Expanding Role of Nephron-Sparing Surgery in Non-syndromic Unilateral Unifocal Wilm’s Tumor—Our Experience and Review of Literature

Abstract

Wilms’ tumor is the most common renal malignancy in the pediatric age group. The unilateral type is the most prevalent, with a tenth of cases being a part of genetic malformation syndromes. The majority of Wilms’ tumors are detected by chance detection of abdominal mass on ultrasound. Treatment protocols established by the Renal Tumor Committee of the Children’s Oncology Group (COG) in North America and the International Society of Pediatric Oncology (SIOP) in Europe emphasize approaches such as surgical resection, neoadjuvant chemotherapy, and, in rare cases, irradiation. Radical nephrectomy with lymph node sampling forms the mainstay in the management of unilateral Wilms’ tumor (uWT). Nephron-sparing surgery (NSS) is becoming increasingly popular for unilateral pediatric cases due to its ability to preserve functional renal tissue. This article reviews various recent studies that explored the role of NSS in uWT. Additionally, two case studies involving NSS for uWT and their outcomes are presented. This study found that factors such as the timing and duration of neoadjuvant chemotherapy, tumor mass size, presence of tumor margins, and intraoperative ischemia time significantly influenced the outcome of NSS.

Introduction

Wilms’ tumor stands as the predominant cause of renal malignancy in the pediatric demographic, with the majority of cases being unilateral (1). The evolution of surgical interventions and the collaborative efforts in various multicenter trials have significantly enhanced survival rates, elevating them from a mere 40% in the early 1940s to over 90% in contemporary times (2, 3). The primary approach for unilateral Wilms’ tumor (uWT) involves radical nephrectomy (RN) via a conventional open transperitoneal method coupled with lymph node sampling (4). Multimodal therapy encompasses systemic chemotherapy in conjunction with surgical management (5). Despite the improved survival rates in children with Wilms’ tumor, the persistent concern revolves around the future risks of renal dysfunction and associated cardiovascular complications (6). In response, nephron-sparing approaches have been developed and honed to safeguard the long-term kidney function of these patients (7).

Nephron-sparing surgery (NSS) is also applied after neoadjuvant chemotherapy in individuals with a known genetic predisposition to Wilms’ tumor, given their heightened susceptibility to metachronous contralateral tumor development. Additionally, an ongoing debate surrounds the utilization of NSS after neoadjuvant chemotherapy in cases of anatomically favorable unilateral Wilms’ tumor (uWT) (4). Traditionally, NSS was reserved for situations where preserving renal function was imperative, such as in bilateral Wilms’ cases or children with a solitary kidney (8). This article provides a comprehensive overview of current treatment strategies with an individualized risk-based therapy approach utilizing nephron-saving surgery for non-syndromic unilateral Wilms’ tumor patients. This concept is supported by two case studies that follow a similar approach.

Materials and Methods

Case 1

An 8-month-old female child presented with incidentally detected left renal mass on routine abdominal ultrasound. Physical examination revealed mild fullness in the left renal angle. The abdomen was soft and painless without any masses. All other findings were normal, including urine and blood tests. Contrast-enhanced abdominal CT, EC renogram, and renal vessel Doppler were performed for diagnostic workup. Abdominal CECT showed a heterogeneous, enhancing mass ~49 × 40 mm occupying the mid and lower poles of the left kidney (Figure 1). There was no evidence of abdominal lymphadenopathy or presence of renal vein or IVC thrombus. After the tumor board meeting, the decision was taken to perform an upfront nephrectomy followed by adjuvant chemotherapy.

Figure 1:

(A) & (B) CECT Abdomen showing heterogeneous enhancing mass ~4.9 × 4.0 cm involving left kidney mid and lower pole (Yellow arrow). (C) FDG PET-CT done 1 year after left partial nephrectomy showing no residual or recurrent lesion at tumor bed or elsewhere (Blue arrow).

After assessing preoperative fitness, an open left lower pole partial nephrectomy along with hilar and para-aortic lymph node sampling was performed. Warm ischemia time was around 16 min. The postoperative course was uneventful. The histopathology report revealed a favorable histology with WT1-positive on immunohistochemistry (Figure 2). All margins and lymph nodes were free of tumor cells. Six cycles of adjuvant chemotherapy with Vincristine and Dactinomycin were administered. The child tolerated the chemotherapy well and is being serially followed up with FDG PET-CT and physical examination. At 1 year of follow-up, the child shows a normal growth pattern without any recurrences (Figure 1C).

