Multiple Tumor Excisions in Ipsilateral Kidney Increase Complications After Partial Nephrectomy

Introduction

In sporadic renal-cell carcinoma (RCC), the incidence of ipsilateral synchronous multifocality (ISM), multiple concurrent masses within the same kidney, is as high as 25%, presenting a unique diagnostic and therapeutic challenge. ^{1 –3} Excisional, non-enucleation PN is the recommended treatment for T1 renal masses in healthy patients. ⁴ Although contemporary clinical practice guidelines do not address ISM management, PN has been shown to be effective in this setting. ^{5 –7} In particular, robotic partial nephrectomy (RPN), now the predominant approach in the United States, is feasible for ISM. ^{8 –10} However, the surgical morbidity of ISM is not well studied. ISM increases the anatomic and surgical complexity of the entire renal unit, potentially necessitating multiple mass excisions and renorrhaphies. Since the anatomic complexity of unifocal tumors has been linked to the risk of postoperative complications, we hypothesized that ISM, too, may contribute to this risk. ¹¹ In this study, we aimed to characterize the postoperative morbidity of RPN for treating multiple masses within the same renal unit.

Patients and Methods

Using our institutional review board-approved, prospectively maintained, institutional RPN database, we identified 1121 consecutive RPNs performed between 2006 and 2015. All masses were excised sharply, including a rim of normal parenchyma. The RPN technique and its evolution at our institution have been detailed previously. ^{12 –14} Essential steps include exposure of the renal capsule leaving fat overlying any masses, ultrasonic mass identification with capsular scoring, vascular control, mass excision, early unclamping, and a two-layered closure with or without methylcellulose bolster and/or hemostatic agents. For ISM, resection of easier, exophytic lesions is performed off clamp first, followed by resection of more difficult lesions, using clamping as needed. Easier lesions are considered those with smaller size, polar location, primarily exophytic component, and decreased proximity to the collecting system, renal sinus, and/or hilum.

Patient, tumor, and operative variables included age; gender; race; nonage-adjusted Charlson comorbidity index (CCI) score; body mass index (BMI); history of chronic kidney disease, solitary kidney, bilateral masses, or prior PN; clinical tumor size; R.E.N.A.L. nephrometry score; tumor histology; number of renal masses; number of mass excisions; surgeon experience; estimated blood loss (EBL); positive surgical margins, warm ischemia time; operative duration; and hospital length of stay (LOS). In the case of multiple ipsilateral masses, the clinical tumor size and nephrometry score were assigned based on the largest and most complex mass(es), respectively. Surgeon experience was defined based on case volume (≤30 cases or >30 cases) at the time of RPN in accordance with the RPN learning curve. ¹⁵

Multifocality burden was described in two ways as follows: [1] the number of ipsilateral renal masses present on preoperative imaging (1, 2, or ≥3.) and [2] the number of mass excisions performed per case based on operative and pathologic data (1, 2, or ≥3). An excision was defined as surgical resection of a mass from a separate and distinct site of the kidney requiring multilayered renorrhaphy. Two or more masses excised en bloc was considered a single excision. For analysis, masses and excisions were further categorized as 1 versus >1 and ≤2 versus >2.

We investigated the association between [1] number of ipsilateral renal masses or [2] number of mass excisions and 30-day postoperative complications, our primary outcome. Complications were graded using the Clavien–Dindo system and classified as any complication (Clavien 1–5) and major complications (Clavien 3–5). For patients with complications affecting multiple organ systems, only the complication with the highest Clavien grade was counted. For completeness, the number and rate of all complications, grouped by organ system(s), were expressed.

Continuous variables were analyzed by Mann–Whitney U tests, and categorical variables were analyzed by chi-squared and Fisher's exact tests. Variables found to be significant on univariable analysis were identified and analyzed by multivariable logistic regression. Statistical tests were performed using SAS^® University Edition (SAS Institute, Inc., Cary, NC). p Values <0.05 were considered statistically significant.

Results

Overall, 1237 renal masses were excised during 1121 RPNs in a total of 1082 patients. Of these, 999 (80.8%) masses were malignant and 238 (19.2%) were benign. ISM was detected on preoperative imaging in 59 (5.3%) cases and diagnosed on final pathologic analysis in 76 (6.8%) cases. In 50 (4.5%) cases, >1 mass excision was performed. There was a higher prevalence of chronic kidney disease (33.9% vs. 14.7%), solitary kidney (11.9% vs. 2.0%), bilateral renal masses (52.5% vs. 9.4%), and prior PN (22.0% vs. 4.5%) in RPNs for multiple masses compared with cases for a unifocal mass (Table 1). Except for chronic kidney disease, these characteristics were also shared by cases involving multiple mass excisions.

