Utility of Intraoperative Frozen Section During Robot-Assisted Partial Nephrectomy: A Single Institution Experience

Abstract

Background and Purpose:

Intraoperative frozen section (FS) analysis has been regarded as a paramount tool for immediate evaluation of tumor margin status during partial nephrectomy procedures. The aim of this study was to assess the utility of FS during robot-assisted partial nephrectomy (RAPN).

Patients and Methods:

A retrospective review of our Institutional Review Board-approved prospectively maintained minimally invasive partial nephrectomy database yielded 342 consecutive RAPN procedures from June 2007 to September 2011. Of these, the initial 128 cases underwent FS evaluation, whereas the following 214 cases did not. Patient demographics, perioperative outcomes, and final pathology results were analyzed and compared between the two groups.

Results:

Body mass index, Charleson Comorbidity Index, tumor size, renal score, preoperative creatinine level, and estimated glomerular filtration rate (eGFR) were similar between both groups. Operative time was significantly longer in the no-FS group (193 vs 180 min; P=0.04). Warm ischemia time (median 19 vs 19 min), estimated blood loss (150 vs 200 mL), postoperative creatinine level (1.0 vs 1.1 mg/dL), and postoperative eGFR (75.6 vs 75.9) were similar between the no-FS group and FS group, respectively. Complications occurred in 32 (15.0%) and 31 (24.2%) cases in no-FS and FS, respectively (P=0.06). Final pathology results demonstrated seven cases of positive margins, 1 (1%), in the FS group and 6 (3%) in the no-FS group (P=0.19). Of the cases with positive margins at final pathology analysis, a R.E.N.A.L. score of 3/3 was found on closeness to renal sinus. Overall, three intraoperative positive margins were noted in the FS group (2.3%): One patient underwent radical nephrectomy and one reresection; one case was managed with observation only.

Conclusion:

Routine application of FS analysis during RAPN seems to provide a limited benefit. FS might be advisable for tumors with sinus invasion because they seem to carry a higher likelihood of positive surgical margin at final pathology determination.

Introduction

A paradigm shift has occurred in the surgical management of renal tumors with nephron-sparing surgery replacing nephrectomy as the standard approach over the last decade.¹ Among the minimally invasive nephron-sparing approaches, robot-assisted partial nephrectomy (RAPN) is becoming increasingly popular, with reported encouraging outcomes for a wide range of surgical indications.^2

–6 Whether an open, laparoscopic, or robotic approach to partial nephrectomy (PN) is applied, the risk of incomplete resection of tumor remains a key issue during any PN procedure. Intraoperative frozen section (FS) of the tumor bed has been traditionally proposed to alleviate concerns of incomplete resection,^7,8 but its routine use has been questioned because it can be associated with increased costs and time without any clear advantage.^9,10 The aim of this study was to assess the usefulness of FS during RAPN.

Patients and Methods

Study population

A retrospective review of our Institutional Review Board-approved prospectively maintained minimally invasive PN database yielded 342 consecutive RAPN procedures from June 2007 to September 2011. Of these, the initial 128 cases underwent FS evaluation; the following 214 cases did not. Patient demographics, perioperative outcomes, and final pathology results were analyzed and compared between the two groups.

Surgical technique

The surgical technique for RAPN has been described.^2,11 In summary, after insertion of ports in our standard configuration, the robot is docked over the shoulder of the patient. The colon is mobilized, followed by identification and dissection of the renal hilum. Bulldog clamps are placed on the renal artery and vein after 12.5 g of mannitol is administered. The tumor is resected followed by renorrhaphy using a horizontal sliding clip technique. Bulldog clamps are then removed and the specimen is extracted and sent for pathologic review.

Two techniques of FS have been applied. The majority of our patients had FS performed after the renorrhaphy was completed. At that time, the mass was taken to the pathologist who analyzed the specimen by inking capsular, parenchymal, and hilar margins of the mass en bloc. In selected cases, a standard frozen section analysis of the resection bed was performed before completion of the renorrhaphy. In both cases, final pathology results were based on subsequent histologic examination.

Follow-up

Oncologic follow-up consisted of CT or MRI and chest radiography at 6 months to a year followed by yearly imaging. Recurrence was defined as radiologically verified local recurrence or progression to nodal or metastic disease during the study period. Estimating the glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease study equation assessed renal function.¹² Postoperative complications were graded according the Clavien-Dindo classification.

Analysis

Data were presented as means or medians with standard deviation or interquartile range, respectively. Percentages or proportions represented counts or frequencies. For continuous variables, an independent samples t test was used. Categorical variables were analyzed using a chi-square test or Fisher exact test.

