- Email: [email protected]
Management of bilateral Wilms tumor over three decades: The perspective of a single center
Journal of Pediatric Urology (2015) 11, 118.e1e118.e6
Management of bilateral Wilms tumor over three decades: The perspective of a single center
a
Department of Pediatric Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
b
Pediatric Pathology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey c Pediatric Oncology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence to: S. Ekinci, Hacettepe University Faculty of Medicine, Department of Pediatric Surgery, 06100 Ankara, Turkey, Tel./fax: þ90 312 3115541 [email protected] (S. Ekinci) Keywords Child; Bilateral; Wilms tumor; Renal salvage surgery; Survival Received 2 March 2014 Accepted 19 November 2014 Available online 30 January 2015
I.R. User a, S. Ekinci a, G. Kale b, C. Akyu ¸u c, ¨z c, M. Bu ¨yu ¨kpamukc a a a a ¨ I. Karnak , A.O. C ¸ iftc ¸i , F.C. Tanyel , M.E. S‚enocak Summary Introduction Outcomes of Wilms tumor improved in last 50 years and excellent survival rates can be achieved especially in case of non-metastatic disease and favorable histology. Nevertheless, bilateral cases still stand as a therapeutic challenge. Prognosis of bilateral Wilms tumor (BWT) is not as good as the unilateral tumors of similar stage and histology in terms of survival and renal function. Objective Management of BWT is constantly evolving and still stands as a therapeutic challenge. This study is designed to review and share our experiences on this topic from a surgical standpoint. Study design The records of patients treated in our clinic between 1980 and 2013 according to Turkish Pediatric Group of Oncology protocol were analyzed retrospectively and clinical data, surgical details, pathology results, long term outcomes were analyzed. Results Thirteen girls and 7 boys with a mean age of 2,5 years were treated. There were 2 patients with Wilms tumor-Aniridia-Growth Retardation complex and one with isolated hemihypertrophy. Metastasis were detected in lungs of 4 patients; liver of 2 and in the cranium of one. All patients except one with the presumptive diagnosis of unilateral Wilms tumor were given preoperative chemotherapy. To sum up; 19 nephroureterectomies, 8 partial nephrectomies and 13 enucleations were performed to 36 kidneys without any major early or late postoperative complications. Pathologic results revealed positive surgical margins in 2 lesions with enucleation and in 2 with partial nephrectomies and anaplasia in 4 patients. Two patients were not operated due to parental disapproval. Two patients had the need of dialysis; one was anephric and the others’ renal functions recovered over a year. Seven patients received radiotherapy for pulmonary metastasis, positive surgical margins or local recurrences. Overall, 13 patients survived and 7 died due to metastasis, recurrences, and complication of dialysis and refusal of surgical treatment. Survival among all patients was 65% and 72.2% among operated ones. Of the 7
patients with the partial nephrectomy, 2 died and 5 survived. Among enucleation group, 8 out of 10 survived and 2 died. Survival was slightly higher among enucleation group (80% vs 71.4%). Median time of follow-up for survivors of disease is 5.8 years (min: 6 months and max: 14 years). Discussion Outcomes of BWT management have changed dramatically during the last few decades from only survival, to a long life expectancy without the need of renal replacement therapy owing to improvements in treatment options. We argue that positive surgical margins do not necessarily lead to local recurrence. For this reason it may be wiser to favor on more nephron sparing surgery than to achieve negative surgical margins. Adjuvant chemotherapy and radiotherapy may be adequate to prevent local recurrence. Also, survival did not differ significantly between different ways of nephron sparing surgeries, so it may be wiser to choose enucleation over partial nephrectomy which preserves more nephrons. Nephron-sparing surgery should have utmost importance despite the risk of positive margins. On the other hand, there is not enough data to interpret if positive surgical margins have role on distant metastases or not. Presence of metastasis and recurrence seems to be an important determinant of prognosis given the fact that none of the survivors had any metastasis or recurrence. Conclusion Nephron preservation should be the aim while taking positive surgical margin risk on nephron sparing surgery side relying on postoperative chemotherapy and carefully planned radiotherapy to avoid recurrence. However, there is significant diversity on the management BWT in different centers and a certain Survival among different surgical procedure groups. Table
Survival Partial nephrectomy þ unilateral nephrectomy Enucleation þ unilateral nephrectomy Overall (among operated patients)
http://dx.doi.org/10.1016/j.jpurol.2014.11.012 1477-5131/ª 2015 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
71.4% (5/7) 80% (8/10) 72.2% (13/18)
Management of bilateral Wilms tumor over three decades
118.e2
validated guideline or protocol to provide the optimal treatment is still lacking.
Introduction Wilms tumor is the most common primary renal tumor, and 5e7% of all Wilms tumors present as bilateral disease [1]. The outcomes of Wilms tumor have improved in last 50 years and excellent survival rates can be achieved, especially in cases with non-metastatic disease and favorable histology. Nevertheless, bilateral cases still stand as a therapeutic challenge [2]. The prognosis of bilateral Wilms tumors (BWT), in terms of survival and renal function, is not as good as the unilateral tumors of similar stage and histology [3]. Bilateral Wilms tumor management has evolved over the years from an aggressive surgical approach, which may lead to renal failure, to a conservative approach, which will provide an opportunity to reach adulthood without the necessity of renal transplantation. Preoperative chemotherapy may lead to tumor shrinkage and allow easier tumor resection whilst preserving more kidney parenchyma and decreasing the risk of tumor spillage [4]. Although the surgical treatment of BWT is based on renal salvage, deaths due to disease are mostly secondary to recurrences, and total resection of the tumor should retain importance. To determine the optimum treatment of this relatively rare entity, experiences should be shared. The present study examined three decades of surgical experience from a single center on synchronous BWT.