Figure 2:

(A–C) Histopathological examination along with IHC showed favorable histology Wilms’ tumor (Blue arrow).

Case 2

A 10-year-old male child presented with a history of right-sided flank pain for 2–3 weeks. Abdominal CECT scan showed an exophytic heterogeneously enhancing predominantly cystic lesion, ~8.2 × 7.1 × 7.7 cm, arising from the lower pole of the right kidney, closely abutting the right psoas muscle and showing focal abutment of the IVC with loss of fat planes. A few enhancing lymph nodes were appreciated along the root of the mesentery (Figures 3A and 3B). USG-guided renal mass biopsy showed Wilms’ tumor with WT1- and PAX8-positive cells on IHC. The child received vincristine and Actinomycin D chemotherapy for 6 weeks (SIOP protocol). Post-chemotherapy repeat CT abdomen showed favorable response with a partial reduction in mass size.

Figure 3:

(A) & (B) Initial presentation showed a solid-cystic mass involving right kidney ~8.2 × 7.1 × 7.7 cm with loss of fat planes with right psoas muscle and IVC (Yellow arrow); (C) Follow-up FDG PET-CT at 1 year after surgery (done after NACT) showed absence of any recurrent disease in tumor bed or elsewhere in the body (Blue arrow).

The child underwent open right lower pole partial nephrectomy. Warm ischemia was 23 min, and the postoperative course was uneventful. Histopathology examination showed favorable histology of Wilms’ tumor, 33% viable tumor with blastema component (Figure 4). Retroperitoneal lymph nodes sampled were negative for metastases. However, in view of positive surgical margins, the child received adjuvant chemotherapy with Cyclophosphamide, vincristine, and carboplatin along with 25 Gy EBRT to the right renal bed in 14 fractions. Posttreatment FDG PET-CT showed no residual disease or metastases, and at 1 year of follow-up, the child is free of any disease (Figure 3C).

Figure 4:

(A)–(C) Histopathology and IHC confirmed favourable pathology Wilms’ tumor with high-risk features which include blastemal histology involving more than 66% viable tumor (Blue arrow).

Informed consent was obtained from the parents of both children before publication of this article. All data saved in our departmental database are available upon request.

Results

Both children completed a 1-year follow-up and showed a normal growth pattern without any local or distant recurrences.

Discussion

Almost 5% of all pediatric tumors comprise renal solid tumors, among which Wilms’ tumors constitute over 90% of these cases (9, 10). The annual incidence rate is estimated to range from 7 to 10 cases per million in children under 15.7. According to the World Health Organization (WHO), the incidence in India is around 4.4 age-standardized rates per million, suggesting an expected annual incidence of 1600 cases of Wilms’ tumor in the country. As per the latest SEER database, 5.7 cases per million children aged 0–19 years is the age-adjusted incidence rate of Wilms’ tumor, with the most affected population being females (6.3 per million), children between 0–4 years, and the non-Hispanic black population (6.3, 17.2, and 7.1 per million, respectively) (11). Wilms’ tumor, also known as nephroblastoma, typically manifests sporadically. However, 10–15% of the cases may be associated with genetic malformation syndromes such as Beckwith–Wiedemann, Denys–Drash, or WAGR (Wilms’ Tumor, Aniridia, Genitourinary anomalies, Range of intellectual disabilities) (12). The majority of Wilms’ tumors are unilateral, and only 4–8% of cases involve bilateral presentation (13). Typically, Wilms’ tumor presents as an asymptomatic, painless abdominal mass, similar to the presentation of Case 1 in this article. However, in 20% of cases, children may exhibit symptoms such as malaise, pain, fever, hematuria, or renal hypertension (5, 14). Case 2 presented with right-sided flank pain.

The diagnosis of Wilms’ tumor typically occurs through the incidental discovery of an abdominal mass during palpation or routine sonography scans. Therefore, abdominal ultrasound is the primary choice for confirming the presence of a renal mass. CT scans and MRIs serve as the standard imaging modalities to assess the arteriovenous structure of the kidneys and the relationship between the tumor and the collecting system. Urine analysis for catecholamines and metaiodobenzylguanidine scintigraphy can help distinguish neuroblastoma from Wilms’ tumor. Additionally, diffusion-weighted imaging MRI may provide an estimate of the cellularity of Wilms’ tumors and aid in distinguishing tumors with blastemal differentiation from those with stromal or skeletal muscle differentiation (5, 15).

