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Nephron-sparing surgery for unilateral primary renal tumor in children
Nephron-Sparing Surgery for Unilateral Primary Renal Tumor in Children By D.A. Cozzi, A. Schiavetti, F. Morini, M.A. Castello, and F. Cozzi Rome, Italy
Purpose: Definition of the role of nephron-sparing surgery (NSS) in the treatment of children with primary unilateral renal tumor (URT). Methods: Between January 1992 and June 2000, 28 children with URT were admitted to our surgical unit. Criteria for selection of patients eligible for NSS were at least 50% of affected kidney preservable and stage I at surgery (frozen section biopsies from regional lymph nodes, perirenal fat, and surrounding renal parenchyma). Preoperative 2-drug chemotherapy was given to all patients more than 6 months of age. Between 1992 and 1995, 3-drug chemotherapy was used after NSS. Thereafter, following NSS, 2-drug chemotherapy was given if no microscopic residual disease was found on final histologic examination. Results: NSS was feasible in 10 of 28 children (35%). Enucleation of 6 tumors (1 metachronous) was performed in 5 patients. NSS was elective in 5 patients, mandatory in 3 patients (1 with aniridia and genitourinary anomalies, 1 with
I
N 1996, we reported preliminary data on a pilot study investigating whether tumor enucleation may be feasible and effective in selected children with stage I nephroblastoma and a normal contralateral kidney.1 The main impediment to this approach is that nephron-sparing surgery (NSS) may increase the risk of local relapse, thus, adversely affecting morbidity and mortality. A contribution on this issue comes from recent data on NSS (partial nephrectomy or enucleation) for the treatment of children with bilateral Wilms’ tumor (BW).2 After NSS, the 4-year survival rate was 81.7%. The presence of residual disease after NSS, whether macroscopic or microscopic, did not have a major impact on survival or on the local recurrence rate. These excellent results were obtained with a more aggressive chemotherapy.2 The potential morbidity of more aggressive chemoFrom the Universita` di Roma “La Sapienza,” Policlinico Umberto I, Pediatric Surgery Unit, Rome, Italy. Presented at the 47th Annual International Congress of the British Association of Paediatric Surgeons, Sorrento, Italy, July 18-21, 2000. Address reprint requests to D.A. Cozzi, MD, Policlinico Umberto I, Chirurgia Pediatrica, Viale Regina Elena, 324, 00161 Rome, Italy. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3602-0026$35.00/0 doi:10.1053/jpsu.2001.20717 362
chronic glomerulonephritis, 1 with bilateral hyperplastic nephroblastomatosis), and advisable in 2 patients (1 with familial vesicoureteric reflux and 1 with cystic nephroma). Seven children had standard histology nephroblastoma, 1 highly differentiated epithelial type nephroblastoma, 1 oncocytoma, and 1 cystic nephroma. The only post-NSS complication was macroscopic hematuria in 1 patient. None of the patients had a relapse. All children are alive and disease free with good functioning of the affected kidney after NSS, at a mean follow-up of 40.7 months (range, 2 to 100 months).
Conclusion: NSS should be considered in selected children with URT, especially in patients with increased risk for metachronous tumor or renal disease, and in patients with benign or low-grade malignant URT. J Pediatr Surg 36:362-365. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Renal tumor, partial nephrectomy, Wilms’ tumor, cystic nephroma.