Materials and methods Following approval from the Human Research Ethics Committee of Hacettepe University, all patients who presented _ to Hacettepe Ihsan Dogramacı Children’s Hospital with the diagnosis of synchronous BWT between 1980 and 2013 were identified. All of the patients’ medical records were reviewed. Two children that were operated on or received chemotherapy in another facility were excluded from the study. The following were documented: age at presentation; gender; bodyweight; associated syndromes and anomalies; presenting signs and symptoms; preoperative and postoperative creatinine levels; presence of metastasis; preoperative chemotherapy regimens and duration of preoperative chemotherapy; preoperative biopsy results; details of surgical intervention (radical nephrectomy, partial nephrectomy, enucleation of tumor); early and late complications of surgery; pathology results of excised tumors; radiotherapy applications; and prognosis and survival rates. A multidisciplinary team consisting of pediatric surgeons, pediatric oncologists, pediatric radiologists and radiation oncologists made all of the decisions about the treatment plans. Some children had surgery after a first cycle of chemotherapy, and some needed further chemotherapy to achieve nephron-sparing surgery. The surgery was performed on both kidneys during the same operation. If the tumor was located in upper pole or lower pole, partial nephrectomy was performed to achieve negative surgical margins. If the tumor was close to the renal hilum and excision with partial nephrectomy was not possible,
enucleation was preferred. Enucleation was also favored when there was more than one lesion in the same kidney. Partial nephrectomy was performed by excision of the upper or lower pole that contained the tumor. Enucleation was performed by excision of the lesion, with a thin rim of surrounding renal parenchyma if possible.
Results Epidemiology Twenty children, who were diagnosed with BWT, were treated during a 30-year period. They were aged between 2 months and 7 years old, and the median age at diagnosis was 2.5 years. The gender ratio was 1.8 (13 girls and seven boys). The presenting symptoms were: abdominal distention noted by the family (n Z 7), abdominal pain (n Z 6), bloodstained urine (n Z 3), and fever (n Z 2). Two children had aniridia and were regularly followed up for the possibility of Wilms tumor. Therefore, there were two children with WAGR complex and another child with isolated hemihypertrophy that was detected synchronously with Wilms tumor (Table 1). During physical examination, growth retardation was noted in four children, hypertension in three, and undescended testicle in three. Preoperative laboratory investigations revealed that three children had proteinuria, five had hematuria, and one, whose kidneys were totally invaded by the tumor, had abnormal renal function tests and he ended up with bilateral nephroureterectomies. Those with proteinuria and undescended testis were all different children, and none of them had DenyseDrash syndrome. Conventional angiography, computed tomography angiography or magnetic resonance imaging angiography were utilized in the preoperative period in order to define the anatomy of the renal vasculature of the nephron-sparing
Table 1
Clinical characteristics of patients. Number (percentage)
Gender Female Male Age at presentation 0e1 years 1e2 years 2e3 years 4 years Presentation Abdominal distention Abdominal pain Bloodstained urine Fever Other Associated findings WAGR complex Isolated hemihypertrophy
13 (65%) 7 (35%) 2 5 7 6
(10%) (25%) (35%) (30%)
7 6 3 2 2
(35%) (30%) (15%) (10%) (10%)
2 (10%) 1 (5%)
118.e3
I.R. User et al.
kidney more precisely. Five children had Tru-cut biopsies before surgery because of unresponsiveness to chemotherapy. Pulmonary metastases were detected in four children, liver metastasis in two, and one had intracranial metastasis. Thrombosis in the inferior vena cava and renal vein were detected in three children at the time of diagnosis, but only one had tumor thrombosis at the time of surgery. The children were treated according to the Turkish Pediatric Oncology Group (TPOG) Protocol. All except one received preoperative chemotherapy of one to six cycles. Neoadjuvant chemotherapy consisted of vincristine 1.5 mg/ m2 (maximum 2.0 mg), once weekly for four weeks, and actinomycin-D 15 mcg/kg/day for 5 days of the first week. Children who were unresponsive to beginning chemotherapy received adriamycin 20 mg/m2/day for 3 days, in addition to vincristine and actinomycin-D. Six children had more than two cycles of chemotherapy; four of these had anaplastic tumors and two had necrotic tumors. Adriamycin was also added to the preoperative chemotherapy regimen of three children due to their unresponsiveness to chemotherapy or progression of tumor under treatment. The child who was operated on without preoperative chemotherapy was assumed to have unilateral Wilms tumor before the surgery and the tumor on the contralateral side was detected during the surgery. None of the children received preoperative radiotherapy. Those with local recurrence, positive surgical margins or distant metastases received 9e27 Gy radiotherapy, according to disease extent and histopathological subtype.
Surgical details and pathology results A total of 18 children were operated on. The parents of two children, who were not operated on, did not accept the offered bilateral nephroureterectomy and dialysis, and
Table 2
declared that they only approved of conservative therapy for their children. A transverse (n Z 11) or Chevron incision (n Z 7) were used. The renal salvage procedure was performed by partial nephrectomy or enucleation of the lesion. Partial nephrectomy was performed by excision of the upper or lower pole that contained the tumor. Enucleation was performed by excision of the lesion, with a thin rim of surrounding renal parenchyma if possible. Intraoperative ultrasonography was performed on two children in order to detect the location of small lesions. Frozen pathological examinations were performed in two children because the gross appearance of the excised lesion created the doubt of positive margins. To sum up, 19 nephroureterectomies, eight partial nephrectomies and 13 enucleations (enucleation of two masses located in the upper and lower poles of one kidney in one child, and enucleation of four masses located in the upper and lower poles of one kidney in another one) were performed on 36 kidneys. There were no major complications during surgery like massive bleeding, tumor rupture or adjacent organ injury. Eleven children required erythrocyte suspension transfusion during surgery, which did not exceed 10 ml/kg. The mean duration of surgery was 180 min (range 120e300 min). Pathological results revealed positive surgical margins in two lesions with enucleation, and in two with partial nephrectomies. Anaplasia was detected in four children. Nephrogenic rest was observed in nine kidneys and nephroblastomatosis in four. Routine biopsies were not performed before preoperative chemotherapy. Most of the pathologically examined specimens obtained during the operations did not have any viable tumor cells, because of complete necrosis. Therefore, it was not possible to see if the tumor was blastemal, epithelial, stromal or triphasic. Local staging was applied in 11 children and revealed: Stage 1 in seven kidneys, Stage 2 in seven kidneys, and Stage 3 in eight kidneys (Tables 2 and 3).