Joint research efforts conducted by the National Wilms’ Tumor Study Group (NWTS) and the Renal Tumor Committee of the Children’s Oncology Group (COG) in North America, as well as collaborative studies by the International Society of Pediatric Oncology (SIOP) in Europe, established the foundation for treatment plans guided by protocols (5, 16). A multidisciplinary treatment strategy including neoadjuvant chemotherapy and surgery followed by adjuvant radiation therapy is widely practised worldwide and well established based on the existing literature (5). Presently, a comprehensive approach combining surgical resection, adjuvant, and/or neoadjuvant chemotherapy, and, in certain instances, irradiation, has resulted in an overall survival (OS) rate exceeding 90, 75, and 50% for localized, metastasized, and recurrence cases of Wilms’ tumor (17).

Over the past decades, RN has been the primary approach for treating uWT, due to its effectiveness in preventing positive margins, minimizing tumor spillage, limiting residual tumors, and reducing the risk of recurrence (18, 19). Despite these advantages, concerns have arisen regarding its efficiency due to its potential to diminish renal function by substantially removing unaffected renal tissue (2, 8). Additionally, the nephrotoxic effects of cancer therapies, genetic predisposition (such as WT1 mutation), and hyperfiltration injury have been identified as factors contributing to the decline in renal function (20). For instance, Cost et al. reported a decrease in renal function in children who underwent RN during a mean follow-up of 2.1 years (21). Similarly, Kern et al. and Cozzi et al. documented a reduced glomerular filtration rate following RN, noting an inverse relationship between extended follow-up periods and postsurgical renal function (22, 23). A meta-analysis by Chen et al. observed a negative impact on renal function (eGFR, −0.16; mean follow-up, 10.6 years) in cases undergoing RN (2).

Previously, NSS was primarily reserved for cases of bilateral Wilms’ tumor where the preservation of functional renal parenchyma was deemed essential. In instances of uWT, the COG guidelines allowed for NSS in specific scenarios, including patients with a solitary, horseshoe, or a nonfunctional contralateral kidney, those at risk of renal failure, and individuals with genetic syndromes prone to oncological recurrences (such as WAGR and Denys–Drash) (24). For non-syndromic uWT cases, NSS was not considered a standard procedure. However, the Surgical Panel of the International Society of Pediatric Oncology Renal Tumor Study Group (SIOP-RTSG) established a set of conditions under which NSS for uWT could be considered. These conditions included factors such as the tumor being confined to one pole, tumor volume less than 300 mL, no tumor rupture, absence of tumors in the renal pelvis, no continuous organ invasion, no venous tumor thrombus, and the presence of a functioning kidney remnant after NSS (25).

Nephron-sparing surgery can be performed through partial nephrectomy (involving tumor resection with a rim of normal renal tissue) or enucleation of the tumor (involving tumor resection without a rim of normal renal tissue) (16). Currently, there is a lack of available data comparing these two methods. The choice of method depends significantly on factors such as tumor localization, size, and the presence of multifocal lesions. The primary objective of NSS is to preserve as much healthy kidney tissue as possible (26). Table 1 outlines the characteristics and outcomes of patients suffering from uWT in recent studies.

Table 1:

Patient characteristics and outcomes of the patients with Wilms’ tumor who underwent nephron-sparing surgery (NSS).

Year of publication	Author name	Mean age (months)	No of patients	Type of uWT	Type of surgery	Preop CHT	Outcome	Follow-up
2012	Szymik Kantorowicz et al. (30)	33.5	43	NS	Mix, 18.6% NSS	Y	100%	73 months
2014	Nerli et al. (48)	19.7	09	NS	NSS	Y	100%	12 years
2014	Wang et al. (39)	39	1834	Mix	Mix, 4.03% NSS	-	90%	64 months
2014	Cost et al. (21)	30	15	NS	NSS	Y (40%)	93.3%	8.4 years
2014	Wilde et al. (41)	-	2800	NS	Mix, 3% NSS	Y	100%	43 months
2018	Ceccanti et al. (47)	27.8	12	NS, stage 1	NSS 66%	Y (75%)	100%	18.5 years
2023	Tracy et al. (36)	17.9	16	B/L WT	65.6% NSS	Y		26.3 months
Current study	Pethe et al.	64	2	NS	NSS	Y (50%)	100%	1 year

^*NS: Non-Syndromic, Y: Yes, UHRWT: Unilateral High Risk Wilms’ Tumor.

