Nephron-Sparing Surgery in Nonsyndromic Unilateral Wilms' tumor: An Insight into the Ongoing Surgical Controversy.

Background: Unilateral Wilms' tumor (uWT) is the most common renal malignancy in the pediatric population. Although the onset of surgical intervention like radical nephrectomy (RN) has substantially reduced the mortality rate, recent evidence has raised concerns regarding several postoperative complications associated with this procedure. Nephron-sparing surgery (NSS) has been reported to avoid such postoperative complications and have high technical success rate. However, not much literature is available comparing the efficacy of RN and NSS for managing nonsyndromic uWT, which makes it less acceptable globally. Materials and Methods and
Results: A systematic identification of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines on four academic databases: MEDLINE, Scopus, EMBASE, and CENTRAL. Out of 1017 records, 20 manuscripts including 312 patients were included in the review; 4 patients treated by the author (unpublished data) have also been included. The studies included 7 retrospective case series with no comparison group, 4 retrospective case series with comparison group, 4 retrospective series with a cursory mention of NSS in uWT, 2 case reports, 1 protocolized prospective trial with comparison group, 1 administrative database analysis with comparison group, and 1 randomized controlled study. In all, 316 patients with nonsyndromic uWT were studied. The pretherapy volumes of the WT ranged from 2.4 to 640 ml. Majority of them were administered preoperative chemotherapy. About half of the patients (n = 159) (50.3%) were Stage I tumors. Stage II, III, and IV tumors were seen in 23 (7.3%), 20 (6.3%), and 3 (1%) patients. Stage was not specified in 111 (35.1%) patients. Majority of them were "intermediate risk" WT. All these tumors were nonanaplastic. Surgical margins were reported positive in 13 (4%) patients. Overall and event-free survivals were 100% in most of the studies; only handful of relapses were noted in this systematic review. Conclusions: This qualitative systematic review recommends the use of NSS for nonsyndromic uWT. The procedure accounts for higher postoperative renal function and lesser incidence of hypertension as compared to the radical nephrectomy. Overall and event-free survivals are comparable or even better with NSS. Copyright:

INTRODUCTION

“However true it may be that some diseases baffle the skill of the medical practitioner, resisting all his curative and palliative attempts, yet these disappointments ought never so to influence his mind as to damp his exertions, or restrain his endeavors in acquiring a more accurate knowledge of the malady under which his patient labors, for as diseases become more difficult to remove, so should his researches become the more unwearied and assiduous.…”

Thus wrote Rance of London in 1814[1] when he reported the first case of nephroblastoma, 85 years before Wilms' classical description. These words are as true today as they were more than two centuries ago.

Wilms' tumor (WT) is one of the success stories of pediatric oncology with long-term overall survival (OS) approaching ~90% in localized disease and over 70% for metastatic disease quoted in the developed world. This is marked improvement from the OS of ~30% reported seven decades ago. This improvement is due to the development of multimodal treatment for this disease based through international collaboration on trials conducted by the International Society of Pediatric Oncology (SIOP) and the Children's Oncology Group (COG). Besides these two major groups, there have many other groups had been working for the guidelines for the management of WT such as the United Kingdom group, the Italian group, the French Group, the German Group, the Polish Group, Japanese Group, the Brazilian Group,[2] and more recently even an Indian Group.

The treatment of WT is multimodal, where surgery plays an important role in removing the bulk of the disease. It is not conclusively known whether it was Jessop[3] or Kocher and Langhans[4] who performed the first successful extirpation of a WT in a child. The addition of radiotherapy (XRT) in 1916[5] and chemotherapy (ChT) in 1955[6] has not changed the place of surgical extirpation in the treatment of WT. The radical nephroureterectomy (RN) along with lymph node sampling has been unquestionably the gold standard for surgical extirpation of unilateral WT (uWT) since 1963 after Robson described it for renal cell carcinoma.[7] In 1957, Rickham[8] first described a case of bilateral WT (BWT) treated by nephrectomy on one side and partial nephrectomy (PN) on the other side. However, the pendulum over the next half century has conclusively moved in favor of bilateral NSS in this context. The role of nephron-sparing surgery (NSS) or PN in the management of BWT, in single anatomic or functional kidney, in fused kidneys (e.g., horse-shoe kidney), in the presence of bilateral nephroblastomatosis or in patients with syndromic disposition, is indisputable now.

