Rolf Gillitzer, Department of Urology, University Medical Centre, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. e-mail: email@example.com
Study Type – Therapy (outcomes research)
Level of Evidence 2b
What’s known on the subject? and What does the study add?
We hypothesized that taking intraoperative frozen section (FS) biopsies of the peripheral margins of resection during radical prostatectomy would allow an intraoperative systematic scan of resection margins. In the case of positive FS, extended resection could be performed with the aim of completely excising residual tumour, improving biochemical recurrence-free survival of patients with positive surgical margins at the inked specimen. To our knowledge, the prognostic value of achieving a negative resection status by systematically taking intraoperative FS of the peripheral margins of resection during radical prostatectomy has not been established to date.
• To determine the value of systematic intraoperative peripheral frozen sections (FS) with or without extended resection during nerve-sparing radical prostatectomy for prediction of biochemical recurrence (BCR) compared with inked surgical margins.
PATIENTS AND METHODS
• Between 1999 and 2003, in a prospective study, multiple peripheral FS (median 14; range 5–20) were taken from the urethral stump, circumferentially from the bladder neck, and from the lateral pedicles in 200 consecutive bilateral nerve-sparing radical prostatectomies for clinically localized prostate cancer by a single surgeon.
• Patients with stage pT3b or more and/or positive lymph nodes were excluded.
• Of the 188 patients, 178 (94.7%) were followed over a median of 82 months (62–124).
• BCR, defined as prostate-specific antigen (PSA) ≥ 0.2 ng/mL, was related to status of both, inked specimen margins and FS.
• Of all 188 prostatectomy specimens, 49 (26.1%) had positive surgical margins (PSM); these were found posterolaterally in 15 (30.6%), apically in 13 (26.5%), basally in 10 (20.4%) and at multiple sites in 11 (22.4%) specimens.
• Intraoperative peripheral FS were positive in 19 (10.7%) patients, including 6.2% at urethral stump, 3.3% at lateral pedicles and 1.1% at bladder neck.
• In organ-confined disease, BCR-free survival was 93.3% (111/119) for patients with negative surgical margins (NSM) and 72% (18/25) for patients with PSM (inked specimen), but negative peripheral FS (P < 0.001).
• Five- and 10-year BCR-free survival for NSM was 94.9% and 92.8%, for PSM with negative peripheral FS it was 75.3% and 70.6%, and for PSM with positive peripheral FS it was 62.5% and 62.5%, respectively.
• Frozen section biopsies of peripheral resection margins during nerve-sparing radical prostatectomy are not reliable in predicting PSM.
• Intraoperative achievement of a locally disease-free status, as monitored by negative circumferential intraoperative FS of peripheral margins, is not associated with a statistically significant BCR-free survival benefit compared with patients with negative surgical margins on the prostatectomy specimen.
• Based on these findings, we do not recommend a routine of systematically taking intraoperative FS biopsies during nerve-sparing radical prostatectomy.
Positive surgical margins (PSM) of radical prostatectomy specimens are histopathologically defined by tumour reaching the inked surface of the specimen. This may be a result of accidental surgical incision of organ-confined (OC) prostate cancer, or of incomplete excision of extracapsular extension (ECE) of prostate cancer during radical prostatectomy. However, definition of PSM may be imprecise at the apex and the bladder neck, where the prostate is not covered by a fibrous capsule . Apical PSM may be artificial as the result of surgery-related trauma or pathological processing.
A PSM is a recognized predictor of prognosis and use of adjuvant therapy for the patient [2–10]. Intraoperative biopsies for frozen section (FS) analysis taken from the peripheral margins of resection enable the surgeon to decide on extended resection of tissue to achieve a negative margin status. The apex, the posterolateral prostate – region of the neurovascular bundles (NVB) – and the base of the prostate are the recognized areas at increased risk of PSM [1,2,5,6,11]. We hypothesized that taking intraoperative FS of the peripheral margins of resection (urethral stump, lateral pedicles, bladder neck) would allow an intraoperative systematic scan of prostatectomy resection margins. In case of positive FS, extended resection could be performed with the aim of completely excising residual tumour. If this hypothesis were true, biochemical recurrence (BCR) -free survival of patients with PSM at the inked specimen but negative peripheral FS margins should be similar to that of patients with negative surgical margins (NSM). To our knowledge, the prognostic value of achieving a negative resection status by systematically taking intraoperative FS of the peripheral margins of resection during radical prostatectomy has not been established.