Nephron-sparing surgical techniques are particularly attractive for application in pediatric cases. Both radiotherapy and chemotherapy present nephrotoxic effects, and there is potential for hypertension, proteinuria, and chronic kidney disease in survivors of childhood cancer (27). In light of this, neoadjuvant chemotherapy can facilitate NSS and the preservation of renal tissue by reducing tumor size and promoting the formation of a pseudocapsule. This, in turn, decreases the risk of renal rupture during surgery (5, 28). Notably, the importance of implementing NSS in uWT was provided by two groups: Cost et al. from the University of Texas in Dallas, USA, and Cozzi et al. from La Sapienza University in Rome, Italy (21, 23). A recent article from Germany emphasized the crucial role of NSS in the individualized and optimized risk-adapted therapy for children with uWT, aiming to mitigate the long-term consequences of reduced renal parenchyma (29). In 2012, Szymik-Kantorowicz et al. concluded that RN was overly aggressive for Stage I Wilms’ tumor in children, suggesting the use of NSS for uWT up to 4 cm in diameter and simple nephrectomy for larger Stage I uWT (30).

Contemporary treatment approaches are grounded in the principle of individualized, risk-adapted therapy, incorporating surgery, chemotherapy, and radiation. Protocols based on the NWTS and COG emphasize upfront tumor resection guided by its stage. On the other hand, the SIOP protocol employs presurgical chemotherapy to reduce and downstage the tumor. The only exception is patients under 6 months, for whom SIOP recommends immediate tumor resection (5).

The choice between NSS and RN for tumor resection is determined by the anatomic characteristics of the tumor and the remaining normal kidney tissue. Studies evaluating the feasibility of NSS in uWT established criteria for an ideal surgical candidate, including a unifocal mass located outside the renal hilum, sparing a third or more of the normal kidney; favorable histology; the absence of renal sinus or segmental vascular tumor invasion; no lymph node metastasis, intraoperative tumor spill, or gross regional disease at surgery; and a distinct interface between the tumor and renal parenchyma (31).

The umbrella protocol of the SIOP-RTSG suggests that ideal NSS candidates have a small tumor volume (<300 mL), negative regional lymph nodes, and substantial remaining kidney function. 16 NSS is further categorized into NSS A (partial nephrectomy) and NSS B (enucleation), with a preference for NSS A. Minimally invasive or laparoscopic surgery is discouraged unless NSS can be safely performed (32, 33).

Both cases in this article met all criteria, leading to the decision to open NSS with positive outcomes. SIOP has formulated a standardized NSS “formula” encompassing documentation of surgical technique, intraoperative assessment of resection margins, pathologic resection margins, and the estimated remaining renal parenchyma percentage (34). Any intraoperative tumor spill or gross residual positive margins must be documented. The pathologist assesses the microscopic resection margins and lymph node positivity. Lymph node sampling during surgery of Wilms’ tumor is considered essential for local staging, involving paracaval, paraaortic, aortocaval, and parahilar lymph nodes on each side. Tumor specimen is assessed under SIOP posttreatment histology risk by calculating the percentage of necrosis, blastema, and any diffuse anaplasia (31).

Several studies indicate that perioperative complications are notably higher in NSS compared to radical nephroureterectomy. However, these complications, including intraoperative blood loss and postoperative urine leak, can be effectively managed without compromising OS rates (4, 35).

Nephron-sparing approaches show a significantly higher rate of microscopic positive margins than radical nephroureterectomy. In cases of positive margins, adjuvant flank radiotherapy on the affected side becomes necessary. A study by Vujanic et al. observed positive margins in 36% of kidneys in patients undergoing NSS (31). However, with the appropriate use of adjuvant chemotherapy and radiation, local recurrence rates and OS remain excellent even in cases with positive microscopic margins (36, 37).

