The current evidence on surgical management for synchronous bilateral renal tumors: results from a scoping review

Purpose Synchronous bilateral renal masses (SBRM) account for a low percentage of kidney tumors, and there is no current recommendation for their management. The objective was to review evidence regarding the best surgical approach for SBRM in terms of type and timing of surgery. Methods A broad literature search was performed on 28th January 2023 using Scopus, PubMed, and EMBASE. Only English papers dealing with adults were included. Meeting abstracts were excluded. Results Twenty-four papers were accepted and included. SBRM behave less aggressively than metachronous tumors, and partial nephrectomy (PN) is the preferred therapeutic option to preserve renal function. Open, laparoscopic, and robot-assisted approaches were found to be similar in oncological outcomes, though robot-assisted surgery resulted in lower comorbidities. Same-sitting PN was demonstrated to be a safe approach, particularly in the robotic-assisted one. Finally, the same-siting and staged NSS were similar in preserving renal function. Conclusions PN should be the desirable treatment for SBRM whenever feasible and if patients are fit, but surgeon expertise should also be taken into the account. Supplementary Information The online version contains supplementary material available at 10.1007/s00345-023-04503-y.


Introduction
Synchronous bilateral renal masses (SBRM) are uncommon [1]. Up to 5% of patients with Renal Cell Carcinoma (RCC) present with SBRM [2]. SBRM can be sporadic or occur in hereditary cancer syndromes, where their incidence increases due to genetic variation [3]. Furthermore, patients with hereditary SBRM tend to have a more aggressive biological behavior than sporadic tumors [4].
Yet, malignant and benign concordance rates of bilateral kidney tumors are reported to be 89% and 71%, respectively [5]. In an international multicenter study of 10,337 patients with RCC, no difference in comparison in terms of cancerspecific survival (CSS) between SBRM and unilateral kidney tumor was reported, with similar 10-year survival rate [6]. The management of patients with SBRM has not yet been well-defined, and international guidelines do not report evident recommendations, mostly due to limited data. The factors influencing the therapeutic decision are similar to those for solitary tumors, such as tumor characteristics, 1 3 patient comorbidities, and surgeon expertise. Nevertheless, the rationale of surgery in patients presenting with SBRM surgery is to ensure oncological radicality and, at the same time, minimize the potential risks of increased perioperative surgical complications and the detriments to renal function. Therefore, considering the tendency to chronic renal disease (CKD) in patients after nephrectomy and the consequent increased risk of cardiovascular mortality [7,8], nephronsparing surgery (NSS) may be a valid option for SBRM to preserve renal function. However, it is still not clear which is the best approach for such patients that is to say same-sitting or staged NSS.
We aimed to perform a scoping review focusing on the outcomes of renal surgery in patients with SBRM, evaluating surgical and oncological outcomes by either comparing simultaneous and staged procedures or comparing different surgical procedures.

Literature search
In this study, we performed a scoping review evaluating surgical, functional, and oncological outcomes of bilateral NSS for kidney tumors. Literature search was performed on 28th January 2023 using EMBASE, PubMed, and Scopus. The following term and Boolean operators were used: (partial nephrectomy OR nephron-sparing surgery) AND bilateral AND (renal OR kidney) AND (tumor OR cancer OR neoplasm). No date limit was imposed.

Selection criteria
Only English papers dealing with adults were accepted. Preclinical and pediatric studies were excluded. Reviews, letters to the editor, case reports, and meeting abstracts were also excluded.

Study screening and selection
Only studies reporting the surgical management of SBRM were considered. Our main objective was to evaluate the oncological radicality and functional outcomes of the surgical management of SBRMs, with a secondary aim of assessing its safety. The PICOS model (Patient Intervention Comparison Outcome Study type) was used to frame and respond to the clinical question; P: adult men with SBRM; I: partial or radical nephrectomy; C: comparison with patients with metachronous bilateral renal masses or who underwent different approach, type of surgery or timing; O: overall survival, cancer-specific survival, perioperative complications, postoperative renal function; S: prospective and retrospective studies.
All retrieved studies were screened by two independent authors through Covidence Systematic Review Manage-ment® (Veritas Health Innovation, Melbourne, Australia). A third author solved discrepancies. The full text of the screened papers was selected if found pertinent to the purpose of this review. This review was registered on https:// osf. io/ regis tries/ (number osf.io/hs96k).