therapy is a reasonable price to pay for the treatment of the children with BW in whom the risk of renal failure is high. Conversely, in children with primary unilateral renal tumor (URT) the risk of renal failure is considered small. We have revised our protocol. Tumor enucleation or partial nephrectomy were performed only in those patients with URT, who, after NSS, receive the same postoperative chemotherapy as they would have received if submitted to nephrectomy or in those patients at higher risk for renal failure. We present our experience using NSS in children with URT. MATERIALS AND METHODS All children undergoing surgery for URT between January 1992 and June 2000 at our institution were identified prospectively. A total of 28 children with URT entered into the study protocol. Mean age at diagnosis was 43.3 months (range, 1 day to 12 years). All patients were evaluated with a medical history, physical examination, urinalysis, serum creatinine assay, and complete blood count. Imaging studies included ultrasound scan, chest x-rays, and computerized tomography or magnetic resonance imaging. Preoperative actinomycin D and vincristine according to the International Society of Pediatric Oncology (SIOP) protocol was given to all patients over 6 months of age. Abdominal imaging studies were repeated after preoperative chemotherapy. We considered appropriate for NSS all those patients with stage I disease on imaging studies in whom at least 50% of the affected kidney could be preserved. Further reassessment was made at surgery by frozen section biopsies from lymph nodes in the renal hilum and paraaortic regions, perirenal fat, and surrounding renal parenchyma. Journal of Pediatric Surgery, Vol 36, No 2 (February), 2001: pp 362-365
NEPHRON-SPARING SURGERY
363
Since 1996, partial nephrectomy with a 0.5- to 1-cm rim of normal parenchyma, whenever feasible, was considered the NSS procedure of choice. Postoperatively, multiple serial section histologic examinations (every 0.5 cm) were performed to confirm intraoperative findings, particularly with regard to the integrity of the pseudocapsule or resection margin of the tumor. Between 1992 and 1995, 3-drug chemotherapy was used after NSS.1 Subsequently, 2-drug postoperative chemotherapy was used in absence of microscopic residual disease. The follow-up of the present series of patients submitted to NSS was no different from that we reported in the previous series.1 We adopted the SIOP staging system and histopathologic classification of renal tumor. A tumor was defined central or peripheral depending on whether it extended into the renal sinus.
RESULTS
Eighteen of 28 (60%) patients with URT presented with stage I disease after preoperative chemotherapy. Of these 18, 11 were considered eligible for NSS (Table 1). The details of patients 1, 2, and 10 have been reported elsewhere.1 A synopsis of the others follows. In 1 eligible patient (case 15), with a familial history of adult renal polycystic disease and with a huge tumor, preoperative chemotherapy led to a dramatic reduction in tumor size and also in large areas of tumor necrosis. At surgery, NSS was considered inadvisable on account of thick adherence of the tumor to the surrounding renal parenchyma. Patient 17 presented with a kidney tumor discovered incidentally during an ultrasound examination in a girl with bilateral glomerulonephritis after Henoch-Scho¨nlein purpura. The tumor was excised with 1 cm clear margin. The final diagnosis was oncocytoma; therefore, no postoperative chemotherapy was given. Patient 19 presented with bilateral hyperplastic nephroblastomatosis and a small nephroblastoma on the right kidney. This was enucleated, and histopathologic examination showed no invasion of the pseudocapsule. All nodules responded to chemotherapy and disappeared on both sides. However, after 4 months and during chemotherapy, a new nodule appeared on the left side indicating the development of a contralateral nephroblas-
toma. This was enucleated, and 3-drug chemotherapy was administered. Patient 21 presented with a nephroblastoma associated with vesico-ureteric reflux. The father previously had undergone renal transplantation for chronic renal failure associated with vesico-ureteric reflux. In this case, partial nephrectomy was complicated by gross hematuria, which resolved spontaneously. In addition, the final histologic examination showed penetration of the pseudocapsule in proximity to the margin corresponding to the collecting system, which was entered during excision of the tumor. This girl was treated with carboplatin and etoposide in association with vincristine and actinomycin D. Patient 24 had a very small nephroblastoma, which was excised with a 1-cm clear margin of normal renal parenchyma. Postoperative chemotherapy was no different from that he would have received if submitted to nephrectomy. Case 25 was incidentally discovered at an ultrasound renal study request for an episode of significant bacteriuria. The patient was submitted to partial nephrectomy with a 0.5-cm clear margin; the final histologic diagnosis was nephroblastoma with highly differentiated epithelial type; no postoperative chemotherapy was administered. Patient 26 had a cystic nephroma that was enucleated because a good portion of renal parenchyma was found unexpectedly at surgery. No blastematous areas were found at frozen section biopsies from excised tumor. No chemotherapy was given either before or after surgery. Finally, case 28 was a huge tumor (18 cm in diameter) localized to the upper pole and invading the renal sinus. The tumor was excised with a 1-cm margin. Postoperative chemotherapy was no different from that she would have received if nephrectomized. All procedures were performed without hypothermia or vascular occlusion. No recurrence occurred after NSS, and all patients are alive and disease free with good function of the previously affected kidney at a mean follow-up of 40.7 months (range, 2 to 100 months).
