Abstract
Background:
Wilms tumor (WT) is the most common pediatric renal malignancy and bilateral disease (BWT) occurs in 5% of cases and is associated with poor outcomes. Management of BWT includes chemotherapy and oncologic resection while preserving renal function. Previous literature has demonstrated variable approaches in BWT treatment. The aim of this study was to examine a single institution experience and outcomes with BWT.
Methods:
A retrospective chart review was performed for all patients with WT treated at a free-standing tertiary children’s hospital between 1998 and 2018. Patients with BWT were identified and treatment courses were compared. Outcomes of interest included need for dialysis post-operatively, need for renal transplantation post-operatively, disease recurrence, and overall survival.
Results:
Of 120 children with WT, 9 children (6F:3M) of median age 32 months (IQR: 24–50 months) and median weight 13.7 kg (IQR: 10.9–16.2 kg) were diagnosed with and treated for BWT. Pre-operative biopsies were obtained in 4/9 patients, 3 of whom received neoadjuvant chemotherapy and 1 who underwent radical nephrectomy. Of the 5 patients who did not undergo biopsy, 4/5 were treated with neoadjuvant chemotherapy, and 1/5 underwent upfront nephrectomy. Post-operatively, 4/9 children required dialysis, of whom 2 subsequently underwent renal transplantation. Two patients were lost to follow-up, and of the remaining 7 patients, disease recurrence occurred in 5/7 children and overall survival was 71% (n=5).
Conclusion:
Management of BWT varies regarding the use of pre-operative biopsy, neoadjuvant chemotherapy, and extent of disease resection. Further guidelines on treatment protocols may optimize outcomes in children with BWT.
Keywords: pediatric surgery, surgical oncology
Introduction
Wilms tumor (WT) is the most common renal malignancy in children and the second most common intra-abdominal pediatric malignancy.1–3 Unilateral WT treatment has been well-studied and advances in treatment have led to excellent outcomes with greater than 85% 4-year event-free survival.4,5 Bilateral WT (BWT) is an uncommon entity that occurs in 5–10% of WT cases and is associated with poor prognosis and survival compared to unilateral WT.3,6 BWT poses considerable challenges, as the goals of treatment are to achieve adequate oncologic resection for definitive treatment while also preserving renal function and minimizing long-term morbidity through nephron-sparing surgery.2,3,7–9 The management of BWT remains to be standardized, and previous literature has demonstrated variability in BWT treatment due to lack of a universalized protocol.3,6,10 The aim of this study was to examine our institutional experience and outcomes with BWT.
Methods
A retrospective chart review of all children who underwent treatment for BWT at Children’s Hospital Los Angeles between 1998 and 2018 was performed. Patients were identified through pathology records for WT and BWT. Patients who did not have electronic medical records available for review were excluded from the study. Aspects of patient charts that were reviewed included history and physical notes, consult notes, operative reports, inpatient progress notes, outpatient progress notes, discharge summaries, and pathology reports. Operations were performed by pediatric surgeons or pediatric urologists. Individual patient treatment courses and outcomes were compared. Outcomes included need for dialysis, need for renal transplantation, disease recurrence, and death. Descriptive statistics were performed using Microsoft® Excel version 16.69 (Microsoft Corporation, Redmond, WA, USA). The study was approved by the Institutional Review Board.
Results
Overall, 120 patients were identified with WT, of whom 9 (7.5%) patients were diagnosed with BWT and treated between 2006–2017. The median age at diagnosis was 31.0 months (IQR: 14.5–39.5 months), and the median age at time of index surgery was 32.0 months (IQR: 24.0–50.0 months) (Table 1). The majority of the patients were female (n = 6, 66.7%), White (n = 5, 55.6%), and of Hispanic ethnicity (n = 4, 44.4%). One patient had a known predisposition to WT with a diagnosis of Beckwith-Wiedemann syndrome.
Table 1.
Demographics and Clinical Characteristics of Patients With Bilateral Wilms Tumor; IQR (Interquartile Range).
| Patient Characteristic | |
|---|---|
| Age at diagnosis, months, median (IQR) | 31 (14.5–39.5) |
| Sex, n (%) | |
| Female | 6 (67) |
| Male | 3 (33) |
| Race, n (%) | |
| Asian | 0 (.0) |
| Black | 1 (11) |
| Other | 3 (33) |
| White | 5 (56) |
| Ethnicity, n (%) | |
| Hispanic | 4 (44) |
| Non-Hispanic | 3 (33) |
| Unknown | 2 (22) |
| Genetic predisposition, n (%) | 1 (11) |
| Metastasis at diagnosis | 4 (44) |
| Lungs | 4 (100) |
| Inferior vena cava or aorta | 2 (50) |
| Liver | 1 (25) |
| Age at index surgery, months, median (IQR) | 32 (24.0–50.0) |
| Pre-operative weight, kg, median (IQR) | 13.7 (10.9–16.2) |
The treatment course for each patient is listed in Table 2. Initial management of the BWT patients included pre-operative biopsy in 4/9 patients (Table 2). Of the 5 patients who did not undergo pre-operative biopsy, 4 patients received neoadjuvant chemotherapy and 1 patient proceeded to upfront radical nephrectomy. Overall, unilateral radical nephrectomy without neoadjuvant chemotherapy was performed in 2 of the 9 patients (patients #1, 5), 1 of whom eventually underwent a contralateral radical nephrectomy for disease recurrence (patient #1).
Table 2.