Characteristics of patients who survived the disease.
Sex
Age (years)
Metastasis and recurrence
Surgical intervention
F M F M F F
5 1 3 1 1 5
e e e e e e
Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy
F F
2 a
e e
Nephroureterectomy þ enucleation Nephroureterectomy þ partial nephrectomy
e e e e e
Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy
F M F F F a b
1 5 5 b
5 6 months. 10 months.
Pathology þ þ þ þ þ þ
þ þ þ þ þ
enucleation enucleation partial nephrectomy enucleation enucleation partial nephrectomy
partial nephrectomy enucleation enucleation enucleation partial nephrectomy
Necrosis, nephroblastomatosis Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephroblastomatosis, Positive surgical margins Nephrogenic rest Necrosis, anaplasia Positive surgical margins Nephrogenic rest Necrosis, anaplasia Nephrogenic rest Nephrogenic rest Necrosis, anaplasia
Management of bilateral Wilms tumor over three decades Table 3
118.e4
Characteristics of patients who died from the disease.
Sex
Age (years)
Metastasis and recurrence
Surgical intervention
Pathology
M
3
Nephroureterectomy þ partial nephrectomy
Necrosis þ nephroblastomatosis
M F F
2
Bilateral nephroureterectomy e Nephroureterectomy þ enucleation
M F
4 4
Pulmonary, liver, and intracranial metastases Local recurrence Pulmonary metastases e Pulmonary and liver metastases Pulmonary metastases Local recurrence
Necrosis, nephroblastomatosis þ anaplasia e Necrosis, nephrogenic rest Positive surgical margins e Necrosis
M
1
e
a
a
7
e Nephroureterectomy þ partial nephrectomy Nephroureterectomy þ enucleation
Necrosis Positive surgical margins
6 months.
Postoperative period and long-term outcomes Renal insufficiency was observed in two children; one, who became anephric, was confined to permanent dialysis in the postoperative period, and the other had a unilateral nephrectomy and partial nephrectomy to the contralateral kidney. The latter child went on hemodialysis for a year, then her renal functions recovered and she stopped dialysis. All children received postoperative chemotherapy regimens that were individually tailored according to stage and pathology results, with durations ranging between 6 months and 2 years. Seven children received radiotherapy for pulmonary metastases, positive surgical margins or local recurrences. Overall, 13 children survived and seven died due to disease and complications of the various treatment modalities. Overall survival was 65.0% and survival among children who were operated on was 72.2%. Among the seven children with the partial nephrectomy, two died and five survived. Among the enucleation group, eight out of ten survived and two died. Survival seemed to be slightly higher among the enucleation group (80.0% vs 71.4%). Multiple metastases were the cause of death in three children. The anephric child died because of intracranial hemorrhage after hemodialysis. Renal vein thrombosis and local recurrence was the cause of mortality in one child. The children who were not operated on died of cardiomyopathy caused by chemotherapeutic agents and the disease itself. The median time of follow-up for survivors of the disease was 5.8 years (range 6 monthse14 years).
Discussion Outcomes of BWT management have changed dramatically during the last few decades due to improvements in treatment options from only survival, to a long life expectancy without the need of renal replacement therapy [1]. Surgeons are expected to preserve as much renal mass as possible while maintaining tumor-free margins and acceptable complication rates. Pediatric oncologists are
expected to plan the most-effective and least-toxic chemotherapy regimens with minimal short-term and long-term side effects. Radiotherapy is being used more efficiently despite reduced doses and the amount of irradiated fields. These current advancements are providing patients with much less morbidity from the treatment or the disease itself whilst achieving better survival rates. Given the fact that BWT is a relatively rare entity and it is not easy to design a prospective study on this topic, most of the information is gathered from retrospective analysis shared by centers dealing with this disease all over the world. Therefore, it was decided to report the experiences, which were gained at a single referral center, of the treatment of pediatric surgery and oncology for BWT over three decades. The patient population, regarding age and sex distribution, was similar to those that have been previously reported. BWT is slightly more common among girls and presents at an earlier age than unilateral tumors. The presenting signs and symptoms are the same as unilateral tumors; the most common are: abdominal distention, pain, hematuria, a palpable mass and hypertension [5e7]. Children with known Wilms tumor-predisposed genetic syndromes are screened so that the disease can be detected before the symptoms emerge [8]. In the present series, two children had aniridia and were routinely followed with USG examinations; these children did not have any complaints at the time of diagnosis. The importance of physical examination should be emphasized because isolated hemihypertrophy was detected in one child only when he presented with Wilms tumor. Imaging modalities are particularly important in case of BWT because detailed information regarding anatomy is necessary in order to plan nephron-sparing surgery. In the present study, conventional angiography, computed tomography angiography or magnetic resonance imaging angiography were used to define the anatomical relationship between the renal vasculature and the lesion. Two decades ago, one of the children had the diagnosis of BWT during surgical exploration. With the advent of highly sensitive imaging techniques, it is now not routinely recommended to explore the contralateral kidney [9].