Simultaneously, some other newer concepts also crept in the management of WT during the last half century. These include the NSS in nonsyndromic uWT, use of minimally invasive surgery (MIS) in the treatment of WT, preoperative ChT, contralateral exploration, lymph node sampling, adrenal preservation, and pulmonary metastasectomy.[9] Some of these issues seem to have been settled for good, e.g., thorough lymph node sampling is considered mandatory for disease staging and to direct adjuvant therapy. Contralateral exploration has been almost written off in the era of highly sensitive and specific cross-sectional imaging, and data show that it is safe to preserve the ipsilateral adrenal gland where technically feasible. Pulmonary metastasectomy is now known to provide good overrall survival (OS) and also to obviate the need for whole-lung radiotherapy (XRT) in patients with a few nodules (n

MATERIALS AND METHODS

This systematic review was carried in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Four academic databases (MEDLINE, CENTRAL, EMBASE, and Scopus) from inception until July 2021 using MeSH keywords were searched. The following terms in all academic databases in different combinations “Wilms' Tumor,” “Unilateral Wilms' Tumor,” “Unilateral Wilms' tumor,” “Nephron-Sparing Surgery,” “Partial Nephrectomy,” “Radical Nephrectomy,” and “Total Nephrectomy” were used. In addition, we manually screened the bibliography of the included studies for any additional relevant study. The inclusion criteria for the included studies were as follows:

Studies mentioning NSS on uWT in pediatric population, i.e., <18 years old

Studies published in peer-reviewed scientific journals and conferences.

The case reports and case series mentioning NSS in uWT where the contralateral kidney was either congenitally absent or nonfunctional or was removed earlier for WT (metachronous WT) or any other pathology were excluded.

The present study could at best be called a qualitative systematic review.

RESULTS

A preliminary search on four academic databases resulted in a total of 1107 studies; 116 more studies were included after the bibliography of articles were screened. Thereafter, upon excluding the duplicates and applying the inclusion criteria, a total of 20 studies were retained. Qualitative data of 312 patients were then extracted from all the studies and summarized in Table 1;[1011121314151617181920212223242526] 4 patients treated by the author (unpublished data) have also been included. The studies included 7 retrospective case series with no comparison group,[11161721242728] 4 retrospective case series with comparison group,[12222526] 4 retrospective series with a cursory mention of NSS in uWT,[13141518] 2 case reports,[1020] 1 protocolized prospective trial with comparison group,[25] 1 administrative database analysis with comparison group,[23] and 1 randomized controlled study (RCT).[29]