The overall complication rate for the entire cohort was 20.3% (230/1121), and the rate of major complications (Clavien 3–5) was 5.4% (61/1121). Increasing number of ipsilateral renal masses was associated with a higher overall complication rate, 20.2% (215/1062) for 1 mass and 25.4% (15/59) for >1 mass, but this difference was not significant (p = 0.338) (Table 2). The overall complication increased significantly when multiple mass excisions were performed (20.2% for ≤2 excisions vs. 42.9% for >2 excisions, p = 0.037). For patients requiring multiple mass excisions, the most common complications were bleeding requiring transfusion in one case (7.1%), urine leak in one case (7.1%), arrhythmia managed with medications in two cases (14.3%), venous thromboembolism in two cases (14.3%), and ileus requiring nasogastric tube in two cases (14.3%) (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/end). Of these, there were two major complications, including one persistent urine leak requiring ureteral stent placement and one lower extremity deep venous thrombosis requiring inferior vena cava filter insertion. Major complications were higher for >2 excisions, but this difference was not statistically significant (14.3% vs. 5.3%, p = 0.174).

Other variables significantly associated with overall complications were age, race, CCI, BMI, tumor size, R.E.N.A.L. score, and surgeon experience (Table 3). After adjusting for these factors on multivariable analysis, the number of mass excisions remained a significant predictor of overall complications (Table 4). Greater than two excisions were associated with 3.1-fold higher odds of postoperative complication than two or fewer excisions (OR 3.1, 95% CI 1.03–9.33, p = 0.041). Other independent predictors of complications were older age (p = 0.013), nonwhite race (p = 0.008), higher CCI (p = 0.001), higher BMI (p = 0.001), higher R.E.N.A.L. score (p = 0.019), and decreased surgeon experience (p = 0.001).

Operative times and inpatient LOS increased significantly as the number of masses or excisions increased (Table 3). Mean operative time (±standard deviation) was 216 (56) minutes for ≥3 masses versus 187 (59) minutes for 1 mass (p = 0.001) and 240 (101) minutes for ≥3 excisions versus 188 (59) minutes for 1 excision (p = 0.037). Mean warm ischemia time was not significantly different based on the number of masses (p = 0.236) or excisions (p = 0.075). Positive surgical margin rates did not differ significantly based on the number of masses (p = 0.948) or the number of excisions (p = 0.781). Median hospital LOS (IQR) was 4 (2–5) days for ≥3 masses versus 3 (2–4) days for 1 mass (p = 0.033) and 5 (3–5) days for ≥3 excisions versus 3 (2–4) days for 1 excision (p = 0.046).

Discussion

In our institutional RPN experience, the postoperative complication rate associated with multiple ipsilateral renal masses (on imaging) was 25%, which is comparable to rates reported in the literature. ^{5,7 –9,16} The rate of postoperative complications associated with multiple mass excisions, which has not been previously characterized, was substantially higher, ranging between 29% and 43%. We found that excisional burden (the actual number of separate excisions performed during RPN), as opposed to radiographic mass burden, was an independent predictor of postoperative complications. In fact, RPNs involving >2 excisions were associated with a >20% higher risk of overall complications and a nearly 10% higher risk of major complications. While this difference was statistically significant for overall complications, it did not reach statistical significance for major complications, likely due to the low rate of major complications (5.4%). By contrast, the number of ipsilateral renal masses on preoperative imaging had a less profound impact on postoperative complications. We found that ISM was associated with a 5%–6% higher rate of complications; however, this difference was not statistically significant. Other than complications, multiple masses and multiple excisions were both associated with increased operative time and prolonged LOS, emphasizing their clinical relevance.

Excisional burden rather than mass burden appears to be the true measure of ISM morbidity, and the risk of postoperative complication becomes greatest after three or more excisions. This finding parallels the increased morbidity risk associated with PN versus radical nephrectomy, which likely results from renal excision and reconstruction. ^17,18 It makes sense that multiple excisions during PN would increase perioperative morbidity, commensurate with the number of excisions performed. As might be expected, surgical complications, including blood transfusion and urine leak, occurred more frequently after multiple excisions. However, medical complications also were frequent, including arrhythmia, venous thromboembolism, and ileus, which may be related to the increased operative time associated with multiple excisions.