118.e5 According to the TPOG protocol, in cases of BWT, chemotherapy is administered without the need of tissue diagnosis [10]. Only five of the children who were unresponsive to treatment had Tru-cut biopsies to confirm the diagnosis. In some instances, a response to chemotherapy cannot be determined, due to the increments in size of the mass seen with necrosis and this can lead to a false pretense that the tumor is unresponsive to treatment. Two of the children who were supposed to be unresponsive to chemotherapy had totally necrotic tumors. However, a tumor that does not shrink, despite chemotherapy, is not always unresponsive. Thus, surgery should be considered earlier instead of extending preoperative chemotherapy. Nowadays, novel imaging techniques like f-fluorodeoxyglucose positron emission tomography (FDG-PET) or quantitative MRI are promising for giving additional information about biological responses [8]. A surgical approach to BWT is a controversial topic and the goal of the surgeon is to ensure that the patient has a tumor-free but adequate nephron reserve for a life without renal replacement therapy. This spectrum ranges from: aggressive surgery to achieve negative surgical margins with the suspicion of anaplasia, to a much more conservative approach with nephron-sparing surgery on both sides. Either options carry risks for mortality and morbidity (i.e. end-stage renal disease with the former, and recurrence with the latter case [11e13]. In the present study, nephronsparing surgery was performed on 17 kidneys by partial nephrectomy or enucleation, with four positive surgical margins and 19 nephroureterectomies. Only two children had a need for dialysis; one of them was anephric, and the other went onto dialysis for a year, then her renal function recovered. Although, for the time being, the children who have survived the disease don’t need renal replacement treatment, it is wondered if their renal reserve will be enough for them in the adulthood. According to The National Wilms Tumor Study Group, a surgically positive margin is an independent risk factor for local recurrence [3]. On the other hand, Davidoff et al. reported that patients with microscopic positive resection margins were not at higher risk for locoregional recurrence, compared to patients with negative margins, when they had adjuvant flank radiotherapy [4]. All of the children in the present study with positive surgical margins (n Z 4) underwent radiotherapy and none of them had local tumor recurrence, but one had distant pulmonary and liver metastases. It can be argued that positive surgical margins do not necessarily lead to local recurrence; for this reason, it may be wiser to favor nephron-sparing surgery than to achieve negative surgical margins. Adjuvant chemotherapy and radiotherapy may be adequate to prevent local recurrence. Also, in the present study, survival did not differ significantly between the different ways of performing nephron-sparing surgery, so, it may be wiser to choose enucleation over partial nephrectomy, which preserves more nephrons. Thus, nephron-sparing surgery should be of the utmost importance, despite the risk of positive margins. On the other hand, there is not enough data to interpret if positive surgical margins have an effect on distant metastases or not. The presence of metastasis and recurrence seems to be an important determinant of prognosis, given the fact that
I.R. User et al. none of the survivors had any metastases or recurrence. Another factor may be the greater amount of nephron preservation with enucleation and, hence, the lower possibility of future kidney failure, which leads to long-term morbidity. At the present time, none of the children need renal replacement therapy, but longer follow-up is necessary to make further conclusions. The causes of mortality are diverse in BWT because the treatment includes surgery, chemotherapy and renal replacement therapy in a child whose immune system has already been compromised by chemotherapeutics. These children require the highest standard of care during the treatment process given by both the parents and medical staff. In the present study, one child died due to complications related to dialysis; two others, whose parents refused the offered surgical treatment and claimed that it could not provide the appropriate care for a possibly anephric child, died. In the light of these experiences, it can be assumed that the socioeconomic status of caregivers is a significant determinant of survival. The major limitations of this retrospective study were the relatively short period of follow-up and small number of patients. However, this series presents a single-center surgical experience for patients, all of who were operated on by a standard classical technique. None of the children experienced any surgical complication during the surgery and the early or late postoperative period. The management of patients with BWT is tailored individually in a multidisciplinary manner with a team consisting of pediatric surgeons, pediatric oncologists, pediatric radiologists, radiation oncologists and pediatric nephrologists. Multimodal treatment with appropriate chemotherapy and radiotherapy, and classical surgical techniques achieve low complication rates with preservation of renal functions. In most cases of BWT, they decrease both mortality and morbidity. Longer and more-aggressive preoperative chemotherapy regimens may be necessary in order to perform safer surgery. Nephron preservation should be the primary aim, while taking positive surgical margin risk on the nephron-sparing surgery side. Postoperative chemotherapy and carefully planned radiotherapy should be conducted in order to avoid recurrence. However, there is significant diversity in different centers for the management of BWT, and validated guidelines or protocols are still lacking with which to provide the optimal treatment.
Conflict of interest statement None declared.
Funding None declared.
References [1] Ehrlich PF. Bilateral Wilms tumor: the need to improve outcomes. Expert Rev Anticancer Ther 2009;7:963e73.
Management of bilateral Wilms tumor over three decades [2] Aronson DC, Slaar A, Heinen RC, et al. Long-term outcome of bilateral Wilms tumors. Pediatr Blood Cancer 2011;56:1110e3. [3] Shamberger RC, Haase GM, Argani P, et al. Bilateral Wilms tumor with progressive or nonresponsive disease. J Pediatr Surg 2006;41:652e7. [4] Davidoff AM, Giel DW, Jones DP, et al. The feasibility and outcome of nephron-sparing surgery for children with bilateral Wilms tumor. Cancer 2008;112(9):2060e70. [5] Sarhan OM, El-Baz M, Sarhan MM, et al. Bilateral Wilms tumor: single center experience with 22 cases and literature review. Urology 2010;76(4):946e51. [6] Millar AJW, Davidson A, Rode H, et al. Bilateral Wilms tumor: a single center experience with 19 cases. J Pediatr Surg 2005; 40:1289e94. [7] Hadley GP, Mars M, Ramdial PK. Bilateral Wilms tumor in a developing country. Pediatr Surg Int 2013;29:419e23.
