilmstumors are multicentric. However, this review was based on patho-logical findings. Patients were identified as having separate tumornodules of distinct histology. There was no correlation with imagingin that review. Therefore, we do not know how many children pre-senting with unilateral Wilms tumor can be categorized as multicen-tric tumors based on initial/preoperative evaluation. It was 6% of thechildren in this small series.

It is well known that patients with nephrogenic rests are at in-creased risk for renal relapse (references 1 and 4 in article). Theterminology of nephrogenic rests has been extensively reviewed byBeckwith. There is clearly a distinction between diffuse hyperplastic

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periolobar nephrogenic rests (DHPLNR) and multiple nephrogenicrests. DHPLNR have a thickened rind around the entire kidney andcan develop focal masses due to hyperplastic rests and/or Wilmstumors. Patients with DHPLNR are at high risk for Wilms tumor.Initial observation of DHPLNR has been rarely reported.1, 2 In bothcases subsequent Wilms tumor development was noted at 13 monthsand 4 years, respectively. Observation of these patients is not rec-ommended. Most of these patients present with bilateral disease,although unilateral cases have been reported. This is different fromlesions identified in patients with a known syndrome such as theBeckwith-Wiedemann syndrome. These children are followed withserial ultrasound at 3-month intervals. If a small lesion is detected,it can be observed for growth before a decision is made for interven-tion.3

Nephrogenic rests are found in 25% to 40% of children with Wilmstumor. They are usually small foci found on pathological examina-tion of the otherwise normal kidney tissue adjacent to the tumor. Theoverwhelming majority of these lesions will not be identified onpreoperative imaging. In addition, distinguishing nephrogenic restsfrom true Wilms tumor is difficult. It has been suggested that imag-ing studies are useful in this regard (reference 5 in article). Size,shape and MRI appearance have all been considered but have neverbeen studied prospectively in large numbers of patients. Gylys-Morinet al demonstrated that they could identify nephrogenic rests but theoverall sensitivity on gadolinium enhanced images was 58% and theyonly reported data on 12 patients (reference 5 in article).

Another question that needs to be addressed regarding unilateralmulticentric tumors is the risk for recurrence. Coppes et al showedthat there is an increased risk of metachronous tumor in infants whounderwent nephrectomy for Wilms tumor and who also had nephro-genic rests in the specimen (reference 4 in article). Of note, they didnot show a significant increased risk in patients with known syn-dromes such as the Beckwith-Wiedemann syndrome, although thenumber of patients was small. The Children’s Oncology Group renaltumor committee is planning to prospectively collect imaging infor-mation on children presenting with Wilms tumor. Data on multicen-tricity will be collected and correlated with histological and surgicalfindings. Followup of these children will help determine the risk forrelapse.

In conclusion, the authors state that hyperplastic nephrogenicrests portend a high risk to Wilms tumor in both kidneys. Publisheddata have only proven this for infants younger than 1 year. There arenot enough data to support this statement for all patients withunilateral multicentric tumors. Until it is shown that there is clearlya higher risk of metachronous tumors to warrant nephron sparingsurgery, such an approach must be considered with caution. Theauthors are commended for their well defined protocol describingnephron sparing surgery in children with Wilms tumor with theintent to completely remove all tumor but renal sparing proceduresfor Wilms tumor do have an increased risk of positive tumor marginsand local recurrence.4 This known increased risk would have to beoutweighed by a proven benefit of nephron sparing surgery. To datethere is no documentation that there is an increased risk for renalfailure in children with unilateral multicentric tumors. The nephronsparing approach advocated by the authors is more feasible in theSIOP study as patients routinely receive preoperative therapy. InNorth America patients initially undergo surgery for Wilms tumors.Few tumors are amenable to renal sparing surgery at diagnosis.After chemotherapy there is often a marked reduction in tumor size,and more patients are amenable to nephron sparing surgery at thattime.