While the use of fewer excisions may decrease postoperative morbidity, it also may sacrifice greater healthy parenchyma and consequently impair functional outcomes. ¹⁹ Radical nephrectomy is an extreme example of this tradeoff. Thus, the morbidity associated with an additional excision must be weighed against the benefits of parenchymal preservation. Although RPN for ISM was associated with a higher risk of complications, in experienced hands, most complications were minor. Therefore, we believe that radical nephrectomy should be avoided, if at all possible, especially in those with strong indications for nephron sparing (i.e., solitary kidney or chronic kidney disease, or hereditary kidney cancer). Given the fact that PN outcomes are heavily influenced by case volume, the use RPN for ISM is probably best reserved for high-volume surgeons who have experience with complex or multiple tumor PN. ²⁰

Cross-sectional imaging is well suited for characterizing the size and complexity of unifocal renal masses, but it may be inadequate for assessing ISM burden and its associated morbidity. ¹¹ In fact, cross-sectional imaging misses up to 75% of satellite lesions, which are better visualized on intraoperative ultrasound. ^21,22 Hence, the surgical plan, in terms of the number and extent of excisions, may not be known until the kidney is examined intraoperatively. For example, adjacent masses may be amenable to a single excision, whereas disjointed masses may require separate excisions. Therefore, the failure to detect a difference in complications based on clinical assessment of mass burden is not surprising given the tendency of preoperative imaging to underestimate true mass burden, and in our series, correlate poorly with actual number of excisions performed.

Despite its limitations, diagnostic imaging is still the mainstay of surgical planning. Unfortunately, a standardized protocol for characterizing and reporting ISM based on preoperative imaging does not currently exist. Since the number of excisions rather than the number of masses seem to determine surgical morbidity, a clinical proxy for the number of mass excisions eventually performed is needed. Developing a standardized system for preoperative ISM reporting may be useful. Several factors would be important to consider, including the number and size of ipsilateral renal masses, the proximity of one mass to another, and the likelihood of having to perform one excision versus multiple.

ISM may be present in 5%–25% of cases of sporadic RCC. ^{1 –3} Based on the treatment of familial RCC, it is generally accepted that all detectable solid lesions within the renal unit should undergo PN at the time of treating the primary lesion to limit the number of future renal surgeries. ²³ However, unlike familial RCC, for which tumor enucleation is routinely performed, most sporadic cases are still managed with excisional PN. In light of the increased morbidity associated with multiple excisions, this practice may warrant reconsideration, especially given alternative management options. Aside from enucleation, thermal ablation and active surveillance may decrease surgical morbidity by avoiding surgical excision altogether, although with slightly higher oncologic risk. ^4,24,25

The main limitations of our study include its retrospective design, relatively small number of ISM cases, inclusion of somewhat historic data, and potential lack of generalizability. Although this is one of the largest series of ISM, the study may have benefited from even more cases. Furthermore, the study period spanned 9 years; therefore, changes in technique and/or experience over time may have influenced outcomes. Although we tried to adjust for surgeon experience in our analysis, this adjustment may have been insufficient to account for subtle changes in surgical technique and experience over time. In terms of external validity, all surgeries were performed robotically at a single high-volume center; thus, our results may not apply to open surgery or lower volume institutions. It is also important to mention that R.E.N.A.L. score is not validated for use in the setting of ISM; therefore, our decision to report the R.E.N.A.L. score for the most complex mass, if multiple masses were present, was not evidence based. Nonetheless, R.E.N.A.L. score did predict postoperative complications, giving credence to this approach. Furthermore, after adjusting for the R.E.N.A.L. score of the primary lesion, excisional burden was an independent predictor of complications, emphasizing the need for better preoperative ISM characterization. Finally, three or more excisions predicted complications after RPN, whereas two or more excisions did not, suggesting that further investigation is needed to further clarify the morbidity risk of excisional burden.

Conclusions

Multiple mass excisions increase the risk of postoperative complications after RPN. In the future, preoperative assessment of excisional burden may help inform treatment decisions.

Author Disclosure Statement

Dr. Kaouk is a consultant for Endocare, Inc. Dr. Kara and Dr. Malcoç were supported by a grant for life expenses from TUBITAK: Technology and Innovation Support Programs, Directorate of the Scientific and Research Council of Turkey.