Surgeons’ preferences and practice patterns regarding intraoperative frozen section during partial nephrectomy

Surgeons’ preferences and practice patterns regarding intraoperative frozen section during partial nephrectomy

Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎ Original article Surgeons’ preferences and practice patterns regarding intr...

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Urologic Oncology: Seminars and Original Investigations ] (2014) ∎∎∎–∎∎∎

Original article

Surgeons’ preferences and practice patterns regarding intraoperative frozen section during partial nephrectomy Abhinav Sidana, M.D.*, James F. Donovan, M.D., Krishnanath Gaitonde, M.D. Division of Urology, University of Cincinnati College of Medicine, Cincinnati, OH Received 8 January 2014; received in revised form 14 February 2014; accepted 15 February 2014

Abstract Purpose: Intraoperative frozen section (FS) evaluation for tumor margin during partial nephrectomy (PN) is a matter of controversy in urologic oncology. We evaluated the preferences and practice patterns of urologists regarding intraoperative FS during PN. Methods: A 17-item questionnaire was designed to collect information on surgeons’ preferences and practice patterns regarding FS during PN. The survey was sent to the members of the Society of Urologic Oncology and Endourological Society. Results: A total of 197 responses were received. Overall, 69% and 58% of respondents chose to obtain FS (always or sometimes) during open PN (OPN) and laparoscopic PN (LPN), respectively. There was a strong correlation between the surgeons’ preferences during OPN and LPN. Younger surgeons are less likely to obtain FS during OPN. For surgeons who did not routinely obtain FS, “confidence about complete resection” was the most common reason (79%), followed by “no change in management with positive margins” (35%). Most surgeons (75%) believed the margins to be negative, if surgical margin was free of tumor microscopically by a single cell layer. Older surgeons considered negative margins to be free of tumor microscopically by Z5 mm. Overall, 54% and 42% of respondents would repeat FS for positive microscopic margins during OPN and LPN, respectively. Of the respondents, 95% would not recommend additional treatment for positive margins on final pathology. Conclusion: Despite recent literature pointing to low clinical utility of FS, most surgeons still obtain FS during PN. Older surgeons tend to obtain FS more often. Fellowship training and practice type do not appear to influence preferences and practice patterns in regard to FS. r 2014 Elsevier Inc. All rights reserved.

Keywords: Frozen section; Partial nephrectomy; Surgical margins; Renal cell cancer

1. Introduction Nephron-sparing surgery for renal cell carcinoma has been the procedure of choice for renal tumors less than 4 cm in size and is increasingly being used for larger tumors provided an adequate surgical margin is obtained safely [1]. The risk of incomplete tumor removal, however, is a matter of concern with partial nephrectomy (PN) [2]. Traditionally, a 1-cm rim of normal parenchyma was considered adequate margin [3]. However, several studies, indicate that any negative margin is adequate for cancer control as long as tumor is completely excised [4,5]. To ensure negative margins, intraoperative frozen section (FS) analysis of resected tumor is commonly obtained. Corresponding author. Tel.: þ1-513-558-0983. E-mail address: [email protected] (A. Sidana). *

http://dx.doi.org/10.1016/j.urolonc.2014.02.015 1078-1439/r 2014 Elsevier Inc. All rights reserved.

Positive margins on FS are usually followed by resection of more tissue or complete nephrectomy. The practice of obtaining FS is widespread throughout United States. In a study, evaluating partial nephrectomies from 1991 to 2002, intraoperative FS was obtained in 54% of the cases [6]. However, several studies have shown that FS analysis has its own diagnostic pitfalls, resulting in inaccurate or inconclusive results that do not correlate well with the final pathology [7–9]. These studies have questioned the utility of FS analysis during PN and have recommended against its routine use during PN [10,11]. We evaluate the preferences and practice patterns of urologists pertaining to intraoperative FS during PN using a survey-based study. Through this survey, we have also assessed the attitude of urologists regarding surgical margins and their management preferences in presence of positive margins.