In the second case presented in this article, postoperative positive surgical margins (PSM) were observed. In cases of PSM, adjuvant flank radiotherapy on the affected side becomes necessary (35). Tracy et al. observed that the PSM ranged from 3 to 45% in patients with Wilms’ tumor who underwent NSS. However, it did not lead to higher tumor recurrence rates, especially when postoperative radiation therapy was administered (36). With the appropriate use of adjuvant chemotherapy and radiation, the rates of local recurrence and OS remain excellent even in cases with positive microscopic margins in other studies (37, 38). The child subsequently underwent adjuvant chemotherapy, including Cyclophosphamide, vincristine, and carboplatin, along with 25 Gy external beam radiation therapy (EBRT) to the right renal bed administered in 14 fractions. Following the treatment, an FDG PET scan revealed no residual disease or metastases, and at 1-year follow-up, the child was confirmed to be disease-free.

Regarding postoperative complications, recent literature suggests that NSS outperforms RN in preserving long-term renal function and cardiovascular functionality and reducing recurrence (8, 23, 39). Studies by Lopes et al. reported a higher risk of renal failure with RN, while Chen et al. noted negligible relapse in patients who underwent NSS (2, 40). In a retrospective trial of 2800 patients, Wilde et al. reported a tumor relapse rate of 13% in cases treated with RN compared to only 4% in those undergoing NSS (41). Interestingly, the authors did not observe a significant difference in survivability between the two approaches. Conversely, Cozzi et al. compared the survivability rates between the two approaches over a mean follow-up of 11.5 years, reporting a 100% survival rate for cases treated with NSS and only 74% for those treated with RN (23).

The role of NSS in the pediatric population presents certain challenges, including technical considerations associated with removing a large tumor from a small kidney while preserving functional renal parenchyma. Longo et al., in their study, compared simple enucleation with partial nephrectomy for T1 renal masses. They found that enucleation was associated with similar warm ischemia time but exhibited lower intraoperative blood loss, shorter operative time, and a decreased risk of positive surgical margins (42). Deciding on the timing and duration of adjuvant chemotherapy to minimize nephrotoxic effects while achieving the desired effects is crucial (8).

Choosing the right patients is crucial. The research by Cost et al. and Ferrar et al. indicates that only 25% of children with uWT were eligible for NSS, and just 1% underwent NSS. Therefore, future research should explore NSS for children with generous residual normal kidneys, regardless of tumor size (21, 43). In some cases, the benefits of saving renal parenchyma may outweigh the risks of radiation therapy required for positive tumor margins. Van der Zee et al. introduced the concept of “virtual resection,” utilizing real-time manipulation of 3D reconstructions to plan NSS and estimate the expected residual renal volume after resection (44). Preoperative nephrometry scoring, proven effective in adult renal tumors, can be initiated in pediatric cases (45). Fluorescence-guided surgical approaches may assist in distinguishing normal kidneys from tumor tissue, especially in cases of multifocal tumors in each kidney (46).

Limited studies with prolonged follow-ups are available. Ceccanti et al. demonstrated enhanced renal function (using 99mTc dimercaptosuccinic acid renal scintigraphy) and improved renal outcome (ultrasonography) in their cohort after zero-ischemic NSS (47). These improvements were reported in follow-up screenings conducted after 5, 10, and 17.3 years. In meta-analyses by Chen et al., significant improvements (eGFR, 0.76; follow-up, 8.7 years) in renal function outcomes were observed in children who underwent NSS (2).

Conclusion

Nephron-sparing surgery has demonstrated positive results in unilateral non-syndromic Wilms’ Tumor, offering the benefit of preserving renal parenchyma. Successful execution of this extensive surgery to minimize the incidence of positive margins requires specialized technical expertise. Further, comprehensive long-term follow-up studies are essential for OS rates and renal function evaluations.

Author Contributions

Sahil Kiran Pethe (First Author) contributed to the conception and design, data acquisition, data analysis and interpretation, and drafting the manuscript. Virender Sekhon and Rajesh Ahlawat were involved in reviewing and final approval of the manuscript. Atanu Kumar Pal (Corresponding Author) contributed to drafting the manuscript. All authors contributed to the critical revision of the manuscript for scientific and factual content.

Mandatory Disclosure on Use of Artificial Intelligence

The authors declare that no AI-assisted tools were used in the preparation of this manuscript. All references have been manually verified for accuracy and relevance.

Conflict of Interest

The authors declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article.

Funding

None.