Literature screening
Literature search found 2238 papers. 712 duplicates were automatically excluded, and 1526 papers were left for screening against title and abstract. Among them, 1453 papers were further excluded, because were irrelevant to this review purpose. The remaining 73 full-text papers were screened for appropriateness. A total of 49 papers were excluded for the following reasons: 25 were meeting abstracts, 1 was a review, 16 articles were not in English, 5 had wrong outcomes, 1 had wrong indications and 1 had wrong study design. Finally, 24 papers were accepted and included . Supplementary Fig. 1 shows the flow diagram of the literature search.

Results from case-series studies
Eleven case series analyzed patients with SBRM, reporting on varying surgical strategy, functional, and oncological data ( Table 1). The management of SBRM is still challenging 1 3 and different strategies can be considered, namely, PN or RN; open, laparoscopic, or robot-assisted approaches; single or staged procedures; surgery or ablative techniques. The decision is mainly based on surgeon preference, patient's comorbidity, and tumor characteristic. However, the main goal of treatment is the complete resection of all tumors and the preservation of adequate renal function [33].
Grimaldi et al. [9] evaluated 29 patients with synchronous or metachronous tumors. Twenty-five patients underwent PN and contralateral RN, while the remaining 4 cases had bilateral. Four patients developed metastases, and one patient had a local recurrence after a median follow-up of 52 months. The 5-year overall survival (OS) and CSS were 84.5 and 93.3%, respectively.
Whenever feasible, NSS is also recommended for completely endophytic SRM, given the maintenance of oncological radicality, minimizing the excision of healthy parenchyma [34]. In a retrospective study of 33 patients with central tumors [10], 7 had SBRM. Among the latter, 2 patients underwent staged bilateral PN, while RN followed by PN was performed in the remaining 5 cases. Two patients suffered from a urinary fistula requiring a ureteral stent, while the others showed optimal renal function preservation.
In a study by Blute et al. [11], surgical experience and extended survival outcomes were assessed in 94 patients presenting with sporadic SBRM. Patients were treated with RN + contralateral PN (69%), bilateral PN (26%), or bilateral RN (5%), with most cases (70%) operated on a single session. Among 85 patients with RCC histology, the reported 5-and 10-year OS, CSS, metastasis-free survival (MFS), and local recurrence-free survival (RFS) were 67 and 44%, 81 and 59%, 73 and 66%, and 96 and 93%, respectively. Patients with bilateral RCC (n = 71) showed lower 5-and 10-year CSS than those with unilateral RCC (n = 14) (79 and 55% vs 91 and 91%, respectively), but this result was not statistically significant. Fuhrman grade 3 disease was associated with metastases, and a significant difference in MFS and CSS was based on the presence of pT3 tumor (p < 0.001) but not for local RFS. On multivariable analysis, RCC grade was related to MFS and RCC size with CSS. Type of surgery (i.e., RN + PN vs bilateral PN vs bilateral RN) significantly affected CSS and MFS, yet not local RFS. There was no difference in survival between tumor enucleation and extended, reinforcing the concept that resecting healthy parenchyma around the tumor has no impact on oncological outcomes.
Another study by the same group [12] evaluated 44 patients with sporadic subtype concordant SBRM. The authors evaluated early complications, long-term renal function, and survival comparing those patients with 1714 patients with unilateral RCC. In addition, they assessed the difference in same-sitting vs staged surgery. Pathology findings in patients with SBRM were similar to those patients with unilateral RCC, while the incidence of multifocality in a kidney was larger in patients with SBRM. After controlling for covariates such as RCC subtype, grade, size, and stage, MFS and CSS rates were comparable to unilateral disease, but SBRM patients were more likely to experience local recurrence. Same-sitting bilateral surgery was performed in 84% of patients.
Booth et al. [13] reported their experience of sporadic SBRM treatment, analyzing treatment strategy and type, renal function, and early survival. Among 43 patients, the majority were treated using a staged approach (82%) using bilateral open or laparoscopic PN (LPN) (53.5%). Excluding patients who underwent bilateral RN (n = 3), no patients required dialysis after surgery. Considering survival outcomes, 86% of patients showed no evidence of local recurrence after a follow-up of 16 months, one developed metastatic disease, and two died: one of postoperative complications and the other of myocardial infarction.
Woodson et al. [16] explored intermediate oncological and renal functional outcomes of 15 patients surgically treated for sporadic SBRM. All patients underwent staged procedures using different modalities (i.e., PN or RN by open, laparoscopic, or robot-assisted approaches (RAPN)), with bilateral RAPN performed in 53.3% of cases. In 73.3% of patients, the largest tumor was treated first. Although, after the second surgery, there was a significant decrease in renal function compared to pre-operative function, no patients required dialysis. At an average follow-up of 1.7 years, the reported OS and RFS were both 92.8%.
Hu et al. [15] aimed to assess the optimal surgical strategy for sporadic SBRM. In this case series of 32 patients, the surgical type, staging, and sequence were based on the Zhongshan score that includes tumor location and size, and the patient's performance status (ranked according to ECOG PS Classification). Bilateral single-stage surgery was considered suitable for patients with no comorbidities (n = 8), while a staged surgery was 4-8 weeks after treating the first side for larger tumors, complex cases, or poor performance status (n = 24,). For bilateral PN (n = 15), the operation was performed first on the kidney with a higher Zhongshan score; for patients scheduled to staged PN and RN, RN was conducted first on the side with the largest diameter tumor, while in cases of challenging PN, the latter was done earlier than RN due to the risk of conversion to RN. After a followup of 89 months, no patients required dialysis, while one patient presented with metastatic disease and one a local recurrence.
Mason et al. [17] reported perioperative outcomes of 76 patients treated with synchronous bilateral PN. In this case series, 29.7% and 38.2% of patients underwent bilateral and unilateral renal ischemia, respectively. Postoperatively, 21.6% of patients showed complications, with 10.8%  [14], which assessed the use of single-setting bilateral hand-assisted LPN in 3 patients with exophytic bilateral smaller than 4 cm. All procedures were performed successfully, and with no conversion to open surgery or intraoperative complications. Furthermore, no positive surgical margins (PSM) were found, and no local recurrence was detected at a mean follow-up of 51 months.
Recently, few studies have suggested the safety and feasibility of simultaneous bilateral RAPN.
Otoshi et al. [18] reported their experience of same-sitting RAPN in 8 patients with SBRM. In this pilot study, no PSM occurred, and no local recurrence or metastases emerged at the follow-up. Moreover, only one patient developed acute kidney injury without the need for dialysis.
Similarly, Gallo et al. [19] evaluated perioperative and functional outcomes of simultaneous RAPN for non-familiar SBRM. The complication rate was 25.9%, mainly Clavien grade II and only one Clavien grade III (i.e., urinary leakage with perirenal urinoma). The PSM rate was 3.7%, and the RFS was 100% at a median follow-up of 30 months.