Table 1

Patients characteristics and outcomes

Authors	Type of study	Country	Study period/year of surgery	n	Male: female	Age at surgery	Laterality right: left	Size (cm)/volume of tumor (ml/cm3)	Site of tumor	Preoperative ChT (Y/N)
Verga and Parigi[10]	Case report	Italy	1979	1	0:1	2.8 years	L	~9 cm×4 cm	Lower pole	N
McLorie et al.[11]	Retrospective case series with no comparison group	Canada	1984-90	4*	-	Mean age 4.5 years (range: 0.8-7.6 years)		-	Lower pole - 2, upper pole - 3	Y
Moorman- Voestermans et al.[12]	Retrospective case series with comparison group	Netherlands	1982-92	7**	4:3	Median age 3.4 years (0.7-10.4 years)	R: L: 2:3**	-	Lower pole - 2, upper pole - 3; two fused kidney**	Y (except 1 who had multilocular cystic tumor
Pringle et al.[13]	Retrospective case series	New Zealand	1977-97	2	-	-	-	-	-	Y
Sen et al.[14]	Retrospective case series	India/Saudi Arabia	1985-95	4***	-	-	-	-	-	-
Acosta et al.[15]	Retrospective case series	Spain	1993-99	1	-	-	-	-	-	Y
Haecker et al.[16]	Retrospective case series with comparison group	Switzerland, Germany****	1994-2001	28#	-	-	-	-	-	64% (18/28) had preoperative ChT
Linni et al.[17]	Retrospective case series with no comparison group	Austria	1981-98	7##	3:4	Mean 4.2 years (range: 1-10.5 years)	5:2	Mean pre-ChT 720.5 ml (range, 17.8 ml-1346 ml); Mean post-ChT 162.3 ml (range 4.2 ml-594 ml) mean tumor reduction rate post-ChT was 79%	-	Y
Gentil Martins and Sousinha[18]	Retrospective case series	Portugal	-	30	-	-	-	-	-	Y
Landolsi et al.[19]	Retrospective case series	Tunisia	-	1	-	-	L	-	-	Y
Sawicz- Birkowska et al.[20]	Case report	Poland	1999	1	1:0	3 years	-	-	-
Apoznański et al.[21]	Retrospective case series with no comparison group	Poland###	1995-2002	6	4:2	Mean: 28.9 months (range: 2-96 months)	2:4	Mean pre-ChT volume - 54.6 cm3 (range: 6.2-154.6 cm3); Mean post-ChT volume - 30.7 cm3 (range: 2.4-109 cm3)	All polar	Y
Szymik- Kantorowicz et al.[22]	Retrospective case series with comparison group	Poland	1993-2008	6^	-	Mean/median age 14.5/15 months	-	Pre-ChT range 3×2 × 2.5 cm–7×7 × 8 cm; post-ChT range-2×2 × 2cm - 5×5 × 4cm	Lower pole - 4, upper pole - 2	5/6 had preoperative ChT
Wang et al.[23]	Administrative database analysis with comparison group	USA	1988-2010	74	-	Mean 1.01 years (range: 0.94-1.08 years)	-	-	-	-
Nerli et al.[24]	Retrospective case series with no comparison group	India	2000- 12	9		Mean 19.7 months (range 8-54 months)	-	Pre-ChT range 6×4 cm–12.5×8 cm; post-ChT range-3×2 cm-7.5×6.8 cm	Lower pole - 4, upper pole - 5	Y
Wilde et al.[25]	Protocolized prospective trial with comparison group	Europe (SIOP WT-2001)	2001-2011	91	-	-	-	Mean pre- ChT~150 ml; mean post- ChT~50 ml	-	Y
Cost et al.[26]	Retrospective case series with comparison group	6 hospitals from USA, Iran, Spain, Italy and Poland	?2002-12	15	9:6	Median age 2.5 years (range: 0.19-8.2 years)	-	Mean pre-ChT volume - 59 ml (range: 2.7-640 ml); Mean post-ChT volume - 21 ml (range: 2.7-640 ml)	-	6 had ChT; 4 underwent primary surgery
Aldrink et al.[27]	Retrospective case series with no comparison group	USA	2010-17	2	-	-	-	-	-	-
Ceccanti et al.[28]	Retrospective case series with no comparison group	Italy	1992-2016	8^^^^	3:5	Mean age 27.8 months (range: 6-51 months)	4:4	Mean diameter 5.2 cm (range: 1.2-12 cm)	Mid-pole-2upperpole-1‡; not mentioned for other 5	Y
Nerli et al.[29]	Randomized control study	India	2006-15	15	-	Mean 46.4±15.8 months	-	Mean preoperative diameter 12±0.11 cm	-	Y
Sarin (unpublished data)	Prospective trial	India	2017-8	4	1:3	Mean age	1:3	Mean pre-ChT volume 251 ml (range: 50-378 ml); Mean post-ChT volume 103.8 ml. Mean tumor volume reduction 38.8% (range: 4-82%)	Upper pole - 1; upper and middle pole - 2; lower pole 1	Y
Total				316				Range pre-ChT volume and post-ChT volume: 2.7-640 ml		Most had preoperative ChT
Authors	Postoperative stage	HPE	Surgical margins (+/−)	Anaplasia (Y/N)	Survival		Postop status of renal remnant	Comments
					EFS	OS
Verga and Parigi[10]	I	Blastema predominant	−	N	100%	100%	Satisfactory at 4-year FU	No event at 6 years 2-month follow-up
Moorman- Voestermans et al.[12]	Stage I - 5; Stage III - 2. In one of the 2 patients with a stage III tumor, a small metastatic node in the mesocolon appeared to be removed incompletely; the other showed a tumor +ve margin at the site of the diaphragm	-	All –ve	N	-	71% -(5 years)	Overall renal function and the functional capacity of the kidney remnant could be assessed in 5 patients after a median follow-up of 88 months (range, 73-151 months) and were all within the normal range	Preoperative imaging showed an accuracy of 87% to predict the possibility for PN. 2 (1 boy and 1 girl) (1 Stage I and other Stage III) died of disease (at 46 and 49 months of surgery)-one because of lung metastases, and one because of liver metastases
Pringle et al.[13]	-	-	−	-	-		-	No relapse
Sen et al.[14]	Only patient with WT In horse-shoe kidney had preoperative ChT	-	−	-	-	-	-	2 with fused kidneys and 1 other patient disease-free. The other tumor recurred twice and had repeat PN
Acosta et al.[15]	-	-	−	-	-	-	-	-