Results

Baseline characteristics

Overall, 342 procedures were included in this analysis: 214 in the no-FS group and 128 in the FS group (Table 1). Median patient age was 57 (49–65) and 61 (54–68) in the no-FS and FS groups, respectively, (P<0.002). The two groups were comparable for preoperative renal function, Charlson Comorbidity Index, body mass index, and sex. There was no significant difference in terms of median tumor size (3.0 and 2.6 cm, P=0.32) as well as nephrometry score 7 versus 7 in no-FS and FS, respectively. The median American Society of Anesthesiologists (ASA) score was 3 (2,3) in the no-FS group and 2 (2,3) in the FS group, demonstrating a significantly higher ASA score in the no-FS group.

Table 1.

Baseline Demographics

		No frozen (n=214)					Frozen (n=128)
	n	Mean	SD	Median	IQR	n	Mean	SD	Median	IQR	P value
Sex											0.41
Male		119 (55.6)					77 (60.2)
Female		95 (44.4)					51 (39.8)
Age	214	57	(12)	57	(49–65)	128	61	(12)	61	(54–68)	0.002
BMI	214	30.9	(7.6)	29.6	(26.1–34.3)	128	30.3	(6.1)	28.8	(26.2–33.9)	0.456
ASA	213	3	(1)	3	(2–3)	127	2	(1)	2	(2–3)	0.003
CCI	197	4	(2)	4	(3–5)	126	4	(2)	4	(3–5)	0.813
Tumor_size_	162	3.3	(1.6)	3.0	(2.1–4.0)	126	3.1	(1.7)	2.6	(2.0–3.5)	0.324
R.E.N.A.L._score	183	7.2	(2)	7	(5–9)	97	7.2	(1.9)	7	(5–9)	0.850
Preoperative creatinine	214	1.0	(0.3)	0.9	(0.8–1.1)	128	1.0	(0.3)	0.9	(0.8–1.1)	0.486
Preoperative GFR	214	86.7	(36.3)	85.5	(71.5–98.6)	128	82.1	(23.0)	83.3	(67.6–95.5)	0.194

Values expressed as mean (SD) or median (IQR) unless otherwise specified.

BMI=body mass index; ASA=American Society of Anesthesiologists; CCI=Charlson Comorbidity Index; R.E.N.A.L.=radius; exophytic/endophytic; nearness; anterior/posterior; location; GFR=glomerular filtration rate.

Perioperative outcomes

Median operative time was longer in the no-FS group (193 vs 180 min; P=0.04) (Table 2). No significant difference existed in median warm ischemia time (WIT) (19 vs 19 min, P=0.36), estimated blood loss (150 mL vs 200 mL, P=0.18), and conversions to open surgery (2 vs 0, P=0.12) in no-FS and FS, respectively.

Table 2.

Perioperative Outcomes

	No frozen (n=214)	Frozen (n=128)	P value
Positive surgical margin, n (%)	6 (0.03)	1 (0.01)	0.19
Operative time, min			0.042
Mean (SD)	200 (61)	185 (42)
Median (IQR)	193 (150–240)	180 (150–200)
WIT, min			0.355
Mean (SD)	19 (11)	18 (12)
Median (IQR)	19 (14–25)	19 (13–26)
EBL, mL			0.176
Mean (SD)	240 (271)	280 (251)
Median (IQR)	150 (100–275)	200 (100–300)
Postoperative serum creatinine (1 month)			0.863
Mean (SD)	1.1 (0.3)	1 (0.4)
Median (IQR)	1.0 (0.8–1.2)	1.0 (0.8–1.2)
Postoperative eGFR (1 month)			0.933
Mean (SD)	75.6 (22.5)	75.9 (22.9)
Median (IQR)	77.2 (58.2–89)	74.7 (62.7–87.3)
Follow-up, months			0.000
Mean (SD)	5.0 (5.0)	13.4 (13)
Median (IQR)	3.0 (1.2–7.4)	11.2 (1.3–19.9)
Complications, n (%)	32 (15)	31 (24.2)	0.03

SD=standard deviation; IQR=interquartile range; WIT=warm ischemia time; EBL=estimated blood loss; eGFR=estimated glomerular filtration rate.

Postoperative outcomes

Postoperative complications for both groups are listed in Table 3 using the Clavien-Dindo classification system. There was a significant difference in complication rates among the FS and no-FS groups, 24% (n=31) vs 15% (n=32), respectively (P=0.03). There were three positive intraoperative margins in the FS group. Nephrectomy was performed in one patient with clear-cell carcinoma on FS analysis followed by reresection in another patient with chromophobe renal-cell carcinoma. The third patient was observed because pathology results demonstrated oncocytoma. Final pathology determination for all three positive FS were residual clear-cell carcinoma in the nephrectomy specimen, chromophobe renal-cell carcinoma in the reresection patient, and oncocytoma. There was one patient with a negative FS that demonstrated clear-cell carcinoma at the parenchymal margin of resection. This patient had bilateral renal tumors with negative margins on the first PN performed 3 months earlier.

Table 3.