Comparison between synchronous and metachronous tumors
A considerable discriminant in bilateral renal tumors is their presentation, which schematically differentiates into synchronous and metachronous. Evidence from the comparative studies included in our review highlights remarkable findings for differences in the biological behavior between those two types of presentation, especially regarding histologic subtypes, prognosis, and impact on renal function.
In a prospective study by Novick et al. [20], 28 patients with SBRM and 28 with metachronous tumors underwent either staged bilateral PN or RN followed by contralateral PN. Tumor recurrence occurred with a higher percentage in metachronous tumors (46.4% vs 25%,), while their 5-year survival rate was lower (52% vs 73%). The authors concluded that PN for SBRM should be always performed to improve the long-term functional outcomes and the OS.
The largest series was reported by Boorjian et al. [21] at the Mayo Clinic between 1970 and 2003. This cohort included 148 cases of synchronous and 162 cases of metachronous RCC. Metachronous tumors showed a greater pathological concordance than synchronous ones, with 87.7% of metachronous tumors having bilateral RCC compared to 69.2% of synchronous tumors. A longer interval between tumor presentation in metachronous RCC was found to be associated with a better prognosis. Conversely, SBRM showed a comparable survival to unilateral RCC according to a precedent study from the same group [12]. A study by Amano et al. [22] reported similar pathology findings. Interestingly, a higher incidence of concomitant metastatic disease at the time of the second tumor presentation (50% for metachronous vs 13% for synchronous tumors) suggested that metachronous contralateral tumors could be considered as a metastasis of the original tumors.
Qi et al. [24] compared the prognosis of patients treated with bilateral surgery vs unilateral surgery vs no surgery. They reported a higher 5-year CSS in patients with bilateral surgery (93.6%) compared with patients with unilateral (81.5%) and no surgery (0%). The authors demonstrated that OS was significantly better for metachronous non-metastatic RCC (more than 80% at 5 years and 70% at 10-year follow-up) compared to unilateral RCC associated with metastatic disease, suggesting a different biologic behavior between bilateral renal cancer and metastatic disease. Moreover, the majority of metachronous RCC occurred without metastatic disease (81%), while no metastatic disease case was reported at the diagnosis of SBRM.
Evaluating the postoperative loss of renal function, Kim et al. [25] compared the outcomes of bilateral surgery for 44 synchronous and 45 metachronous RCCs. No significant differences in variables among the two groups emerged. Nevertheless, on multivariate analysis, for the prediction of, metachronous RCC was a predictor factor of de novo CKD (HR: 2.682, 95%CI 1.032-6.973, p = 0.043).
In summary, SBRM is associated with a more favorable prognosis compared to metachronous tumors. Patients with SBRM exhibit higher OS and CSS rates, along with a lower incidence of distant metastasis. Moreover, no difference in functional outcomes occurs in the surgical management of these tumors.