Table 1. Eligible Patient Characteristics Patient No.
Age (mo)
Indication for NSS
Tumor Location
1 2 10 15 17 19
23 29 22 28 144 13
Associated anomalies Elective Elective Renal polycystic disease in the family Chronic glomerulonephritis Bilateral hyperplastic nephroblastomatosis
21 24 25 26 28
48 48 9 21 48
Central Central Periphral Central Peripheral Peripheral Peripheral Central Peripheral Peripheral Central Central
Familial vesico-ureteric reflux Elective Elective Elective Elective
Operative Technique
Enucleation Enucleation Enucleation Nephrectomy Partial nephrectomy Right enucleation Left enucleation Partial nephrectomy Partial nephrectomy Partial nephrectomy Enucleation Partial nephrectomy
Histology
Standard Standard Standard Standard Oncocytoma Standard Standard Standard Standard Favorable Cystic nephroma Standard
Follow-Up (mo)
100 99 76 46 42 40 35 33 8 4 3 2
364
COZZI ET AL
DISCUSSION
Tumor Enucleation In the current series of patients, 5 children with stage I URT successfully underwent 6 tumor enucleation procedures. In the first 3 patients, enucleation was associated with 3-drug adjuvant chemotherapy.1 The main concern regarding this protocol is that anthracycline increases the risk of cardiotoxicity; therefore, the potential risk of cardiotoxicity must be weighed against the potential risk of renal failure. More recently, we administered adjuvant chemotherapy, as for stage I disease, when multiple microscopic sections of the pseudocapsule of the tumor excluded invasion (patient 19). In this child, epirubicin was added when, after regression of the nodules on both sides, a new tumor appeared on the contralateral kidney during the 2-drug chemotherapy. In patient 26, no chemotherapy was added because the lesion was a cystic nephroma. The other concern regarding tumor enucleation for stage I URT is that in patients with pseudocapsule invasion, enucleation is associated with the risk of a minor spill of the tumor resulting in a transformation to stage II disease.3 The spill of a standard histology tumor may reasonably be treated with longer 2-drug chemotherapy. However, the spill of anaplastic cells may have a dramatic impact on survival rate.4 Enucleation should be reserved for central tumor in children at risk of metachronous nephroblastoma (patients 1 and 19 in our series), in children with benign tumor (patient 26), or in children with a single kidney or a contralateral renal disease. Enucleation also may be considered appropriate for central tumor in patients under 3 years of age, when the risk of anaplasia for stage I disease is very low and when anaplasia is not detected on frozen sections from excised tumor. Partial Nephrectomy Excision of the tumor with a rim of normal renal parenchyma implies greater technical difficulties compared with enucleation. However, even profuse bleeding can be controlled by simple finger compression of the
kidney. Therefore, in the current study, since 1996, partial nephrectomy has been considered the NSS procedure of choice because patients still can receive the same postoperative chemotherapy as they would have received if had they been submitted to nephrectomy. None of the 5 children submitted to partial nephrectomy presented with recurrence. One patient (case 21) was treated with a more aggressive chemotherapy because of postoperative hematuria associated with potential microscopic residual disease. In addition to our 5 cases, we collected from the literature reports of another 21 patients with URT treated with partial nephrectomy.1 Only 1 of these 21 patients presented, 2 years after NSS, with an extra renal local recurrence, which was excised with the residual kidney. Partial nephrectomy should be considered a safe procedure. We have reserved NSS for stage I by the SIOP protocol. Stage II, lymph node positive, or stage III require radiotherapy, which may thwart the advantage of NSS. Because surgical evaluation of lymph node metastasis in Wilms’ tumor is associated with high rates of false-negative and false-positive,5 we tried to exclude metastases by frozen sections studies at operation. An argument in favor of NSS is that the risk of renal failure after nephrectomy may be higher than that accepted currently. Children with a single kidney, studied at follow-up for over 25 years, present with a significant decrease in the glomerular filtration rate and a significant increase in albuminuria compared with those studied at a shorter follow-up.6,7 These findings suggest the possible development of damage to the glomerular capillaries secondary to hyperfiltration, which may later progress to renal failure. Because life expectancy in children is longer than that in adults, the long-term risk of renal failure in nephrectomized patients with URT may be greater than currently suspected. This may be so, especially for some children with a genetic risk of renal disease. Therefore, in our opinion, the importance of NSS in the treatment of children with URT should not be underestimated.