118.e6 [8] Owens CM, Brisse HJ, Olsen ØE, et al. Bilateral disease and new trends in Wilms tumor. Pediatr Radiol 2008;38:30e9. [9] Ko EY, Ritchey ML. Current management of Wilms tumor in children. J Pediatr Urol 2009;5:56e65. [10] Akyu ¨z C, Yıldız I, Hazar V, et al. Treatment of Wilms tumor: a report from Turkish Pediatric Oncology Group (TPOG). Pediatr Hematol Oncol 2010;27:161e78. [11] Kubiak R, Gundeti M, Duffy PG, et al. Renal function and outcome following salvage surgery for bilateral Wilms tumor. J Pediatr Surg 2004;39(11):1667e72. [12] Hamilton TE, Ritchey ML, Argani P, et al. Synchronus bilateral Wilms tumor with complete radiographic response managed without surgical resection: a report from the National Wilms Tumor Study 4. J Pediatr Surg 2008;43:1982e4. [13] Sulkowksi J, Kolon T, Mattei P. Nephron sparing partial nephrectomy for bilateral Wilms tumor. J Pediatr Surg 2012;47: 1234e8.
Management of bilateral Wilms tumor over three decades: The perspective of a single center
a
Department of Pediatric Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
b
Pediatric Pathology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey c Pediatric Oncology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey
Correspondence to: S. Ekinci, Hacettepe University Faculty of Medicine, Department of Pediatric Surgery, 06100 Ankara, Turkey, Tel./fax: þ90 312 3115541 [email protected] (S. Ekinci) Keywords Child; Bilateral; Wilms tumor; Renal salvage surgery; Survival Received 2 March 2014 Accepted 19 November 2014 Available online 30 January 2015
I.R. User a, S. Ekinci a, G. Kale b, C. Akyu ¸u c, ¨z c, M. Bu ¨yu ¨kpamukc a a a a ¨ I. Karnak , A.O. C ¸ iftc ¸i , F.C. Tanyel , M.E. S‚enocak Summary Introduction Outcomes of Wilms tumor improved in last 50 years and excellent survival rates can be achieved especially in case of non-metastatic disease and favorable histology. Nevertheless, bilateral cases still stand as a therapeutic challenge. Prognosis of bilateral Wilms tumor (BWT) is not as good as the unilateral tumors of similar stage and histology in terms of survival and renal function. Objective Management of BWT is constantly evolving and still stands as a therapeutic challenge. This study is designed to review and share our experiences on this topic from a surgical standpoint. Study design The records of patients treated in our clinic between 1980 and 2013 according to Turkish Pediatric Group of Oncology protocol were analyzed retrospectively and clinical data, surgical details, pathology results, long term outcomes were analyzed. Results Thirteen girls and 7 boys with a mean age of 2,5 years were treated. There were 2 patients with Wilms tumor-Aniridia-Growth Retardation complex and one with isolated hemihypertrophy. Metastasis were detected in lungs of 4 patients; liver of 2 and in the cranium of one. All patients except one with the presumptive diagnosis of unilateral Wilms tumor were given preoperative chemotherapy. To sum up; 19 nephroureterectomies, 8 partial nephrectomies and 13 enucleations were performed to 36 kidneys without any major early or late postoperative complications. Pathologic results revealed positive surgical margins in 2 lesions with enucleation and in 2 with partial nephrectomies and anaplasia in 4 patients. Two patients were not operated due to parental disapproval. Two patients had the need of dialysis; one was anephric and the others’ renal functions recovered over a year. Seven patients received radiotherapy for pulmonary metastasis, positive surgical margins or local recurrences. Overall, 13 patients survived and 7 died due to metastasis, recurrences, and complication of dialysis and refusal of surgical treatment. Survival among all patients was 65% and 72.2% among operated ones. Of the 7
patients with the partial nephrectomy, 2 died and 5 survived. Among enucleation group, 8 out of 10 survived and 2 died. Survival was slightly higher among enucleation group (80% vs 71.4%). Median time of follow-up for survivors of disease is 5.8 years (min: 6 months and max: 14 years). Discussion Outcomes of BWT management have changed dramatically during the last few decades from only survival, to a long life expectancy without the need of renal replacement therapy owing to improvements in treatment options. We argue that positive surgical margins do not necessarily lead to local recurrence. For this reason it may be wiser to favor on more nephron sparing surgery than to achieve negative surgical margins. Adjuvant chemotherapy and radiotherapy may be adequate to prevent local recurrence. Also, survival did not differ significantly between different ways of nephron sparing surgeries, so it may be wiser to choose enucleation over partial nephrectomy which preserves more nephrons. Nephron-sparing surgery should have utmost importance despite the risk of positive margins. On the other hand, there is not enough data to interpret if positive surgical margins have role on distant metastases or not. Presence of metastasis and recurrence seems to be an important determinant of prognosis given the fact that none of the survivors had any metastasis or recurrence. Conclusion Nephron preservation should be the aim while taking positive surgical margin risk on nephron sparing surgery side relying on postoperative chemotherapy and carefully planned radiotherapy to avoid recurrence. However, there is significant diversity on the management BWT in different centers and a certain Survival among different surgical procedure groups. Table
Survival Partial nephrectomy þ unilateral nephrectomy Enucleation þ unilateral nephrectomy Overall (among operated patients)
http://dx.doi.org/10.1016/j.jpurol.2014.11.012 1477-5131/ª 2015 Published by Elsevier Ltd on behalf of Journal of Pediatric Urology Company.
71.4% (5/7) 80% (8/10) 72.2% (13/18)
Management of bilateral Wilms tumor over three decades
118.e2
validated guideline or protocol to provide the optimal treatment is still lacking.
