Wilms tumour (WT) is the most frequent kidney tumour in children, very rare in adolescents, and more common in girls than in boys [1]. Interestingly, there are epidemiological differences in incidence between populations. There is also increasing interest in looking to WT as a defect of normal nephrogenesis [2]. With modern therapy, ~ 90% of children diagnosed with WT are expected to be long-term survivors [1, 3]. These factors collectively render WT a complex yet fascinating disease and call for a re-evaluation of what is evident or less evident in the way we approach its diagnosis and treatment. Still, our understanding of WT has a long way to go to be comprehensive and satisfactory.
In their recent manuscript, Taghavi et al. aimed to provide a guide towards a broader use of nephron-sparing surgery (NSS) [4]. The authors have supported this discussion by bringing in issues from fields other than oncology, such as physiology. Acknowledging that radical nephrectomy, either upfront or after neoadjuvant chemotherapy (depending on the protocol adopted), represents the gold surgical standard in most children with WT [1], we read the paper with interest. In short, their take-home messages are that we need to consider more frequently sparing healthy (being sure that it is healthy) kidney tissue also in the presence of unilateral tumours, because of the long-term risk of remaining kidney impairment that radical nephrectomy can cause, and that nephrologists should be involved in a timely manner in this decisional loop. Potential long-term complications of radical nephrectomy may include hyperfiltration syndrome, hypertension, and proteinuria [4]. On the other hand, radical nephrectomy has potential oncological advantages, particularly if there is high tumour complexity (and NSS would be challenging even in experienced hands). In principle, radical nephrectomy may reduce the risk of incomplete tumour resection and positive surgical margins that could occur with NSS since it allows for complete tumour removal without opening Gerota’s fascia.
Taghavi et al. have stimulated us to consider how the discussion on the best surgical approach should affect WT global management in practice. There might be three levels for this debate and three related groups of children.
Level A: Children with bilateral WT or genetically predisposed unilateral WT
In patients with synchronous bilateral WT or a recognised predisposing genetic condition to WT, there is a consensus towards starting with preoperative chemotherapy with the goal of shrinking tumour volume and maximising kidney preservation trough NSS, as shared by the Children’s Oncology Group Renal Tumor Committee and Renal Tumour Study Group of the International Society of Pediatric Oncology [1, 3, 5, 6].
We can estimate that in about 10 to 30% of WT cases, germline predisposing mutations may contribute to tumour development [1, 7,8,9]. Identified driver genes include WT1, TRIM28, REST, and the 11p15 locus, and they are associated with conditions varying from easily recognisable syndromes to only an increased risk of WT [10]. However, the prevalence of (epi)genetic alterations known to predispose to WT likely represents only the tip of the iceberg [11,12,13], and this consideration takes us to level B of the debate.
Level B: Children with WT and mild clinical characteristics of potential cancer predisposition or predisposition to long-term risk of kidney failure
Which is the most appropriate surgical treatment in patients with WT and only mild clinical characteristics (lateralized or segmental overgrowth, genitourinary anomalies, cardiovascular anomalies, multifocal unilateral disease) or family histories that are suggestive of genetic predisposition to cancer or predisposition to the long-term risk of kidney failure (not yet proven)? The adoption of NSS in non-syndromic unilateral WT, or when a genetic predisposition to WT or to nephropathy may only be suspected, falls in a grey zone.
While we know about the risk of kidney disease in children with WT and constitutional WT1 pathogenic variants [14], we do not know how many children who have unilateral WT but otherwise without any suspicious signs of a genetic condition present WT1 pathogenic variants [13, 15]. The phenotypic spectrum associated with the constitutional WT1 pathogenic variant is broad, depending on the type of mutation.
Missense mutations in some WT1 exons can predispose to WT without other clinical manifestations [16]. Relying on phenotype only to identify patients with WT who have the constitutional WT1 pathogenic variant may be difficult. To the best of our knowledge, the prevalence of constitutional WT1 mutations in unselected, nonsyndromic patients with WT has been estimated to be in the range of 2.9 to 7% of cases [15, 17]. Among these patients with incomplete/mild or without phenotypic features of WT1-related syndromes and with WT1 missense or stop pathogenic variants, the impact of the type of mutation on the expected degree of kidney function impairment is unclear. Achieving earlier recognition of the presence of a constitutional WT1 pathogenic variant or of potential genetic predisposition in a child with WT may support in preferring NSS to radical nephrectomy, in relation to the anticipated decline in kidney function and/or the risk of metachronous tumour. Factors that may suggest that a child with normal phenotype carries a constitutional WT1 mutation are age below 1 year, stromal-predominant tumour histology, and the presence of intralobar nephrogenic rests [1], the latter factors being discovered after nephrectomy.
Expanded genetic sequencing (including genetic testing for kidney disorders and WT panel testing along with Beckwith-Wiedemann syndrome methylation studies) in all cases of WT might clarify the frequency of genetic predisposition in children with WT. Obviously, universal referral for genetic counselling and testing will require significant financial resources. Hence, as oncologists and nephrologists, we need to cooperate more consistently in the practical management of this increasingly recognised population of children with WT, also acknowledging that the results of genetic testing are usually available after nephrectomy has been performed.