REFERENCES 1. Cozzi F, Schiavetti A, Bonanni M, et al: Enucleative surgery for stage I nephroblastoma with a normal contralateral kidney. J Urol 156:1788-1793, 1999 2. Horowitz JR, Ritchey ML, Moksness J, et al: Renal salvage procedures in patients with synchronous bilateral Wilms’ tumors: A report from the National Wilms’ Tumor Study Group. J Pediatr Surg 31:1020-1025, 1996 3. Green DM: Letter to the Editor regarding present reference 1. J Urol 158:548, 1997 4. Ritchey ML: Editorial comment to present reference 1. J Urol 156:1791-1792, 1996
5. Othersen HB Jr, DeLorimier A, Hrabovsky E, et al: Surgical evaluation of lymph node metastases in Wilms’ tumor. J Pediatr Surg 25:330-331, 1990 6. Baudoin P, Provoost AP, Molenaar JC: Renal function up to 50 years after unilateral nephrectomy in childhood. Am J Kidney Dis 21:603-611, 1993 7. Wikstad I, Celsi G, Larsson L, et al: Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood. Pediatr Nephrol 2:177-182, 1988
NEPHRON-SPARING SURGERY
365
Discussion E. Wiener (Pittsburgh, PA): The questions that I would propose to you are just what you presented. The trade off is using 3 drugs with cardiotoxicity versus 2 drugs with questionable long-term renal effects. I would underscore the questionable part of that because there are no data from the National Wilms’ Tumours Study patients that have gone on to subsequent renal failure. Do you have long enough follow-up in these patients who receive 2 drugs alone to ensure that you have good outcome, and, secondly, do you believe that you can translate your excellent results to widespread use amongst many surgeons? D.A. Cozzi (response): Thank you very much for your question. A recent study, published in the Journal of Pediatric Surgery, reporting data from the National Wilms’ Tumor Study on bilateral Wilms’ tumor, indicates that many surgeons may use nephron-sparing surgical techniques with excellent results. We have tried to minimize the risk of cardiotoxicity by treating these patients with the same postoperative chemotherapy as they would receive if submitted to nephrectomy. I agree with you that longer follow-up is necessary. As you mentioned, in children with unilateral Wilms’ tumor, the risk of renal failure up to 16 years following nephrectomy is very low. However, many children with a single kidney experience subtle renal deterioration at longer follow-up.
S. Shochat (Memphis, TN): This was a wonderful and eloquent presentation, and I really enjoyed it. My question is that in the United States we do not like to treat patients before operation and staging because we feel we lose some information from preoperative therapy. Have you looked at your prechemotherapy radiologic studies to see if you can predict who will be amenable to unilateral nephrectomy? If you could tell me that information then I may be willing to treat some of these patients earlier, but in a disease that we have almost 100% survival rate in stage I tumours, I am a little bit nervous about doing partial nephrectomy until I know some of this information. D.A. Cozzi (response): I fully agree with you that in North America you achieved excellent results without preoperative chemotherapy. However, these results are comparable with those obtained in Europe with preoperative chemotherapy. In our experience, the feasibility of nephron-sparing surgery is finally ascertained at surgery, particularly for tumors centrally located. I believe that in patients with a single kidney, the risk of renal failure at very long term follow-up is underestimated. Life expectancy in survivors of Wilms’ tumor is longer than that in nephrectomized adults. The ideal is to obtain long-term survivors with good renal function.