Postoperative Complications in this Study Population

Clavien grade	Frozen section (n=128)	No-frozen section (n=214)
I	6 (urine leak, ileus, lymph leak, transient increase in creatinine)	11 (atelectasis, urinary retention, transient elevation in creatinine, postoperative ileus),
II	20 (transfusion [17], oxygen dependent, PE [2])	18 (transfusion [16], permanent O₂ dependence)
IIIa	5 (PE/filter cava [1], angio-embolization [3], hernia)	3 (DVT/filter cava, delayed bleeding/embolization, urine leak with stent insertion)
IVa	0	0

PE=pulmonary embolism; DVT=deep venous thrombosis.

In the no-FS group, final pathology results showed six positive surgical margins. Pathology included clear-cell carcinoma (2), chromophobe (2), angiomyolipoma (1), and papillary (1). At a median follow-up of 8 months (7.6, 9.5), there were no recurrences. One death occurred in the no-FS group secondary to a cardiac event 6 months after surgery.

The FS group had five deaths at a median of 22 months postoperatively. Deaths were secondary to cardiopulmonary events (3), cancer recurrence in the peritoneum (1), and unknown causes (1). Recurrence in the FS group occurred 12 months after surgery.

Moreover, there was a tendency for positive margin cases to have a nephrometry score of 3 on the “nearness of the tumor to the renal sinus” component of the R.E.N.A.L. (radius; exophytic/endophytic; nearness; anterior/posterior; location) system. This was observed in 83% (n=5) of the no-FS group patients, and in all four patients with positive margins in the FS group (three intraoperative and one at final pathology results).

Discussion

RAPN as a surgical treatment for renal masses is becoming a more commonly performed procedure among urologists. Dogmatic components of surgery include oncologic control, renal functional preservation, low morbidity, and fast convalescence. Limiting WIT has been an instrumental cornerstone of renal functional preservation during PN; however, oncologic control remains the primary goal for all renal cancer surgery.¹³

To ensure oncologic success of extirpative renal surgery for renal masses, margin status has been used as an early surrogate for identifying an effective operation. FS during PN has been the primary perioperative intervention implemented to determine real time oncologic success of the PN.¹⁴

There are two approaches of FS used at our institution. The primary technique involves an en-bloc tumor analysis, and pathologic interpretation in this case results in delayed knowledge, possibly minimizing the benefit of the analysis. It can be important for the surgeon, however, especially at the beginning of the surgical experience, to have a timely confirmation from the pathologist about the margin status when there are some uncertainties about the gross appearance of the mass.

On the other hand, with a pathologic analysis performed from the resection bed, according to our second technique, there is no evidence suggesting that this approach might ultimately result in a reduction of the final positive margin rate.¹⁵

Our series confirms the lack of benefit of a routine FS analysis, as shown by the similar final positive surgical margin rates between the two study groups (P=0.19). The low yield of positive margins with intraoperative FS, constraints of WIT, additional cost, and limited long-term benefit have questioned the utility of FS analysis as a standard to nephron-sparing surgery.^7,10,16

In our series, we attempt to determine the benefit of FS during nephron-sparing surgery in a comparison with a contemporary cohort of patients who did not have FS performed. The main rationale for incorporating intraoperative FS is minimizing the risk of postoperative positive surgical margins. One (1%) patient in the FS group had positive surgical margins after a negative intraoperative biopsy. Long-term oncologic impact from a single positive margin appears to be not significant based on recent series.^17,18 Moreover, the accuracy of intraoperative FS is unreliable secondary to a small fraction of the resection bed being biopsied along with insufficient tissue fragments being analyzed.^19,20 In our series, there was a positive FS rate of 3%, exemplifying the minimal yield from routine biopsy.

In an era of cost-benefits, justification for routinely performing FS is difficult. Kubinski and colleagues¹⁰ provided insight into the cost of each frozen section with charges often exceeding $1000.¹⁰ Nevertheless, there was an observation in our study that all patients with postoperative positive margins had sinus or collecting system invasion preoperative imaging, suggesting a role for intraoperative FS in this unique situation.

In the no-FS patients in our group, six positive margins occurred revealing a positive margin rate of 2.8% that is consistent with data from other centers.^2,21 Recurrence of disease did not develop in any patient at a median follow-up of 8 months (7.6, 9.5). Clinical consequences in our short oncologic follow-up for the positive margins are absent, and with the current literature suggesting that disease recurrence with positive margins is rare, FS yield is inconsequential.^17,18

Limitations of this study include the short follow-up, not allowing reliable oncologic assessment, retrospective study design, and the lack of a cost analysis.

Conclusion

Our findings suggest that routine application of FS analysis during RAPN seems to be of limited benefit. FS might be advisable for tumors with sinus invasion, however, because they seem to carry a higher likelihood of positive surgical margin at final pathology determination.

Footnotes

Disclosure Statement

Robert Stein is a consultant for Applied, Georges Pascal Haber is a consultant for Intuitive, and Jihad Kaouk is a consultant for Intuitive, Covedian, and Johnson and Johnson. For all other authors, no competing financial interests exist.

Abbreviations Used

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