The current surgical approach in cases with mild signs of WT predisposition (and hence unknown risk of contralateral metachronous tumour or nephropathy) is less clearly defined. For instance, we refer here to very young children (< 2 years of age at WT onset), and/or with multicentric unilateral disease, and/or some mild overgrowth features. We know that neoadjuvant chemotherapy facilitates kidney preservation; thus, the key issue is whether we should treat all patients with only these few warning signs with preoperative chemotherapy, with the aim of reducing tumour burden to favour delayed NSS. Ehrlich et al. successfully obtained kidney preservation in 65% of predisposed patients with unilateral WT by systematically using neoadjuvant chemotherapy [18].
Level C: Children with unilateral WT and with no “red flags” either for cancer predisposition or for kidney disease predisposition
Despite the positive results of NSS in bilateral WT, NSS is currently rarely used in patients with unilateral tumour not falling under level A or B. Radical nephrectomy with lymph node sampling represents the typical surgical approach for children with nonsyndromic unilateral WT. Based on the available data, the rate of NSS in unilateral cases without WT predisposition or nephropathy predisposition is low (in the range of 5–7%) [19]. Taghavi et al. remind us that efforts to expand the role of NSS in anatomically favourable cases of unilateral WT after neoadjuvant chemotherapy could be justified within the framework of carefully designed clinical trials, because of the risk of long-term kidney impairment.
In previous reports, the 20-year rate of late kidney failure in unilateral WT survivors was estimated to be 0.6% based on the data from the National Wilms Tumor Study [20]. In a more recent study, the 20-year rate was 1.7% [21]. The authors were able to record late-onset kidney failure in more than 2000 WT survivors with extended follow-up. They were able to analyse survivors of unilateral, nonsyndromic WT and sibling controls: the 35-year cumulative incidence of kidney failure of 2.4% was almost 10 times higher than in siblings. The fact that exposure to chemotherapy or radiotherapy was not associated with this outcome suggested that the most important risk factor was nephron loss (i.e., nephrectomy). Notably, the authors estimated that the risk of late kidney failure was also increased in survivors treated with minimal vincristine-actinomycin-D (VA) chemotherapy, which are drugs without known nephrotoxicity. Compared with their siblings, survivors treated with VA had a higher risk of kidney failure (RR, 11.9; 95% CI, 4.2 to 33.6) [21].
In patients with WT, we also have a concrete opportunity to cure a patient after tumour relapse. In this same study, survivors who experienced WT recurrence had an increased cumulative incidence of kidney failure (9.1%, 95% CI, 3.6–17.5) compared with those who did not (2.2%, 95% CI, 1.5–3.1), probably due to the cumulative use of more nephrotoxic drugs and abdominal irradiation [21]. This is an additional reason to consider sparing healthy kidney tissue.
The notion that the risk of kidney failure increases with longer follow-up is crucial. After the fourth decade of life, glomerular filtration rate physiologically decreases due to ageing of the kidneys, regardless of the type of treatment received. The steady increase in incidence of kidney failure with longer follow-up observation suggests that this late morbidity may be an evolving risk for WT survivors. As we do not have a predictive test (clinical or genetic) to anticipate which patients will develop kidney function impairment, hypertension, and albuminuria, survivors should be counselled about their risk for kidney failure with age and the importance of kidney health screening and management of comorbidities (e.g., hypertension and diabetes).
Concluding remarks
We have emphasised the need to implement the choice of NSS and to guide risk-based nephrology screening and follow-up. An experienced team should be able to weigh the expected benefits of NSS against the increased risk of intraoperative spillage or positive resection margins in NSS that upstage to stage III and require radiation therapy [22,23,24].
In addition to the risk of metachronous tumour, there are other reasons to consider improving our approach to preserving healthy kidney tissue. We have already mentioned the risk of kidney function impairment when children become adults. Metabolic syndrome and cardiovascular disease in WT survivors are also a concern [21, 25]. We know that kidney function has an impact on long-term cardiovascular health and events. Severe impairment of kidney function doubles all-cause mortality and significantly increases the risk of cardiovascular disease mortality [26].
Expanding the indications for NSS also means exploring new technologies, such as 3D reconstructions, image-guided surgery, fluorescence-guided surgery, and augmented reality. Most importantly, we need to promote NSS only in centres with expertise in this field. In the adult setting, low-volume centres are defined as those performing < 20–25 kidney cancer surgical procedures per year, and they are reported to have less favourable outcomes [27, 28]. Most paediatric oncology centres are familiar with less than 5–10 cases of kidney tumours per year. We should also strive to achieve a higher rate of NSS in bilateral tumours, as the current rate of bilateral NSS is lower than the expected rate of 50% of cases [29]. In series from a centre highly specialised in bilateral NSS, a rate of NSS of more than 90% of cases has been achieved [30].
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Spreafico, F., Biasoni, D. & Montini, G. Most appropriate surgical approach in children with Wilms tumour, risk of kidney disease, and related considerations. Pediatr Nephrol 39, 1019–1022 (2024). https://doi.org/10.1007/s00467-023-06213-4
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DOI: https://doi.org/10.1007/s00467-023-06213-4