Michael L. RitcheyDivision of UrologyThe University of TexasHouston, Texas

1. deChadarevian, J. P., Fletcher, B. D., Chatten, J. andRabinovitch, H. H.: Massive infantile nephroblastomatosis: a

clinical, radiological, and pathologic analysis of four cases.Cancer, 39: 2294, 1977

2. Rosenfield, N. S., Shimkin, P., Berdon, W., Barwick, K.,Glassman, M. and Siegel, N. J.: Wilms tumor arising fromspontaneously regressing nephroblastomatosis. AJR Am JRoentgenol, 135: 381, 1980

3. McNeil, D. E., Langer, J. C., Choyke, P. and DeBaun, M. R.:Feasibility of partial nephrectomy for Wilms tumor in childrenwith Beckwith-Wiedemann syndrome who have been screenedwith abdominal ultrasonography. J Pediatr Surg, 37: 57, 2002

4. Horwitz, J., Ritchey, M. L., Moksness, J., Breslow, N. E., Smith,G. R., Thomas, P. R. et al: Renal salvage procedures in pa-tients with synchronous bilateral Wilms tumors: a report ofthe NWTSG. J Pediatr Surg, 31: 1020, 1996

REPLY BY AUTHORS

Available data (reference 5 in article) suggest that only half ofmulticentric hyperplastic nephrogenic rests may be depicted on MRI(diameter 4 or greater mm). As 11% to 13% of unilateral Wilmstumor are multicentric on pathological findings (references 17 and 18in article), it seem reasonable to speculate that half of these foci willbe diagnosed on initial preoperative evaluation. Therefore, it is notsurprising that 6% of children in our small series presented withmultiple solid masses at preoperative imaging.

Observation of hyperplastic nephrogenic rests is not recom-mended. Chemotherapy helps to differentiate hyperplastic from neo-plastic nodules and makes nephron sparing surgery more feasible.The implication is that a rather large group of children with unilat-eral WT should be initially treated with chemotherapy. The ongoingstudy of the Children’s Oncology Group Renal Tumor Committee willprovide reliable data on the number of children with the prevalenceof hyperplastic nephrogenic rests detected on imaging.

The presence of microscopic nephrogenic rests increased the risk ofmetachronous tumor in children with the Beckwith-Wiedemann syn-drome, aniridia or hemihypertrophy who underwent nephrectomyfor WT (10 of 211 children with these syndromes had a metachronousbilateral WT compared with 48 of 4,458 children without thesesyndromes, chi-square 18.05, p �0.0001). Therefore, the SIOP 2001study for assessment of the role of NSS in children with thesesyndromes seems appropriate. Present data we collected from theliterature suggest that the risk of bilateral WT in children withhyperplastic nephrogenic rests is even higher than that found inchildren with microscopic nephrogenic rests. Waiting the results ofthe SIOP 2001 study of the safety of NSS in children with hyper-plastic nephroblastomatosis, we limited the indication of NSS only tothose with hyperplastic nephroblastomatosis who had stage I WTwithout anaplasia.

The use of NSS is also supported by recent data from Mayo Clinic1

and Memorial-Sloan Kettering Cancer Center2 showing that inadults with renal cell carcinoma NSS significantly reduces the inci-dence of chronic renal failure following ablative surgery. We studiedrenal function in children with unilateral WT who underwent abla-tive surgery. Our preliminary data suggest that NSS has a renaladvantage over nephrectomy.3

1. Lau, W., Blute, M and Zincke, H.: Matched comparison of radicalnephrectomy versus elective nephron sparing surgery for re-nal cell carcinoma (RCC): evidence for increased renal failurerate on long term followup (�10 years). J Urol, suppl., 163:153, abstract 681, 2000

2. McKiernan, J. M., Simmons, R., Katz, J., Flombaum, C. andRusso, P.: The natural history of renal insufficiency followingpartial or radical nephrectomy for renal tumors less than 4 cm.J Urol, suppl., 165: 160, abstract 658, 2001

3. Cozzi, F., Schiavetti, A., Morini, F., Gambino, M., Pisera, A. andCozzi, D. A.: Kidney function and volume after nephron-sparing surgery for unilateral primary renal tumour. Pre-sented at the annual meeting of the BAPS, Estoril, Portugal,July 2003

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