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2. Methods

Table 1 Characteristic of the respondents

2.1. Survey After reviewing the available literature on the subject, a 17-item questionnaire was designed to collect information on surgeons’ preferences and practice patterns regarding FS during open PN (OPN) and laparoscopic PN (LPN) (pure laparoscopy or robot-assisted laparoscopy). Institutional review board determined that the study did not involve human subjects. Information was obtained on the respondents’ age, practice type, number of partial nephrectomies performed annually, preferred surgical approach, and fellowship training. The survey was sent through email to the members of the Society of Urologic Oncology and the Endourological Society. The email accompanying the survey requested the urologists to participate if they were performing partial nephrectomies. Approximately 4,000 members of the Endourological Society and 632 members of the Society of Urologic Oncology received requests for the study. As both the societies have heterogeneous member population (nonclinicians, residents, etc.), an unknown number of recipients qualified for the study, and therefore the response rate could not be accurately calculated. The responses were automatically collected in an Excel sheet. 2.2. Statistics Data were analyzed using SPSS (Statistical Package for Social Sciences) version 17 (Chicago, IL). Some questions (e.g., related to specific surgical approach or practice pattern) did not pertain to all the respondents and had an additional option of “not applicable.” “Not applicable” responses were excluded from the analysis of that particular question and were treated as missing value. Chi-square tests were run to compare proportions. Univariate and multivariate logistic regression (binomial and ordinal) analysis was done to identify the predictors determining the surgeon’s preferences and practice patterns in regard to FS analysis. Significance of the results was accepted at P o 0.05. 3. Results A total of 197 responses were received. Characteristics of the respondents are depicted in Table 1. A higher percentage of surgeons older than 50 years performed OPN only (38% vs. 6%, P o 0.001). Overall, 50% of respondents practicing in an academic setting were fellowship trained, whereas only 34% in a nonacademic setting were fellowship trained (P ¼ 0.051). Surgeons in an academic setting (44% vs. 26%, P ¼ 0.028) and fellowship-trained surgeons (46% vs. 32%, P ¼ 0.044) were more likely to do 25 or more partial nephrectomies in a year. Open surgeons performed fewer PNs annually than surgeons who performed LPN only or both OPN and LPN (P ¼ 0.003).

n (%) Age (n ¼ 194) o40 y 40–49 y 50–59 y 60 y or older

79 62 33 20

(40.7) (32.0) (17.0) (10.3)

Practice type (n ¼ 195) Academic Nonacademic

148 (75.9) 47 (24.1)

Fellowship trained in urologic oncology (n ¼ 195) Yes No

91 (46.7) 104 (53.3)

No. of partial nephrectomies annually (n ¼ 195) o10 10–25 26–50 450 Approach (n ¼ 196) Open Laparoscopic (with or without robotic assistance) Both Section of AUA (n ¼ 197) Northeastern New England New York Mid-Atlantic Southeastern North central South central Western

47 72 53 23

(24.1) (36.9) (27.2) (11.8)

29 (14.8) 47 (24.0) 120 (61.2) 51 15 11 12 29 36 19 24

(25.9) (7.6) (5.6) (6.1) (14.7) (18.3) (9.6) (12.2)

4. Surgeons’ preferences and practice regarding FS during PN Responses to questions evaluating surgeons’ preferences regarding FS are summarized in Table 2. Only 31.5% and 42.1% of the respondents chose “never” to obtain FS during OPN and LPN, respectively. There was a significant correlation between surgeons’ preferences during OPN and LPN (P o 0.001). On univariate ordinal regression, surgeon’s age (P o 0.001) and surgical approach (P ¼ 0.001) predicted surgeon’s preference to obtain FS during OPN. On multivariate analysis, only age was found to be a significant predictor (odds ratio [OR] ¼ 2.80; 95% CI: 1.42–5.52; P ¼ 0.003) with surgeons older than 50 years, who were 2.8 times more likely to choose “always” than rest of the choices and 2.8 times more likely to choose “more than 50% of time” then the combination of “never” and “less than 50% of the time.” Practice type, fellowship training, section of AUA, and number of PNs performed annually were not significantly associated with preference to obtain FS during OPN on multivariate analysis. No predictors dictating surgeons’ preferences during LPN were identified on multivariate analysis.