Haecker et al.[16]	Stage I - 19, Stage II - 6, stage III - 2, Stage IV - 1	-	−	N	89%	96%	-	3 had recurrences; 2 local and 1 combined. 1 patient with stage IV predominant blastemic type WT in horseshoe kidney died
Linni et al.[17]	Stage I - 4; Stage III - 1; Stage IV - 2. Preoperatively, in 1 patient a unilateral lung metastasis and in another patient bilateral lung metastases combined with liver metastases were diagnosed	Intermediate risk in all	All−ve except 1###	N	71.4%	100% (follow-up time: mean 6.6 years, range: 28 months-11 years)	The mean creatinine clearance was 97 ml/min/1.73 m2 (range: 70-128 ml/min/1.73 m2). The postoperative renal scintigraphy revealed a 40% kidney remnant function rate in other 5 patients. Even the 2 patients had secondary nephrectomy and revealed creatinine clearance levels at the lower range of normality	1 Stage III patient had renal arterial thrombosis. Another Stage IV patient with pulmonary alone metastases had local relapse, and lung metastases 19 months later. Both Stage IV had tumor bed XRT. The Stage IV patient had advanced ChT autologous marrow transplantation and bil lung RT
Gentil Martins and Sousinha[18]	-	-	−	-	93.3%	93.3%		2 were lost to follow-up but reportedly fared well. 2 died with lung metastases but with no local recurrence (confirmed through autopsy). In 4, the remaining kidney parenchyma ceased to function
Sawicz- Birkowska et al.[20]	-	-	−	-	100%	100%		Followed up for 5 years
Apoznański et al.[21]	Stage I - 5; Stage II - 1	Intermediate risk	−	N	83.3%	100%	-	In 1 boy aged 8 years, local recurrence of tumor was seen in the resected pole of the kidney 8 months after the operation. RN was performed in this patient followed by ChT and XRT with an uneventful follow-up of 5 years. Retrospectively, authors felt considered that this patient had been wrongly qualified for NSS for it was large, and didn’t show much reduction in size after neoadjuvant ChT and the HPE didn’t show significant CIC
Szymik- Kantorowicz et al.[22]	All Stage I	Intermediate risk	−	-	100%	100%	-
Wang et al.[23]	-	-	−	-	-	-	-	In the stratified analysis of unilateral WT patients, unknown LN status (P<0.001), smaller tumor size (P<0.001), and more recent surgery year (P=0.04) remained significantly associated with NSS. Other clinical factors such as age, gender, race, or tumor stage were not found to be significantly associated with the use of NSS in bivariate analysis
Nerli et al.[24]	All Stage I	All had FH	All−ve	N	100%	100%		Mean follow-up period was 22.33±11.12 months. Postoperative serum creatinine repeated at the end of 3 months revealed maintenance of good renal function in all children. Mean serum creatinine at 3-month follow-up was 0.46 mg%. Mean creatinine clearance at 1-year follow-up was 82.3 ml/min (range 54.6-97.4)
Cost et al.[26]	Stage I - 10; Stage II - 2; Stage III - 3^^^	3 patients had monophasic - or epithelial- predominant WT; HPE of other 12 not mentioned	−		93.3%	93.3%	The median preoperative eGFR was 91.7 (39.4-237.7) The median eGFR at last follow-up was 135.3 (57.5-185.8). The median change in eGFR during the study period was a gain of 28.6 (51.9-83.0)	In 4 patients nodes were not sampled. Median length of follow-up 8.4 years (range: 0.54-31.8 years). One Stage III patient with LN +ve died from ChT-related sepsis; One Stage II patient had local recurrence 1.9-year postoperative salvaged with repeat NSS and chemo-radiation and event free for 16 years after recurrence
Aldrink et al.[27]	-	-	−	-	-	-	-	-
Ceccanti et al.[28]	All Stage I	HPE mentioned for 4 patients. intermediate risk (standard histology - 3, highly differentiated epithelial type - 1)‡	3 had+ve margins	N	100%	100%	Mean preoperative eGFR was 101.1 (range: 41-145) for all the 8 patients. For those 4 patients whose eGFR was available for 5-year and 10-year follow-ups, mean preoperative eGFR available was 87.8 (range: 41-116), mean eGFR at 5-year follow-up was 101.8 (range: 79-142) and mean eGFR at 10-year follow-up was 110 (94-124). The mean gain of eGFR in these 4 patients at 5-year and 10-year follow-ups was 14 and 22.2, respectively	There are minor discrepancies when compared with the data presented by the same group of authors previously. 3 patients had enucleation, 5 had PN. Compensatory catch-up growth capacity during childhood minimizes OKF/V decline
Nerli et al.[29]	-	-	−	-	100%	100%	Postoperative mean serum creatinine at 1-year follow-up was 0.56±0.08. Mean systolic and diastolic BP were 109.4±5.57 mm and 74.5±5.19 mmHg, respectively	Percentage preservation of kidney in NSS cohort was 42.22±1.21. The children who underwent total nephrectomy presented with considerably higher mean systolic and diastolic blood pressures, as well as significantly elevated mean values of serum creatinine compared to their NSS counterparts. The study conclusively showed a persistent and steep decline in GFR in the children undergoing total nephrectomy
Total	Stage 1-159 (50.3%); Stage II - 23; Stage III - 20; Stage IV - 3; stage not specified - 111	Most had Intermediate risk WT	13 (4%) +ve margins	All nonanaplastic