Introduction Wilms tumor is the most common primary renal tumor, and 5e7% of all Wilms tumors present as bilateral disease [1]. The outcomes of Wilms tumor have improved in last 50 years and excellent survival rates can be achieved, especially in cases with non-metastatic disease and favorable histology. Nevertheless, bilateral cases still stand as a therapeutic challenge [2]. The prognosis of bilateral Wilms tumors (BWT), in terms of survival and renal function, is not as good as the unilateral tumors of similar stage and histology [3]. Bilateral Wilms tumor management has evolved over the years from an aggressive surgical approach, which may lead to renal failure, to a conservative approach, which will provide an opportunity to reach adulthood without the necessity of renal transplantation. Preoperative chemotherapy may lead to tumor shrinkage and allow easier tumor resection whilst preserving more kidney parenchyma and decreasing the risk of tumor spillage [4]. Although the surgical treatment of BWT is based on renal salvage, deaths due to disease are mostly secondary to recurrences, and total resection of the tumor should retain importance. To determine the optimum treatment of this relatively rare entity, experiences should be shared. The present study examined three decades of surgical experience from a single center on synchronous BWT.
Materials and methods Following approval from the Human Research Ethics Committee of Hacettepe University, all patients who presented _ to Hacettepe Ihsan Dogramacı Children’s Hospital with the diagnosis of synchronous BWT between 1980 and 2013 were identified. All of the patients’ medical records were reviewed. Two children that were operated on or received chemotherapy in another facility were excluded from the study. The following were documented: age at presentation; gender; bodyweight; associated syndromes and anomalies; presenting signs and symptoms; preoperative and postoperative creatinine levels; presence of metastasis; preoperative chemotherapy regimens and duration of preoperative chemotherapy; preoperative biopsy results; details of surgical intervention (radical nephrectomy, partial nephrectomy, enucleation of tumor); early and late complications of surgery; pathology results of excised tumors; radiotherapy applications; and prognosis and survival rates. A multidisciplinary team consisting of pediatric surgeons, pediatric oncologists, pediatric radiologists and radiation oncologists made all of the decisions about the treatment plans. Some children had surgery after a first cycle of chemotherapy, and some needed further chemotherapy to achieve nephron-sparing surgery. The surgery was performed on both kidneys during the same operation. If the tumor was located in upper pole or lower pole, partial nephrectomy was performed to achieve negative surgical margins. If the tumor was close to the renal hilum and excision with partial nephrectomy was not possible,
enucleation was preferred. Enucleation was also favored when there was more than one lesion in the same kidney. Partial nephrectomy was performed by excision of the upper or lower pole that contained the tumor. Enucleation was performed by excision of the lesion, with a thin rim of surrounding renal parenchyma if possible.
Results Epidemiology Twenty children, who were diagnosed with BWT, were treated during a 30-year period. They were aged between 2 months and 7 years old, and the median age at diagnosis was 2.5 years. The gender ratio was 1.8 (13 girls and seven boys). The presenting symptoms were: abdominal distention noted by the family (n Z 7), abdominal pain (n Z 6), bloodstained urine (n Z 3), and fever (n Z 2). Two children had aniridia and were regularly followed up for the possibility of Wilms tumor. Therefore, there were two children with WAGR complex and another child with isolated hemihypertrophy that was detected synchronously with Wilms tumor (Table 1). During physical examination, growth retardation was noted in four children, hypertension in three, and undescended testicle in three. Preoperative laboratory investigations revealed that three children had proteinuria, five had hematuria, and one, whose kidneys were totally invaded by the tumor, had abnormal renal function tests and he ended up with bilateral nephroureterectomies. Those with proteinuria and undescended testis were all different children, and none of them had DenyseDrash syndrome. Conventional angiography, computed tomography angiography or magnetic resonance imaging angiography were utilized in the preoperative period in order to define the anatomy of the renal vasculature of the nephron-sparing
Table 1
Clinical characteristics of patients. Number (percentage)
Gender Female Male Age at presentation 0e1 years 1e2 years 2e3 years 4 years Presentation Abdominal distention Abdominal pain Bloodstained urine Fever Other Associated findings WAGR complex Isolated hemihypertrophy
13 (65%) 7 (35%) 2 5 7 6
(10%) (25%) (35%) (30%)
7 6 3 2 2
(35%) (30%) (15%) (10%) (10%)
2 (10%) 1 (5%)
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I.R. User et al.
kidney more precisely. Five children had Tru-cut biopsies before surgery because of unresponsiveness to chemotherapy. Pulmonary metastases were detected in four children, liver metastasis in two, and one had intracranial metastasis. Thrombosis in the inferior vena cava and renal vein were detected in three children at the time of diagnosis, but only one had tumor thrombosis at the time of surgery. The children were treated according to the Turkish Pediatric Oncology Group (TPOG) Protocol. All except one received preoperative chemotherapy of one to six cycles. Neoadjuvant chemotherapy consisted of vincristine 1.5 mg/ m2 (maximum 2.0 mg), once weekly for four weeks, and actinomycin-D 15 mcg/kg/day for 5 days of the first week. Children who were unresponsive to beginning chemotherapy received adriamycin 20 mg/m2/day for 3 days, in addition to vincristine and actinomycin-D. Six children had more than two cycles of chemotherapy; four of these had anaplastic tumors and two had necrotic tumors. Adriamycin was also added to the preoperative chemotherapy regimen of three children due to their unresponsiveness to chemotherapy or progression of tumor under treatment. The child who was operated on without preoperative chemotherapy was assumed to have unilateral Wilms tumor before the surgery and the tumor on the contralateral side was detected during the surgery. None of the children received preoperative radiotherapy. Those with local recurrence, positive surgical margins or distant metastases received 9e27 Gy radiotherapy, according to disease extent and histopathological subtype.