Purpose: Definition of the role of nephron-sparing surgery (NSS) in the treatment of children with primary unilateral renal tumor (URT). Methods: Between January 1992 and June 2000, 28 children with URT were admitted to our surgical unit. Criteria for selection of patients eligible for NSS were at least 50% of affected kidney preservable and stage I at surgery (frozen section biopsies from regional lymph nodes, perirenal fat, and surrounding renal parenchyma). Preoperative 2-drug chemotherapy was given to all patients more than 6 months of age. Between 1992 and 1995, 3-drug chemotherapy was used after NSS. Thereafter, following NSS, 2-drug chemotherapy was given if no microscopic residual disease was found on final histologic examination. Results: NSS was feasible in 10 of 28 children (35%). Enucleation of 6 tumors (1 metachronous) was performed in 5 patients. NSS was elective in 5 patients, mandatory in 3 patients (1 with aniridia and genitourinary anomalies, 1 with
I
N 1996, we reported preliminary data on a pilot study investigating whether tumor enucleation may be feasible and effective in selected children with stage I nephroblastoma and a normal contralateral kidney.1 The main impediment to this approach is that nephron-sparing surgery (NSS) may increase the risk of local relapse, thus, adversely affecting morbidity and mortality. A contribution on this issue comes from recent data on NSS (partial nephrectomy or enucleation) for the treatment of children with bilateral Wilms’ tumor (BW).2 After NSS, the 4-year survival rate was 81.7%. The presence of residual disease after NSS, whether macroscopic or microscopic, did not have a major impact on survival or on the local recurrence rate. These excellent results were obtained with a more aggressive chemotherapy.2 The potential morbidity of more aggressive chemoFrom the Universita` di Roma “La Sapienza,” Policlinico Umberto I, Pediatric Surgery Unit, Rome, Italy. Presented at the 47th Annual International Congress of the British Association of Paediatric Surgeons, Sorrento, Italy, July 18-21, 2000. Address reprint requests to D.A. Cozzi, MD, Policlinico Umberto I, Chirurgia Pediatrica, Viale Regina Elena, 324, 00161 Rome, Italy. Copyright © 2001 by W.B. Saunders Company 0022-3468/01/3602-0026$35.00/0 doi:10.1053/jpsu.2001.20717 362
chronic glomerulonephritis, 1 with bilateral hyperplastic nephroblastomatosis), and advisable in 2 patients (1 with familial vesicoureteric reflux and 1 with cystic nephroma). Seven children had standard histology nephroblastoma, 1 highly differentiated epithelial type nephroblastoma, 1 oncocytoma, and 1 cystic nephroma. The only post-NSS complication was macroscopic hematuria in 1 patient. None of the patients had a relapse. All children are alive and disease free with good functioning of the affected kidney after NSS, at a mean follow-up of 40.7 months (range, 2 to 100 months).
Conclusion: NSS should be considered in selected children with URT, especially in patients with increased risk for metachronous tumor or renal disease, and in patients with benign or low-grade malignant URT. J Pediatr Surg 36:362-365. Copyright © 2001 by W.B. Saunders Company. INDEX WORDS: Renal tumor, partial nephrectomy, Wilms’ tumor, cystic nephroma.