*1 patient had horse-shoe kidney, **2 patients had fused kidneys, one an upper pole tumor in the left half of a horse shoe kidney; and one a lower pole tumor in a crossed ectopic kidney, ***2 patients had fused kidneys, one horse shoe kidney and 1 pelvic fused kidney, ****GPOH branch of the SIOP 93-01 WT study, #1 patient with Stage IV horse-shoe kidney; 9 patients (3 patients of cystic partially differentiated nephroblastoma, 1 patient with malignant rhabdoid tumor of kidney, 2 patients with congenital mesoblastic nephroma and 3 patients of nephroblastomatosis) have been excluded, ##1 patient had massive bilateral nephroblastomatosis that evolved to unilateral WT at 44 months, ###In one the frozen section biopsy sent intraoperatively showed that resection was not radical and another slice of renal tissue was removed, ####1st Polish WT study. ^May have been included in the study by Apoznański et al., ^^3 patients have been probably included in the study by Apoznański et al., ^^^1 patient was managed with preoperative percutaneous tru-cut biopsy and upstaged Stage III, in SIOP/UKCCG studies, it would have been designated Stage I or II depending on locoregional spread, ^^^^4 patients (one with cystic nephroma, 1 with oncocytoma, 1 with bilateral hypertrophic nephroblastomatosis and 1 with syndromic WT) were excluded, ‡Information extracted from previous articles published by the same group. Unit used for GFR is ml/min/1.73 m2. ChT: Chemotherapy, XRT: Radiotherapy, PN: Partial nephrectomy, NSS: Nephron-sparing surgery, CIC: Chemotherapy induced changes, FH: Favorable histology, TN: Total nephrectomy, OKF/V: Operated kidney function/volume, eGFR: Estimated glomerular filtration rate, EFS: Event-free survival, OS: Overall survival, FU: Follow-up, SIOP: International Society of Pediatric Oncology, HPE: Histopathological examination,Y: Yes, N: No, XRT= radiotherapy, ChT: Chemotherapy, LN: Lymph node, RN: radical nephroureterectomy, DMSA: Dimercapto succinic acid, GPOH: German Pediatric Oncology Hematology, UKCCG: United Kingdom Child Canceer Group