Surgical details and pathology results A total of 18 children were operated on. The parents of two children, who were not operated on, did not accept the offered bilateral nephroureterectomy and dialysis, and
Table 2
declared that they only approved of conservative therapy for their children. A transverse (n Z 11) or Chevron incision (n Z 7) were used. The renal salvage procedure was performed by partial nephrectomy or enucleation of the lesion. Partial nephrectomy was performed by excision of the upper or lower pole that contained the tumor. Enucleation was performed by excision of the lesion, with a thin rim of surrounding renal parenchyma if possible. Intraoperative ultrasonography was performed on two children in order to detect the location of small lesions. Frozen pathological examinations were performed in two children because the gross appearance of the excised lesion created the doubt of positive margins. To sum up, 19 nephroureterectomies, eight partial nephrectomies and 13 enucleations (enucleation of two masses located in the upper and lower poles of one kidney in one child, and enucleation of four masses located in the upper and lower poles of one kidney in another one) were performed on 36 kidneys. There were no major complications during surgery like massive bleeding, tumor rupture or adjacent organ injury. Eleven children required erythrocyte suspension transfusion during surgery, which did not exceed 10 ml/kg. The mean duration of surgery was 180 min (range 120e300 min). Pathological results revealed positive surgical margins in two lesions with enucleation, and in two with partial nephrectomies. Anaplasia was detected in four children. Nephrogenic rest was observed in nine kidneys and nephroblastomatosis in four. Routine biopsies were not performed before preoperative chemotherapy. Most of the pathologically examined specimens obtained during the operations did not have any viable tumor cells, because of complete necrosis. Therefore, it was not possible to see if the tumor was blastemal, epithelial, stromal or triphasic. Local staging was applied in 11 children and revealed: Stage 1 in seven kidneys, Stage 2 in seven kidneys, and Stage 3 in eight kidneys (Tables 2 and 3).
Characteristics of patients who survived the disease.
Sex
Age (years)
Metastasis and recurrence
Surgical intervention
F M F M F F
5 1 3 1 1 5
e e e e e e
Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy
F F
2 a
e e
Nephroureterectomy þ enucleation Nephroureterectomy þ partial nephrectomy
e e e e e
Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy Nephroureterectomy
F M F F F a b
1 5 5 b
5 6 months. 10 months.
Pathology þ þ þ þ þ þ
þ þ þ þ þ
enucleation enucleation partial nephrectomy enucleation enucleation partial nephrectomy
partial nephrectomy enucleation enucleation enucleation partial nephrectomy
Necrosis, nephroblastomatosis Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephrogenic rest Necrosis, nephroblastomatosis, Positive surgical margins Nephrogenic rest Necrosis, anaplasia Positive surgical margins Nephrogenic rest Necrosis, anaplasia Nephrogenic rest Nephrogenic rest Necrosis, anaplasia
Management of bilateral Wilms tumor over three decades Table 3
118.e4
Characteristics of patients who died from the disease.
Sex
Age (years)
Metastasis and recurrence
Surgical intervention
Pathology
M
3
Nephroureterectomy þ partial nephrectomy
Necrosis þ nephroblastomatosis
M F F
2
Bilateral nephroureterectomy e Nephroureterectomy þ enucleation
M F
4 4
Pulmonary, liver, and intracranial metastases Local recurrence Pulmonary metastases e Pulmonary and liver metastases Pulmonary metastases Local recurrence
Necrosis, nephroblastomatosis þ anaplasia e Necrosis, nephrogenic rest Positive surgical margins e Necrosis
M
1
e
a
a
7
e Nephroureterectomy þ partial nephrectomy Nephroureterectomy þ enucleation
Necrosis Positive surgical margins
6 months.
Postoperative period and long-term outcomes Renal insufficiency was observed in two children; one, who became anephric, was confined to permanent dialysis in the postoperative period, and the other had a unilateral nephrectomy and partial nephrectomy to the contralateral kidney. The latter child went on hemodialysis for a year, then her renal functions recovered and she stopped dialysis. All children received postoperative chemotherapy regimens that were individually tailored according to stage and pathology results, with durations ranging between 6 months and 2 years. Seven children received radiotherapy for pulmonary metastases, positive surgical margins or local recurrences. Overall, 13 children survived and seven died due to disease and complications of the various treatment modalities. Overall survival was 65.0% and survival among children who were operated on was 72.2%. Among the seven children with the partial nephrectomy, two died and five survived. Among the enucleation group, eight out of ten survived and two died. Survival seemed to be slightly higher among the enucleation group (80.0% vs 71.4%). Multiple metastases were the cause of death in three children. The anephric child died because of intracranial hemorrhage after hemodialysis. Renal vein thrombosis and local recurrence was the cause of mortality in one child. The children who were not operated on died of cardiomyopathy caused by chemotherapeutic agents and the disease itself. The median time of follow-up for survivors of the disease was 5.8 years (range 6 monthse14 years).