therapy is a reasonable price to pay for the treatment of the children with BW in whom the risk of renal failure is high. Conversely, in children with primary unilateral renal tumor (URT) the risk of renal failure is considered small. We have revised our protocol. Tumor enucleation or partial nephrectomy were performed only in those patients with URT, who, after NSS, receive the same postoperative chemotherapy as they would have received if submitted to nephrectomy or in those patients at higher risk for renal failure. We present our experience using NSS in children with URT. MATERIALS AND METHODS All children undergoing surgery for URT between January 1992 and June 2000 at our institution were identified prospectively. A total of 28 children with URT entered into the study protocol. Mean age at diagnosis was 43.3 months (range, 1 day to 12 years). All patients were evaluated with a medical history, physical examination, urinalysis, serum creatinine assay, and complete blood count. Imaging studies included ultrasound scan, chest x-rays, and computerized tomography or magnetic resonance imaging. Preoperative actinomycin D and vincristine according to the International Society of Pediatric Oncology (SIOP) protocol was given to all patients over 6 months of age. Abdominal imaging studies were repeated after preoperative chemotherapy. We considered appropriate for NSS all those patients with stage I disease on imaging studies in whom at least 50% of the affected kidney could be preserved. Further reassessment was made at surgery by frozen section biopsies from lymph nodes in the renal hilum and paraaortic regions, perirenal fat, and surrounding renal parenchyma. Journal of Pediatric Surgery, Vol 36, No 2 (February), 2001: pp 362-365
NEPHRON-SPARING SURGERY
363
Since 1996, partial nephrectomy with a 0.5- to 1-cm rim of normal parenchyma, whenever feasible, was considered the NSS procedure of choice. Postoperatively, multiple serial section histologic examinations (every 0.5 cm) were performed to confirm intraoperative findings, particularly with regard to the integrity of the pseudocapsule or resection margin of the tumor. Between 1992 and 1995, 3-drug chemotherapy was used after NSS.1 Subsequently, 2-drug postoperative chemotherapy was used in absence of microscopic residual disease. The follow-up of the present series of patients submitted to NSS was no different from that we reported in the previous series.1 We adopted the SIOP staging system and histopathologic classification of renal tumor. A tumor was defined central or peripheral depending on whether it extended into the renal sinus.
RESULTS
Eighteen of 28 (60%) patients with URT presented with stage I disease after preoperative chemotherapy. Of these 18, 11 were considered eligible for NSS (Table 1). The details of patients 1, 2, and 10 have been reported elsewhere.1 A synopsis of the others follows. In 1 eligible patient (case 15), with a familial history of adult renal polycystic disease and with a huge tumor, preoperative chemotherapy led to a dramatic reduction in tumor size and also in large areas of tumor necrosis. At surgery, NSS was considered inadvisable on account of thick adherence of the tumor to the surrounding renal parenchyma. Patient 17 presented with a kidney tumor discovered incidentally during an ultrasound examination in a girl with bilateral glomerulonephritis after Henoch-Scho¨nlein purpura. The tumor was excised with 1 cm clear margin. The final diagnosis was oncocytoma; therefore, no postoperative chemotherapy was given. Patient 19 presented with bilateral hyperplastic nephroblastomatosis and a small nephroblastoma on the right kidney. This was enucleated, and histopathologic examination showed no invasion of the pseudocapsule. All nodules responded to chemotherapy and disappeared on both sides. However, after 4 months and during chemotherapy, a new nodule appeared on the left side indicating the development of a contralateral nephroblas-
toma. This was enucleated, and 3-drug chemotherapy was administered. Patient 21 presented with a nephroblastoma associated with vesico-ureteric reflux. The father previously had undergone renal transplantation for chronic renal failure associated with vesico-ureteric reflux. In this case, partial nephrectomy was complicated by gross hematuria, which resolved spontaneously. In addition, the final histologic examination showed penetration of the pseudocapsule in proximity to the margin corresponding to the collecting system, which was entered during excision of the tumor. This girl was treated with carboplatin and etoposide in association with vincristine and actinomycin D. Patient 24 had a very small nephroblastoma, which was excised with a 1-cm clear margin of normal renal parenchyma. Postoperative chemotherapy was no different from that he would have received if submitted to nephrectomy. Case 25 was incidentally discovered at an ultrasound renal study request for an episode of significant bacteriuria. The patient was submitted to partial nephrectomy with a 0.5-cm clear margin; the final histologic diagnosis was nephroblastoma with highly differentiated epithelial type; no postoperative chemotherapy was administered. Patient 26 had a cystic nephroma that was enucleated because a good portion of renal parenchyma was found unexpectedly at surgery. No blastematous areas were found at frozen section biopsies from excised tumor. No chemotherapy was given either before or after surgery. Finally, case 28 was a huge tumor (18 cm in diameter) localized to the upper pole and invading the renal sinus. The tumor was excised with a 1-cm margin. Postoperative chemotherapy was no different from that she would have received if nephrectomized. All procedures were performed without hypothermia or vascular occlusion. No recurrence occurred after NSS, and all patients are alive and disease free with good function of the previously affected kidney at a mean follow-up of 40.7 months (range, 2 to 100 months).