The patients with benign renal tumors (including cystic nephroma) or non-Wilms' renal tumors that were historically included as uWT undergoing NSS were excluded from the systematic review and that explains the discrepancy in the numbers of patients mentioned in Table 1. There were also minor discrepancies in the data regarding the same 8 patients who underwent NSS for uWT in different publications by the Italian group, but all efforts were done to correct the details.

In all, 316 patients with nonsyndromic uWT were studied. The pretherapy volumes of the Wilms' tumors ranged from 2.4 to 640 ml. Majority of them were administered preoperative ChT. About half of the patients (n = 159) (50.3%) were Stage I tumors. Stage II, III, and IV tumors were seen in 23 (7.3%), 20 (6.3%), and 3 (1%) patients. Stage was not specified in 111 (35.1%) patients. Majority of them were “intermediate risk” WT. All these tumors were nonanaplastic. Surgical margins were reported positive in 13 (4%) patients. Overall and event-free survivals were 100% in most of the studies; only handful of relapses were noted in this systematic review [Table 1].

The 4 patients treated by author in 2018–2019 by NSS (unpublished data) are also detailed in Table 1.

DISCUSSION

Although the first recorded PN for nonsyndromic uWT was done in Cuba in 1966,[30] the contralateral kidney of this patient was not normal and eventually warranted its complete suppression (read excision). The real thrust to NSS in uWT was given by two groups - Cozzi et al. working at La Sapienza University, Rome, Italy[31] and Cost et al.[32] from University of Texas, Dallas, USA. There is no denial that the Italian group has published scores of articles but has operated on only 8 patients with nonsyndromic uWT and normal contralateral kidney in the past 3 decades! Met with initial skepticism, publications have accumulated data now on over 300 patients indicating a likely defining role for NSS for localized tumor lesions even in nonsyndromic uWT showing equivalent survival, morbidity - rupture rate(s), recurrence versus RN [Table 1]. A recent article from Germany has touted NSS in uWT as the most promising of the four innovations in the surgical treatment of pediatric solid tumors that would improve the long-term outcomes in the future;[33] they asserted that NSS would play an important role in the individualized and optimized risk-adapted therapy of children of uWT by avoiding the long-term consequences of a reduction in the renal parenchyma. Szymik-Kantorowicz et al.[22] had concluded in 2012 that RN is an overly aggressive treatment modality in children with Stage I WT and had proposed the employment of NSS for uWT up to 4 cm diameter and simple nephrectomy for larger Stage I uWT.

In the past one decade, some researches from USA that follows the philosophy of upfront surgery (COG protocol) did some post hoc feasibility analyses to determine the percentage of cases that could have been amenable to NSS. Cost et al.[34] addressed the issue in a review of pathologic specimens from 78 nonpretreated RN performed for uWT. The ideal surgical candidate for NSS was defined as demonstrating all of the following characteristics on pathologic review: (1) unifocal mass located outside of the renal hilum and sparing a third or more of normal kidney; (2) favorable histology; (3) absent renal sinus or segmental vascular tumor invasion; (4) absence of lymph node metastasis, intraoperative tumor spill, or gross regional disease at surgery; and (5) a distinct interface between tumor and renal parenchyma. They realized that about one-fourth patients met all of the strict criteria and would have been considered ideal surgical candidates for NSS. Ferrer et al.[35] reviewed imaging studies of 60 patients with a mean age of <2 years with very low-risk uWT (mean weight <550 g) to assess the feasibility of PN. They evaluated percentage of salvageable parenchyma, tumor location, and anatomical features preventing a NSS. They found a linear relationship exists between tumor weight and computerized tomography estimated tumor volume. They concluded that NSS was deemed feasible in only 8% of nonpretreated patients.