Treatment Courses Per Bilateral Wilms Tumor Patient, Including Index and Subsequent Operations, Arranged From Earliest (12/2006) to Most Recent (10/2017) Index Surgery (Patient 1–9).
| Patient | Biopsy | Neoadjuvant Chemotherapy | Surgeries | Transplant | Recurrence | Death |
|---|---|---|---|---|---|---|
| 1 | No | No | Radical nephrectomy and contralateral biopsy, contralateral radical nephrectomy | No | Yes | Yes |
| 2 | Yes | Yes | Bilateral partial nephrectomy, unilateral completion nephrectomy | No | No | No |
| 3 | No | Yes | Unilateral partial nephrectomy, contralateral radical nephrectomy | No | No | No |
| 4 | No | Yes | Unilateral radical nephrectomy, contralateral radical nephrectomy | No | Yes | Yes |
| 5 | Yes | No | Unilateral radical nephrectomy | No | No | No |
| 6 | No | Yes | Radical nephrectomy, partial contralateral nephrectomy, completion contralateral nephrectomy | Yes | Yes | No |
| 7 | No | Yes | Unilateral radical nephrectomy and contralateral biopsy, contralateral radical nephrectomy | Yes | No | No |
| 8 | No | No | Unilateral radical nephrectomy and contralateral biopsy | No | No | No |
| 9 | No | No | Partial nephrectomy, contralateral radical nephrectomy | No | Yes | No |
Seven patients total received neoadjuvant and adjuvant chemotherapy, consisting of the standard 3 drug regimen, vincristine, doxorubicin, and dactinomycin. Two of the 9 patients transitioned their care to different hospitals and were lost to follow-up.
Pathology revealed favorable histology in 4/9 patients, diffuse anaplasia in 1/9 patients, and was not specified in 4/9 patients. Nephroblastomatosis is a potential predictor of local disease recurrence and has been recommended for monitoring if present in nephrectomy specimens.1 Nephroblastomatosis was identified in the histology of 5/9 patients, 3 of whom developed recurrent disease.
Over a median follow-up of 65 months (IQR: 13–112 months), 4/9 patients required dialysis post-operatively and 2/9 ultimately underwent renal transplantation (Table 3A). Out of the 7 patients whose care was continued at our institution, 5/7 patients had recurrent disease, and 2/7 patients died, both of whom had recurrent disease and undergone bilateral nephrectomies (Table 3B). The causes of death of the children who died were seizure complicated by respiratory arrest and septic shock with multi-organ failure secondary to central line infection, respectively.
Table 3.
Outcomes of Children With Bilateral Wilms Tumor Including A. Renal Function (n = 9) and B. Disease Recurrence and Overall Survival (Total n = 7).
| A. Outcome | n (%) |
|---|---|
| Dialysis | 4 (44) |
| Renal transplant | 2 (22) |
| B. Outcome | na (%) |
| Disease recurrence | 5 (71) |
| Death | 2 (29) |
Two patients were not included due to transfer of care to a different hospital.
Discussion
The evolution of the medical and surgical management of unilateral WT has yielded good outcomes and survival rates.4,5,9 However, BWT continues to be a difficult clinical scenario in balancing the preservation of functioning renal tissue with optimizing oncologic outcomes.2,3,8,9 Four-year event-free survival and overall survival rates in BWT patients have been estimated to be as low as 56% and 80.8%, respectively, highlighting the ongoing importance of developing standardized protocols to improve survival of BWT patients.11 In the current study, our patients demonstrate a lower overall survival rate of 71%, although this may be related to a small sample size of patients.
Currently, there is no standardized approach to BWT treatment.3,10 Early treatment strategies for BWT included biopsy or upfront radical nephrectomy followed by chemotherapy and subsequent contralateral tumor resection.12 Later recommendations were to administer neoadjuvant chemotherapy until the time that nephron-sparing surgery would be deemed feasible; however, there was a lack of consensus on the minimum and maximum duration of chemotherapy.13 Biopsy has also been recommended in order to identify tumor types that may be better managed with expedited surgical resection or prolonged chemotherapy.14 More recently, following the first prospective clinical trial on BWT (AREN 0534), the Children’s Oncology Group recommends neoadjuvant chemotherapy with vincristine, doxorubicin, and dactinomycin for 6–12 weeks, surgical resection, and adjuvant treatment tailored to the histology of the surgical specimen.5,11 With this protocol, children with BWT have had improved event-free survival and overall survival while preserving renal parenchyma.5
Our study represents a single institution experience with BWT and demonstrates variability in treatment of BWT, similar to previously reported cases.3 Over a time period ranging from 2006 through 2017, management of BWT at our institution has evolved to include biopsy, neoadjuvant chemotherapy, and nephron-sparing surgery on one or both kidneys, where possible.
Nephron-sparing surgery has been proven to be safe and effective in WT patients, without increased risk of tumor recurrence.2,9 Kieran and colleagues9 demonstrated that margin status following nephron-sparing surgery did not affect rates of local disease recurrence, thus supporting the preservation of as much renal tissue as possible in the surgical treatment of BWT.9 Similarly, a case series of children with BWT by Davidoff demonstrated an overall survival rate of 83% and low rate of disease recurrence over a median follow-up of 3.9 years following bilateral partial nephrectomy, supporting the safety and efficacy of nephron-sparing surgery.2 Lastly, of the 2 patients within our cohort who died, both had undergone bilateral nephrectomy and their causes of death were not directly related to the cancer diagnosis.
This study is limited by its retrospective nature and small sample size from a single center experience for a relatively rare disease entity. The variation in treatment may be partially attributed to differences in care teams, and more likely, evolving treatment guidelines over a large period of time. Despite its limitations, this study provides valuable insight into the approaches towards and challenges in treating children with BWT.
Conclusion
Treatment of bilateral Wilms tumor remains challenging and varied. The results of ongoing and future studies are needed to standardize protocols to optimize oncologic outcomes and preserve renal function for bilateral Wilms tumor.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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