Same-sitting vs staged procedures
The surgical treatment of SBRM can be performed in a single session or a staged fashion. No absolute consensus exists on this topic, and current guidelines still lack an optimal surgical approach [35,36]. Same-sitting bilateral NSS would be the ideal setting to avoid two anesthesia and save costs, although postoperative complications may occur, such as bilateral operative trauma, and acute renal insufficiency. On the other hand, a staged procedure allowed scope to alter the treatment strategy for the second renal lesion based on the pathological findings and outcomes of the first surgery. Given the higher frequency of disease progression in a high-stage tumor, the resection of the larger tumor also provides more histopathologicalrelated information for better planning of the staged surgery [30]. Removing the larger mass first would offer the possibility of reducing the chance of dissemination, and the contralateral kidney could function as a backup instead of being traumatized during the operation, minimizing the chance of dialysis, while PN of the smaller mass, at first, would allow a lower risk of acute renal failure in the second surgery [37].
Mason et al. [17] reported the results of 76 patients treated with same-sitting bilateral PN. Eight cases (10.8%) experienced postoperative acute renal failure with a glomerular filtration rate (GFR) decrease after surgery of 19 mL/min/1.73m 2 , although no patients required postoperative dialysis.
Similarly, Di Maida et al. [27], comparing 17 and 24 patients, respectively, treated with a one and a two-stage strategy, reported a significantly higher cumulative operative time (310 vs 240 min; p = 0.01), warm ischemia time (18 vs 10 min; p = 0.03), and length of stay (10 vs 6 d; p = 0.01) for patients receiving the two-stage surgery. However, no significant differences emerged in median eGFR variation from baseline at 3 months and last followup, as well as in RFS between the two groups.
Summarizing, the same-sitting approach for SBRM yielded comparable outcomes in terms of oncological radicality and CSS. In addition, renal function preservation was found to be comparable between these two techniques.

Conservative vs radical surgical strategy
Which is the best surgical approach for SBRM remains unclear as long as oncological principles cannot be compromised vis-a-vis the risk of developing or worsening CKD with subsequent worsening of quality of life [38]; hence, opting for either a bilateral NSS or unilateral RN with contralateral NSS are the only choices available.
Evaluating the study by Kim et al. [25], 44 and 45 patients underwent, respectively, bilateral PN and RN + PN. The former appeared to have less impact on GFR, with the mean postoperative value of 79.4 ml/minute/1.73 m 2 compared to 61.2 when RN followed by PN was the treatment and 41.4 when PN followed by RN performed. Therefore, surgery sequence was a significative and independent predictor of this study.
In a retrospective study recording data from 57 patients [28], 22 bilateral PN and 28 PN followed by RN were performed. The serum creatinine level was significantly different between the two groups, with bilateral NSS showing a lower level than NSS plus RN. Specifically, the serum creatinine level at the latest follow-up was 1.18 mg/dL for patients after bilateral NSS and 1.40 mg/dL after unilateral NSS and contralateral RN (p < 0.05).
Simmons et al. [29] retrospectively analyzed oncological and functional outcomes in 220 patients, whereby 134 patients underwent sequential bilateral PN, 60 had PN followed by RN, and 26 had RN followed by PN, to understand how surgical approaches impact renal function. Comparing the surgical management, a decrease in GFR patients with preoperative stage III CKD was reported in 12%, 43% and 53% of cases in PN-PN, PN-RN and RN-PN groups, respectively. The authors affirmed that patients treated with sequential surgery have 5-and 10-year oncological outcomes comparable to unilateral kidney cancer, with a 10-year CSS of 96%. According to Kaplan-Meier analysis, tumor size greater than 7 was correlated with decreased OS (p = 0.003) but not with CSS (p = 0.14). Therefore, NSS should be conducted for all amenable bilateral kidney masses due to the negative impact of renal function decline on OS.
Wang et al. [30] reported a retrospective study on 60 patients with sporadic SBRM who underwent retroperitoneoscopic treatment. Of the 56 staged surgeries with the kidney having tumors of a higher PADUA score operated upon first, 34 underwent bilateral PN, 12 underwent RN followed by PN, and 10 underwent PN followed by RN: the final GFR was 71, 63, and 59 mL/min/1.73 m2 in, respectively. Therefore, the preservation of renal function resulted better in the former (p = 0.04), while no difference in the order of RN and PN was reported (p = 0.79). They reported that the key findings were that, with the advent of the laparoscopic approach, bilateral PN was superior in renal functional preservation with equivalent oncological results and reduced the high risk of postoperative renal dysfunction without any added morbidity of two surgeries.
The above studies reaffirm that a staged minimally invasive approach to managing the kidney with the higher volume tumor burden by either RN or PN as per oncological principles in the first surgery can help mitigate the chance of acute kidney injury and its related consequences. Considering that CSS and OS are similar in SBRM to that unilateral tumors, surgical intervention in experienced centers should be offered.
In brief, NSS is preferable over radical surgery even for SBRM. The survival rates and recurrence rates are similar, but at the same time, the preservation of healthy parenchyma allows for better renal function.