Table 1. Eligible Patient Characteristics Patient No.
Age (mo)
Indication for NSS
Tumor Location
1 2 10 15 17 19
23 29 22 28 144 13
Associated anomalies Elective Elective Renal polycystic disease in the family Chronic glomerulonephritis Bilateral hyperplastic nephroblastomatosis
21 24 25 26 28
48 48 9 21 48
Central Central Periphral Central Peripheral Peripheral Peripheral Central Peripheral Peripheral Central Central
Familial vesico-ureteric reflux Elective Elective Elective Elective
Operative Technique
Enucleation Enucleation Enucleation Nephrectomy Partial nephrectomy Right enucleation Left enucleation Partial nephrectomy Partial nephrectomy Partial nephrectomy Enucleation Partial nephrectomy
Histology
Standard Standard Standard Standard Oncocytoma Standard Standard Standard Standard Favorable Cystic nephroma Standard
Follow-Up (mo)
100 99 76 46 42 40 35 33 8 4 3 2
364
COZZI ET AL
DISCUSSION
Tumor Enucleation In the current series of patients, 5 children with stage I URT successfully underwent 6 tumor enucleation procedures. In the first 3 patients, enucleation was associated with 3-drug adjuvant chemotherapy.1 The main concern regarding this protocol is that anthracycline increases the risk of cardiotoxicity; therefore, the potential risk of cardiotoxicity must be weighed against the potential risk of renal failure. More recently, we administered adjuvant chemotherapy, as for stage I disease, when multiple microscopic sections of the pseudocapsule of the tumor excluded invasion (patient 19). In this child, epirubicin was added when, after regression of the nodules on both sides, a new tumor appeared on the contralateral kidney during the 2-drug chemotherapy. In patient 26, no chemotherapy was added because the lesion was a cystic nephroma. The other concern regarding tumor enucleation for stage I URT is that in patients with pseudocapsule invasion, enucleation is associated with the risk of a minor spill of the tumor resulting in a transformation to stage II disease.3 The spill of a standard histology tumor may reasonably be treated with longer 2-drug chemotherapy. However, the spill of anaplastic cells may have a dramatic impact on survival rate.4 Enucleation should be reserved for central tumor in children at risk of metachronous nephroblastoma (patients 1 and 19 in our series), in children with benign tumor (patient 26), or in children with a single kidney or a contralateral renal disease. Enucleation also may be considered appropriate for central tumor in patients under 3 years of age, when the risk of anaplasia for stage I disease is very low and when anaplasia is not detected on frozen sections from excised tumor. Partial Nephrectomy Excision of the tumor with a rim of normal renal parenchyma implies greater technical difficulties compared with enucleation. However, even profuse bleeding can be controlled by simple finger compression of the
kidney. Therefore, in the current study, since 1996, partial nephrectomy has been considered the NSS procedure of choice because patients still can receive the same postoperative chemotherapy as they would have received if had they been submitted to nephrectomy. None of the 5 children submitted to partial nephrectomy presented with recurrence. One patient (case 21) was treated with a more aggressive chemotherapy because of postoperative hematuria associated with potential microscopic residual disease. In addition to our 5 cases, we collected from the literature reports of another 21 patients with URT treated with partial nephrectomy.1 Only 1 of these 21 patients presented, 2 years after NSS, with an extra renal local recurrence, which was excised with the residual kidney. Partial nephrectomy should be considered a safe procedure. We have reserved NSS for stage I by the SIOP protocol. Stage II, lymph node positive, or stage III require radiotherapy, which may thwart the advantage of NSS. Because surgical evaluation of lymph node metastasis in Wilms’ tumor is associated with high rates of false-negative and false-positive,5 we tried to exclude metastases by frozen sections studies at operation. An argument in favor of NSS is that the risk of renal failure after nephrectomy may be higher than that accepted currently. Children with a single kidney, studied at follow-up for over 25 years, present with a significant decrease in the glomerular filtration rate and a significant increase in albuminuria compared with those studied at a shorter follow-up.6,7 These findings suggest the possible development of damage to the glomerular capillaries secondary to hyperfiltration, which may later progress to renal failure. Because life expectancy in children is longer than that in adults, the long-term risk of renal failure in nephrectomized patients with URT may be greater than currently suspected. This may be so, especially for some children with a genetic risk of renal disease. Therefore, in our opinion, the importance of NSS in the treatment of children with URT should not be underestimated.