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Tumor bed fulguration after resection (n ¼ 195) Yes

89 (45.6)

Additional specimen from tumor bed for frozen section analysis (n ¼ 194) Yes

53 (27.3)

Vascular occlusion until pathology report is complete during OPN (n ¼ 127) Yes

21 (16.5)

“confidence about complete resection” as their reason not to obtain FS (OR ¼ 3.21; 95% CI: 1.12–9.21; P ¼ 0.030). When asked, what they considered negative margins; majority (75%) believed the margins to be negative if surgical margin was free of tumor microscopically by a single cell layer. On univariate analysis, surgeon’s older than 50 years (P ¼ 0.001) and open-only approach (P ¼ 0.004) were significantly associated with choosing “5 mm or more of normal parenchyma around tumor” as definition of negative margin. On multivariate analysis, only age was found to be a significant factor. Surgeons older than 50 years were around 3.5 times more likely to consider negative margins if there was “5 mm or more of normal parenchyma around tumor” (OR ¼ 3.69; 95% CI: 1.25–10.91; P ¼ 0.018), whereas younger surgeons considered negative margin to be “free of tumor microscopically by a single cell layer.” Only half of the respondents stated that they fulgurate the tumor bed after resection. Number of PNs performed annually by a surgeon was the significant predictor for tendency to fulgurate the tumor bed. Surgeons who perform less than 25 PNs were 2 times more likely to fulgurate the tumor bed after resection (OR ¼ 1.97; 95% CI: 1.09–3.57; P ¼ 0.025). Overall, 27% of the respondents send an additional specimen from tumor bed for FS analysis. Surgeon’s age (OR ¼ 3.39; 95% CI: 1.67–6.92; P ¼ 0.01) and number of PNs performed annually by the surgeon (OR ¼ 2.56; 95% CI: 1.30–5.05; P ¼ 0.007) were significant predictors of the aforementioned practice pattern. Majority (approximately 84%) of surgeons do not continue vascular occlusion while waiting for results of the FS analysis regardless of the surgical approach.

Vascular occlusion until pathology report is complete during LPN (n ¼ 110) Yes

18 (16.4)

5. Positive margins

Table 2 Participants' responses to survey questions n (%) Frozen section during OPN? (n ¼ 184) Never Less than 50% of time More than 50% of time Always

58 58 20 48

(31.5) (31.5) (10.9) (26.1)

Frozen section during LPN? (n ¼ 171) Never Less than 50% of time More than 50% of time Always

72 45 21 33

(42.1) (26.3) (12.3) (19.3)

Reasons for not obtaining routine frozen section (n ¼ 124) Frozen sections are not accurate Positive margin will not change my management I am usually confident that I have completely resected the tumor Facilities for intraoperative frozen section are not available What do you consider negative margin? (n ¼ 195) When surgical margin is grossly free of tumor When surgical margin is free of tumor microscopically by one cell layer When surgical margin is free of tumor microscopically by Z5 mm

During OPN, what action would you take if the microscopic margins are positive? (n ¼ 149) Continue with renorrhapy Resect more tissue from the tumor bed but will not send it for frozen section Resect more tissue from the tumor bed and repeat frozen section Proceed to complete nephrectomy During LPN, what action would you take if the microscopic margins are positive? (n ¼ 115) Continue with renorrhapy Resect more tissue from the tumor bed but will not send it for frozen section Resect more tissue from the tumor bed and repeat frozen section Proceed to complete nephrectomy

38 (30.6) 43 (34.7) 98 (79.0) 6 (4.8) 28 (14.4) 147 (75.4) 20 (10.3)

15 (10.1) 46 (30.9) 81 (54.4) 7 (4.7)

20 (17.4) 38 (33.0) 48 (41.7) 9 (7.8)

For surgeons who did not routinely obtain FS, “confidence about complete resection” was the most common reason (79%), followed by “no change in management with positive margins” (35%). Surgeons who did more than 25 PNs annually were 3 times more likely to choose

Respondents were asked how they would respond in case of positive microscopic margins on FS analysis. Options ranged from doing nothing and continuing with renorrhaphy to complete nephrectomy (Table 2). Overall, 54% and 42% of respondents stated that they would repeat FS for positive microscopic margins during OPN and LPN, respectively. On multivariate analysis, surgeons older than 50 years (OR ¼ 3.49; 95% CI: 1.36–8.97; P ¼ 0.010) and absence of fellowship training (OR 2.93; 95% CI: 1.38– 6.24; P ¼ 0.005) were predictors of a more conservative approach during OPN (i.e., repeating FS or complete nephrectomy). No significant predictors were identified in case of positive margins during LPN. A total of 82 (41.8%) surgeons would follow positive surgical margins on final pathology by imaging at standard intervals, whereas 105 (53.6%) would obtain more frequent imaging. Only 9 (4.6%) would recommend complete nephrectomy to the patients. No surgeons recommended adjuvant therapy (systemic therapy or radiation) for management of positive surgical margins.