The optimal surgical approach for bilateral renal masses
Bilateral surgery can be performed with every approach, depending on the surgeon's expertise and availability [39,40]. Gill et al. reported that laparoscopic PN offers advantages in terms of operative time decrease, less blood loss and ischemia time, and fewer complications compared to open surgery, with both equal renal functional and oncological outcomes, despite the increasing surgical complexity [41].
On the contrary, Ching et al. [31], comparing data and outcomes of 92 patients undergoing bilateral open PN and 22 patients treated with bilateral laparoscopic PN, reported a significantly higher percentage decrease of GFR after laparoscopic compared to open surgery (38% vs 27%, p = 0.03). There was no difference in CSS and RFS rates between the two approaches.
RAPN was reported as a reliable surgical approach to minimize the technical limits linked to LPN, as well as the longer operative time and the risk of CKD, which may occur for simultaneous bilateral PN [42]. RAPN showed to be superior to open and laparoscopic approaches due to a better preservation of renal function, a decrease in intraoperative bleeding, shorter ischemic time and postoperative stay [43,44].
Otoshi et al. [18], summarizing the results of 8 cases of simultaneous RAPN for SBRM, reported no PSM or local recurrence with only one patient who experienced acute renal failure not requiring dialysis.
Hillyer et al. [32] compared the intra-and postoperative outcomes of bilateral RAPN in 9 patients to bilateral LPN in 16 patients. There was no difference in terms of operative complication rate, although a trend toward a shorter warm ischemia time in the RAPN group (19 vs 37 min; p = 0.059) occurred, with a higher postoperative eGFR (68.7 mL/ min/1.73 m2 vs 26.9 mL/min/1.73 m2, p = 0.004). The authors concluded that RAPN is an effective and safe procedure for bilateral PN.
In summary, open, laparoscopic, and robot-assisted approaches have shown similar results in terms of oncological outcomes. However, robot-assisted surgery has demonstrated a distinct advantage in terms of reducing complications associated with the procedure.

Limitations
This scoping review has certain limitations. Most of the included studies were retrospective and evaluated small sample sizes, which inevitably introduces low quality of evidence. Therefore, it is crucial to conduct larger and higher quality investigations in the future to better understand the surgical management of SBRMs. Another limitation is the variation in surgeon expertise across the considered studies, which generally influences the chosen approach. Consequently, performing NSS for complex SBRMs may only be recommended for expert surgeons. Similarly, the choice between open or minimally invasive approaches, as well as the timing of the surgery, were be standardized among included studies. Finally, the significant differences in interventions among the included studies prevent a comprehensive analysis of the overall oncological and functional outcomes. Consequently, definitive conclusion cannot be drawn.

Conclusion
Our review provides valuable insights into the surgical management of SBRM, which showed a better long-term OS and CSS than metachronous tumors. The recommendation for conservative surgery for SBRM relies on the preservation of renal function. Our study also points out that there is currently no oncological advantage of one surgical approach over the others, but RAPN seems to offer better perioperative outcomes in terms of preservation of renal function and early postoperative outcomes. The comparison between same-sitting vis-a-vis staged bilateral NSS is also significant, with similar renal function preservation but better perioperative outcomes for the former. Data availability Data will be provided by the corresponding author upon a reasonable request.

Conflict of interest
The authors have no competing interests to declare that are relevant to the content of this article.

Research involving human participants and/or animals Not applicable.
Informed consent Not applicable.
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