REFERENCES 1. Cozzi F, Schiavetti A, Bonanni M, et al: Enucleative surgery for stage I nephroblastoma with a normal contralateral kidney. J Urol 156:1788-1793, 1999 2. Horowitz JR, Ritchey ML, Moksness J, et al: Renal salvage procedures in patients with synchronous bilateral Wilms’ tumors: A report from the National Wilms’ Tumor Study Group. J Pediatr Surg 31:1020-1025, 1996 3. Green DM: Letter to the Editor regarding present reference 1. J Urol 158:548, 1997 4. Ritchey ML: Editorial comment to present reference 1. J Urol 156:1791-1792, 1996
5. Othersen HB Jr, DeLorimier A, Hrabovsky E, et al: Surgical evaluation of lymph node metastases in Wilms’ tumor. J Pediatr Surg 25:330-331, 1990 6. Baudoin P, Provoost AP, Molenaar JC: Renal function up to 50 years after unilateral nephrectomy in childhood. Am J Kidney Dis 21:603-611, 1993 7. Wikstad I, Celsi G, Larsson L, et al: Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood. Pediatr Nephrol 2:177-182, 1988
NEPHRON-SPARING SURGERY
365
Discussion E. Wiener (Pittsburgh, PA): The questions that I would propose to you are just what you presented. The trade off is using 3 drugs with cardiotoxicity versus 2 drugs with questionable long-term renal effects. I would underscore the questionable part of that because there are no data from the National Wilms’ Tumours Study patients that have gone on to subsequent renal failure. Do you have long enough follow-up in these patients who receive 2 drugs alone to ensure that you have good outcome, and, secondly, do you believe that you can translate your excellent results to widespread use amongst many surgeons? D.A. Cozzi (response): Thank you very much for your question. A recent study, published in the Journal of Pediatric Surgery, reporting data from the National Wilms’ Tumor Study on bilateral Wilms’ tumor, indicates that many surgeons may use nephron-sparing surgical techniques with excellent results. We have tried to minimize the risk of cardiotoxicity by treating these patients with the same postoperative chemotherapy as they would receive if submitted to nephrectomy. I agree with you that longer follow-up is necessary. As you mentioned, in children with unilateral Wilms’ tumor, the risk of renal failure up to 16 years following nephrectomy is very low. However, many children with a single kidney experience subtle renal deterioration at longer follow-up.
S. Shochat (Memphis, TN): This was a wonderful and eloquent presentation, and I really enjoyed it. My question is that in the United States we do not like to treat patients before operation and staging because we feel we lose some information from preoperative therapy. Have you looked at your prechemotherapy radiologic studies to see if you can predict who will be amenable to unilateral nephrectomy? If you could tell me that information then I may be willing to treat some of these patients earlier, but in a disease that we have almost 100% survival rate in stage I tumours, I am a little bit nervous about doing partial nephrectomy until I know some of this information. D.A. Cozzi (response): I fully agree with you that in North America you achieved excellent results without preoperative chemotherapy. However, these results are comparable with those obtained in Europe with preoperative chemotherapy. In our experience, the feasibility of nephron-sparing surgery is finally ascertained at surgery, particularly for tumors centrally located. I believe that in patients with a single kidney, the risk of renal failure at very long term follow-up is underestimated. Life expectancy in survivors of Wilms’ tumor is longer than that in nephrectomized adults. The ideal is to obtain long-term survivors with good renal function.