Discussion Outcomes of BWT management have changed dramatically during the last few decades due to improvements in treatment options from only survival, to a long life expectancy without the need of renal replacement therapy [1]. Surgeons are expected to preserve as much renal mass as possible while maintaining tumor-free margins and acceptable complication rates. Pediatric oncologists are
expected to plan the most-effective and least-toxic chemotherapy regimens with minimal short-term and long-term side effects. Radiotherapy is being used more efficiently despite reduced doses and the amount of irradiated fields. These current advancements are providing patients with much less morbidity from the treatment or the disease itself whilst achieving better survival rates. Given the fact that BWT is a relatively rare entity and it is not easy to design a prospective study on this topic, most of the information is gathered from retrospective analysis shared by centers dealing with this disease all over the world. Therefore, it was decided to report the experiences, which were gained at a single referral center, of the treatment of pediatric surgery and oncology for BWT over three decades. The patient population, regarding age and sex distribution, was similar to those that have been previously reported. BWT is slightly more common among girls and presents at an earlier age than unilateral tumors. The presenting signs and symptoms are the same as unilateral tumors; the most common are: abdominal distention, pain, hematuria, a palpable mass and hypertension [5e7]. Children with known Wilms tumor-predisposed genetic syndromes are screened so that the disease can be detected before the symptoms emerge [8]. In the present series, two children had aniridia and were routinely followed with USG examinations; these children did not have any complaints at the time of diagnosis. The importance of physical examination should be emphasized because isolated hemihypertrophy was detected in one child only when he presented with Wilms tumor. Imaging modalities are particularly important in case of BWT because detailed information regarding anatomy is necessary in order to plan nephron-sparing surgery. In the present study, conventional angiography, computed tomography angiography or magnetic resonance imaging angiography were used to define the anatomical relationship between the renal vasculature and the lesion. Two decades ago, one of the children had the diagnosis of BWT during surgical exploration. With the advent of highly sensitive imaging techniques, it is now not routinely recommended to explore the contralateral kidney [9].
118.e5 According to the TPOG protocol, in cases of BWT, chemotherapy is administered without the need of tissue diagnosis [10]. Only five of the children who were unresponsive to treatment had Tru-cut biopsies to confirm the diagnosis. In some instances, a response to chemotherapy cannot be determined, due to the increments in size of the mass seen with necrosis and this can lead to a false pretense that the tumor is unresponsive to treatment. Two of the children who were supposed to be unresponsive to chemotherapy had totally necrotic tumors. However, a tumor that does not shrink, despite chemotherapy, is not always unresponsive. Thus, surgery should be considered earlier instead of extending preoperative chemotherapy. Nowadays, novel imaging techniques like f-fluorodeoxyglucose positron emission tomography (FDG-PET) or quantitative MRI are promising for giving additional information about biological responses [8]. A surgical approach to BWT is a controversial topic and the goal of the surgeon is to ensure that the patient has a tumor-free but adequate nephron reserve for a life without renal replacement therapy. This spectrum ranges from: aggressive surgery to achieve negative surgical margins with the suspicion of anaplasia, to a much more conservative approach with nephron-sparing surgery on both sides. Either options carry risks for mortality and morbidity (i.e. end-stage renal disease with the former, and recurrence with the latter case [11e13]. In the present study, nephronsparing surgery was performed on 17 kidneys by partial nephrectomy or enucleation, with four positive surgical margins and 19 nephroureterectomies. Only two children had a need for dialysis; one of them was anephric, and the other went onto dialysis for a year, then her renal function recovered. Although, for the time being, the children who have survived the disease don’t need renal replacement treatment, it is wondered if their renal reserve will be enough for them in the adulthood. According to The National Wilms Tumor Study Group, a surgically positive margin is an independent risk factor for local recurrence [3]. On the other hand, Davidoff et al. reported that patients with microscopic positive resection margins were not at higher risk for locoregional recurrence, compared to patients with negative margins, when they had adjuvant flank radiotherapy [4]. All of the children in the present study with positive surgical margins (n Z 4) underwent radiotherapy and none of them had local tumor recurrence, but one had distant pulmonary and liver metastases. It can be argued that positive surgical margins do not necessarily lead to local recurrence; for this reason, it may be wiser to favor nephron-sparing surgery than to achieve negative surgical margins. Adjuvant chemotherapy and radiotherapy may be adequate to prevent local recurrence. Also, in the present study, survival did not differ significantly between the different ways of performing nephron-sparing surgery, so, it may be wiser to choose enucleation over partial nephrectomy, which preserves more nephrons. Thus, nephron-sparing surgery should be of the utmost importance, despite the risk of positive margins. On the other hand, there is not enough data to interpret if positive surgical margins have an effect on distant metastases or not. The presence of metastasis and recurrence seems to be an important determinant of prognosis, given the fact that
I.R. User et al. none of the survivors had any metastases or recurrence. Another factor may be the greater amount of nephron preservation with enucleation and, hence, the lower possibility of future kidney failure, which leads to long-term morbidity. At the present time, none of the children need renal replacement therapy, but longer follow-up is necessary to make further conclusions. The causes of mortality are diverse in BWT because the treatment includes surgery, chemotherapy and renal replacement therapy in a child whose immune system has already been compromised by chemotherapeutics. These children require the highest standard of care during the treatment process given by both the parents and medical staff. In the present study, one child died due to complications related to dialysis; two others, whose parents refused the offered surgical treatment and claimed that it could not provide the appropriate care for a possibly anephric child, died. In the light of these experiences, it can be assumed that the socioeconomic status of caregivers is a significant determinant of survival. The major limitations of this retrospective study were the relatively short period of follow-up and small number of patients. However, this series presents a single-center surgical experience for patients, all of who were operated on by a standard classical technique. None of the children experienced any surgical complication during the surgery and the early or late postoperative period. The management of patients with BWT is tailored individually in a multidisciplinary manner with a team consisting of pediatric surgeons, pediatric oncologists, pediatric radiologists, radiation oncologists and pediatric nephrologists. Multimodal treatment with appropriate chemotherapy and radiotherapy, and classical surgical techniques achieve low complication rates with preservation of renal functions. In most cases of BWT, they decrease both mortality and morbidity. Longer and more-aggressive preoperative chemotherapy regimens may be necessary in order to perform safer surgery. Nephron preservation should be the primary aim, while taking positive surgical margin risk on the nephron-sparing surgery side. Postoperative chemotherapy and carefully planned radiotherapy should be conducted in order to avoid recurrence. However, there is significant diversity in different centers for the management of BWT, and validated guidelines or protocols are still lacking with which to provide the optimal treatment.
Conflict of interest statement None declared.
Funding None declared.
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