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6. Discussion The efficacy of PN in localized renal cancer has been well documented with cancer-specific survival rates comparable to radical nephrectomy while offering an added advantage of renal function preservation [2,12,13]. The major disadvantage of PN, though, is increased risk of local recurrence owing to microscopic foci of residual tumor at the resection site [2]. To decrease the risk of local recurrence on tumor bed, recommended excision of tumor with 1-cm normal parenchymal margins [3]. A host of studies in the last 2 decades has refuted that recommendation and has shown excellent oncological outcome with margins much smaller than 1 cm. These studies have demonstrated that any negative margin will suffice to achieve good oncological outcome as long as the tumor is completely excised [4,5]. Therefore, to ensure complete resection, intraoperative pathologic evaluation of the margins of the specimen is routinely obtained. This practice is a matter of controversy in urologic oncology. First, the accuracy of margin evaluation during FS analysis is poor, with most of positive margins not reconfirmed at the final pathologic evaluation [9,11,14]. Normal constituents of renal parenchyma with crush-and-freeze artifacts can pose a diagnostic dilemma and might be interpreted as neoplasia [9]. In addition, the results of FS analysis have minimal effect on surgical approach and long-term cancer-specific survival [11]. Kubinski et al. [8] concluded that FS analysis may prove to be an unnecessary expense without providing meaningful and reliable information. They recommended against obtaining FS as long as a rim of grossly normal parenchyma is excised with the tumor. Marszalek et al. [15] also concluded that routine FS analysis delivers no additional information of clinical significance. Despite presence of adequate literature showing no efficacy and low utility of FS analysis for margin evaluation, the practice of obtaining FS during PN is widespread. In this study, we evaluated the attitude, preferences, and practice patterns of surgeons in regard to FS analysis during PN. In our study, more than a half of the respondents still obtain FS during PN (sometimes or always). Older surgeons tend to obtain FS more often than younger surgeons. This could be owing to difficulty in modifying the established practice pattern despite recent literature pointing to low clinical utility of intraoperative pathologic consultation. Also, older surgeons still believed in obtaining greater than 5 mm of normal renal parenchyma for adequate resection, whereas younger surgeons considered even a single cell layer of normal parenchyma as negative margins. More respondents tend to obtain FS during OPN than LPN. In our study, younger surgeons were found to perform LPN more often than older surgeons (94% of surgeons younger than 50 years performed either LPN only or both LPN and OPN, whereas only 62% of the surgeons older than 50 years fell in that category). Despite the difference in age distribution in different approaches, age was not a significant factor on

regression analysis of LPN preferences. It can only be assumed that lower percentage of surgeons obtain FS during LPN owing to increased time consumption and technical difficulty. Timsit et al. [16] demonstrated good concordance between surgeon’s intraoperative assessments and the final histologic diagnosis, recommending FS analysis only when surgeon is doubtful about margin status. In our study, the surgeons who do not routinely obtain FS cited “confidence about resection” as the most common reason for not obtaining FS, which falls in line with the conclusion drawn by Timsit et al. Surgeon’s experience played a part in deciding what is adequate resection as the surgeons who were doing more than 25 PNs annually chose “confidence about resection” more often than surgeons with lower volume. Tumor bed fulguration after resection of tumor is usually done with intent to aid in hemostasis. It can potentially result in destruction of microscopic tumor foci in the bed, resulting in lower recurrences. In our study, surgeons with lower case volumes fulgurate tumor bed more often though it is unclear whether tumor bed fulguration is performed for oncological control or for hemostasis. Tumor bed biopsy represents a small fraction of resection margin and, in general, delivers unreliable results. Hagemann and Lewis [17] demonstrated a combination of FS analysis of resection specimen and tumor bed biopsy to be more sensitive than either method alone. In our study, only 27% of the surgeons send an additional specimen from tumor bed. Older surgeons and surgeons with higher case volumes are more likely to send tumor bed biopsy for pathological analysis. Overall, 54% and 42% of the respondents who choose to obtain intraoperative FS will repeat FS in case of positive margins during OPN and LPN, respectively. Only a minority (10% during OPN and 17% during LPN) will ignore the results of FS and continue with renorrhaphy. Older surgeons and surgeons not fellowship trained in urologic oncology tend to have a more conservative approach (repeating FS or complete nephrectomy) in dealing with positive margins on FS analysis. This could be owing to ignorance of recent literature or inability to change established practice patterns. Positive surgical margins after PN are rare. Yossepowitch et al. [18] reviewed outcomes in 77 (of 1,344 PNs) patients with positive surgical margins and did not find increased local recurrence or metastatic progression in 10 years of follow-up. Their results were supported by other smaller studies [14,15]. Overall, 95% of the surgeons in our study stated that they would manage positive margins on final pathology by active surveillance and not resort to adjuvant treatment or complete nephrectomy. The limitation of the present study is evident in the survey format implying reporting bias. In addition, we lack the information on nonrespondents. The survey might have appealed more to surgeons who were more cognizant of this controversy than general urologists who perform PN. Despite these limitations, we believe this study provides valuable information about the practice trends of the