The low number of kidney-conserving interventions above can to a certain extent be explained by the lack of guidelines for NSS previously. Umbrella protocol of SIOP-Renal Tumor Study Group (SIOP-RTSG) recently suggested that ideal candidates for NSS include those with small tumor volume (<300 ml), negative regional lymph nodes and those who would have substantial remnant kidney function.[36] A new classification system for NSS was also suggested in the Umbrella protocol to optimize the comparison of patient outcomes [Table 2].[37] Umbrella protocol differentiates the two popular techniques of NSS into NSS A (PN) and NSS B (enucleation) [Figure 1][38] and suggests to go for NSS A. It was further emphasized that minimally invasive or laparoscopic surgery should not be done in patients in whom NSS can be safely performed.[36] As such, there are very few examples of NSS in uWT performed laparoscopically.[3940]

Table 2

Nephron-sparing surgery (NSS)*

Aspect	Description
Surgical technique	NSS (A)=PN+=resection of tumor with a rim pf normal renal parenchymaNSS (B)=Enucleation=resection of tumor without a rim of normal renal parenchyma
SRM	Intact pseudo-capsule=0Doubt=1Tumor breach=2
PRM	Safe rim of renal parenchyma on resection margin, except nephroblastomatosis=0Intact pseudocapsule along the resection margin=1Tumor breach=2
RRP	A subjective evaluation is done by the surgeon of the percentage of renal parenchyma remaining on thee operated kidney=(n%)For example, a polar nephrectomy usually corresponds to a RRP of 70%

*A classification for each case would be reported as follows: NSS (X)-SRM (n)-PRM (n)-RRP (n%). Adapted from Godzinski et al., 2014.[37] PN: Partial nephrectomy, SRM: Surgical resection margin, RRP: Remaining renal parenchyma, NSS: Nephron-sparing surgery, PRM: Pathological resection margin

Figure 1

Different types of nephron-sparing surgery (NSS). (a) Partial nephrectomy: NSS A. (b) Enucleation (tumorectomy): NSS B (Reproduced from Mrad et al. 2020[38] with permission from Wiley)

The systematic review of all reported patients of nonsyndromic uWT with normal contralateral kidney globally [Table 1] clearly demonstrates that upfront ChT approach purported by SIOP is far better way to go for NSS for uWT. Mean reduction in volume of tumor after neoadjuvant ChT was 38% (Sarin; unpublished data) to 79% in series by Linni et al.[17] Even a tumor as big as 1346 ml was pretreated with ChT and was amenable to NSS when it shrank to 594 ml.[17] Even the author had a patient with pretreated tumor volume of 378 ml in his series of patients of uWT undergoing NSS.

As of date, some excellent systematic reviews[4041] and meta-analysis[42] on the topic of NSS in uWT are available. The first and only (RCT) study hitherto on the topic has been recently reported by a team of urologists from Belgaum, Karnataka, India.[29]

Romao and Lorenzo[40] reviewed the existing literature pertaining to renal function in these patients. Incidence rates, causes, and methods to mitigate renal dysfunction are presented in 3 distinct clinical situations: sporadic uWT, syndromic uWT, and BWT. They emphasized that renal function in pediatric cancer survivors must be carefully ascertained prospectively using methods that allow diagnosis of mild cases, rather than focus solely on extreme cases represented by the development of end-stage renal disease (ESRD).

Low incidence of ESRD that is often quoted as one of the reasons why paradigm shift from RN to NSS should not be considered for nonsyndromic uWT is the most dramatic, final stage of chronic kidney disease (CKD) and represents just the tip of the iceberg. There could be a significant number of patients who underwent nephrectomy and had further exposure to other nephrotoxic treatments for WT in childhood growing up with under-recognized CKD. Direct toxicity from ChT and XRT radiation as well as direct nephron ablation from surgical treatment (nephrectomy) renders the kidney susceptible to a multitude of problems over time in patients with WT.[40]

Romao and Lorenzo[40] stressed on the individualized treatment of children with nonsyndromic uWT keeping molecular stratification for disease aggressiveness as well as multifocality and renal dysfunction in mind [Figure 2].[40] They emphasized a maintaining balance between survival with preservation of renal function and mentioned that the role and potential benefits of NSS deserve careful exploration under well-designed protocols.

Figure 2

Individualized care of unilateral Wilms' tumor (WT) based on molecular stratification based on biomarkers that could influence WT treatment (Reproduced from Romao et al. 2015;[40] reproduced with permission from Elsevier)

An excellent recent systematic review available in French states that NSS for uWT seems to be a credible therapeutic alternative.[41] The authors emphasize on new technologies such as 3D reconstruction that could help surgeons define the best parameters to select ideal tumors for this surgery in the near future. They believed that small tumors (<4 cm), distant from the renal hilum (ideally on the upper pole) that respect at least 50% of the renal parenchyma (ideally superficial with exophytic development), seem to be the perfect indication for NSS.

Chen et al.[42] in a recent meta-analysis recommended the use of NSS for uWT. The procedure accounted for higher survivability and postoperative renal function and lesser incidence of relapse as compared to RN.

Nerli et al.[29] in a recent RCT concluded that the oncological outcome of NSS was as good as RN in children with uWTs. NSS also minimized the loss of renal function. The children who underwent RN presented with considerably higher mean systolic and diastolic blood pressures, as well as significantly elevated mean values of serum creatinine compared to their NSS counterparts. The feasibility criteria were based on post-ChT CT as follows: (a) ≥50% reduction in the size of the tumor; (b) feasibility to excise the tumor by clamping the main renal vessels; and (c) after resection, the residual renal parenchyma should be a minimum of 20% of the original volume.

It is importance to note that over the last two decades, the criterion for size of the renal remnant has shifted from being two-third of the kidney[12] to even as low as 20% of the kidney.[29] Historically, it was believed that at least 50% of renal tissue should be spared after the tumor resection with a margin of healthy tissue, to give any worthwhile protection against hyperperfusion.[44]

Next is the issue of paradigm shift about positive surgical margins (PSMs) after NSS. Although complete tumor removal is an oncologic principle of paramount importance, accumulating data suggest that completion nephrectomy might not be the treatment of choice in all patients with PSMs after NSS. PSMs are present in 0%–7% of patients after open NSS, in 0.7%–4% after laparoscopic NSS, and in 3.9%–5.7% after robot-assisted NSS. As indicated by intermediate follow-up data, the majority of patients with PSMs after PN remain without disease recurrence, and a surveillance strategy seems preferable to surgical reintervention.[45]

The operative steps of NSS in WT are beyond the purview of this article. These are beautifully illustrated elsewhere.[2746474849505152]

Warmann and Fuchs[52] have highlighted the use of magnetic resonance imaging (MRI) in NSS. MRI can better visualize the soft tissue boundary between kidney tissue and tumor. Furthermore, it can provide information on the histological background of different tumor areas based on the different weightings and diffusion analyses. However, general anesthesia is usually necessary to perform a high-quality MRI in the infants and younger children. Even if MRI is performed, a CECT scan cannot be written off as it displays the vascular situation far better. They have also highlighted the use of Uro-MRI and scintigraphy for the patients undergoing NSS so as to know the split renal function. They also emphasized on doing an intraoperative contrast-enhanced sonography to verify the findings of the preoperative imaging and to determine the procedure for tumor resection. The same group of authors had earlier described longitudinal PN for central tumors involving the renal hilum.[53] When the renal pelvis is involved and has to be resected, care must be taken to leave a sufficient margin of renal pelvis tissue on the kidney side for subsequent reconstruction of the collecting system. The author (Sarin) has routinely used preoperative and postoperative DMSA scans for all patients undergoing NSS, and none of the patients had any adverse oncological result on 2-year follow-up. He had also resected part of the pelvis along with the botryoid WT and closed the pelvis over a double-J stent in one of the patients.

CONCLUSIONS

This qualitative systematic review recommends the use of NSS for nonsyndromic uWT. The procedure accounts for higher postoperative renal function and lesser incidence of hypertension as compared to the radical nephrectomy. Overall and event-free survivals are comparable or even better with NSS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.