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urologists regarding intraoperative FS. Although the value of routine FSs has been shown to be low, further research to determine specific scenarios where this modality may prove more beneficial and guide intraoperative management of patients should be undertaken. 7. Conclusion Despite recent literature pointing to low clinical utility of routine intraoperative FS analysis, more than half of the surgeons still opt for intraoperative FS. Surgeon’s age, fellowship training, and surgical volume influence preferences and practice pattern in regard to FS analysis to some extent. Surgical approach, practice setting, and region of practice do not appear to dictate a surgeon’s preferences in regard to intraoperative FS during PN. References [1] Fergany AF, Hafez KS, Novick AC. Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year followup. J Urol 2000;163:442–5. [2] Lau WK, Blute ML, Weaver AL, Torres VE, Zincke H. Matched comparison of radical nephrectomy vs nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc 2000;75:1236–42. [3] Vermooten V. Indications for conservative surgery in certain renal tumors: a study based on the growth pattern of the cell carcinoma. J Urol 1950;64:200–8. [4] Berdjis N, Hakenberg OW, Zastrow S, Oehlschlager S, Novotny V, Wirth MP. Impact of resection margin status after nephron-sparing surgery for renal cell carcinoma. BJU Int 2006;97:1208–10. [5] Lam JS, Bergman J, Breda A, Schulam PG. Importance of surgical margins in the management of renal cell carcinoma. Nat Clin Pract Urol 2008;5:308–17.

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[6] Miller DC, Shah RB, Bruhn A, Madison R, Saigal CS. Trends in the use of gross and frozen section pathological consultations during partial or radical nephrectomy for renal cell carcinoma. J Urol 2008;179:461–7:[discussion 7]. [7] Hillyer SP, Yakoubi R, Autorino R, et al. Utility of intraoperative frozen section during robot-assisted partial nephrectomy: a single institution experience. J Endourol 2013;27:324–7. [8] Kubinski DJ, Clark PE, Assimos DG, Hall MC. Utility of frozen section analysis of resection margins during partial nephrectomy. Urology 2004;64:31–4. [9] McHale T, Malkowicz SB, Tomaszewski JE, Genega EM. Potential pitfalls in the frozen section evaluation of parenchymal margins in nephron-sparing surgery. Am J Clin Pathol 2002;118:903–10. [10] Sterious SN, Simhan J, Smaldone MC, et al. Is there a benefit to frozen section analysis at the time of partial nephrectomy? Can J Urol 2013;20:6778–84. [11] Duvdevani M, Laufer M, Kastin A, et al. Is frozen section analysis in nephron sparing surgery necessary? A clinicopathological study of 301 cases. J Urol 2005;173:385–7. [12] Lerner SE, Hawkins CA, Blute ML, et al. Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol 1996;155:1868–73. [13] Herr HW. Partial nephrectomy for unilateral renal carcinoma and a normal contralateral kidney: 10-year followup. J Urol 1999;161:33–4: [discussion 4-5]. [14] Raz O, Mendlovic S, Shilo Y, et al. Positive surgical margins with renal cell carcinoma have a limited influence on long-term oncological outcomes of nephron sparing surgery. Urology 2010;75:277–80. [15] Marszalek M, Carini M, Chlosta P, et al. Positive surgical margins after nephron-sparing surgery. Eur Urol 2012;61:757–63. [16] Timsit MO, Bazin JP, Thiounn N, et al. Prospective study of safety margins in partial nephrectomy: intraoperative assessment and contribution of frozen section analysis. Urology 2006;67:923–6. [17] Hagemann IS, Lewis JS Jr. A retrospective comparison of 2 methods of intraoperative margin evaluation during partial nephrectomy. J Urol 2009;181:500–5. [18] Yossepowitch O, Thompson RH, Leibovich BC, et al. Positive surgical margins at partial nephrectomy: predictors and oncological outcomes. J Urol 2008;179:2158–63.