PATIENTS AND METHODS
Between January 1999 and December 2003, in a prospective study of 200 consecutive patients who underwent bilateral nerve-sparing retropubic prostatectomy with bilateral lymphadenectomy of the obturator fossa for localized prostate cancer systematic intraoperative FS of the peripheral resection margins were taken by a single surgeon. Mean (range) age of the patients was 62 (45–77) years, median (range) preoperative PSA was 8.1 (1.0–30.0) ng/mL. Eleven patients with pathological stage pT3b or greater and/or positive lymph nodes, and one patient receiving postoperative adjuvant treatment were excluded from analysis. Minimum follow-up of 5 years was obtained in all patients. Altogether, 178 (94.7%) of the remaining 188 patients were followed over a median (range) of 82 (62–124) months. None of the patients received neoadjuvant hormonal treatment.
Multiple FS (median 14, range 5–20) were taken and numbered consecutively by the surgeon from the urethral stump (ventral and dorsal circumference), circumference of the bladder neck and the posterolateral pedicles (three or four per side). If a biopsy was positive, extended resection at this site was performed and additional FS were obtained, until a negative FS biopsy was obtained. The FS biopsies were reviewed by an expert uropathologist.
All radical prostatectomy specimens were inked and processed according to the Stanford protocol. The inked specimen margins and intraoperative FS findings were related to BCR-free survival. Biochemical progression was defined as a PSA ≥ 0.2 ng/mL on any measurement. The PSA was measured in 3-month intervals for the first year, biannually for the next 4 years and yearly thereafter.
Statistical analysis was performed using the chi-squared test for categorical variables and the Mann-Whitney U-test for continuous variables. Survival analysis was performed using Kaplan-Meier curves with the log-rank test for comparing groups. A Cox proportional hazards model was used to detect independent predictors of BCR in multivariate analysis. The significance level was fixed at α= 0.05.
Disease was confined to the prostate in 152/178 (85.4%) patients but 26/178 (14.6%) patients had ECE. Median (range) postoperative Gleason score was 7 (3–9). The incidence of PSM was 21.7% (33/152) and 61.6% (16/26) for pathological stages T2 and T3a, respectively. Location of PSM is shown in Table 1. Single PSM were found in 30.6% (15/49) at the posterolateral border in the region of the NVB, including two patients with ECE. Overall, six patients (3.3%) had positive intraoperative peripheral FS at the posterolateral border, prompting complete resection of the ipsilateral NVB in five. Final histopathological analysis of the resected NVB revealed residual tumour in only three of these five patients. This finding correlated with the PSM of the prostate specimen. In the other two patients, neither the resected NVB nor the prostate specimen showed residual cancer at this site. In the remaining patient with a single positive FS at the NVB, further resection was negative and the NVB was not resected. Overall, three patients (11.5%) with posterolateral PSM (including patients with multiple PSM) also had intraoperative positive FS of the corresponding site (Table 2).
Table 1. Location of positive surgical margins on the prostatectomy specimen
Overall, 11 patients (6.2%) had positive FS at the urethral margin. In five patients, further resection was negative but the prostate specimen showed tumour at the inked margin. In four patients further resection was negative and the prostate specimen revealed no tumour at the apex. In two patients, no attempt was made to obtain a negative margin to avoid compromising continence, including one with a positive FS on repeated resection. A total of seven patients (29.2%) with positive urethral FS had PSM at the apex of the prostate (Table 2). Two patients (1.1%) had positive FS at the bladder neck. Further resection was negative in only one of these patients, in the other, no further resection was possible because of the vicinity to the ureteric orifices. No patients with NSM had positive intraoperative FS. Of 11 patients with PSM at the prostate base, 18.2% (2/11) had positive FS at the bladder neck (Table 2).
Postoperative Gleason score and prostate weight did not correlate with positive FS and PSM (data not shown).
The overall BCR rate was 16.3% after a median of 48 months (12–90). In cases with NSM at the inked specimen, BCR-free survival was 93.3% (111/119) for OC disease and 70% (7/10) for ECE. In univariate analysis, preoperative PSA (P= 0.001) and postoperative Gleason score (P= 0.001) correlated positively with BCR rates.
Of patients with OC disease and PSM, 75.8% (25/33) had negative intraoperative FS of the peripheral resection margins. Of those, 72% (18/25) remained BCR-free after a median (range) follow-up of 78 (38–124) months. Another five patients with OC disease and PSM had initial positive intraoperative FS of peripheral margins (four at the apex, one at the prostate base), which by extended resection were converted into a ‘margin negative’ state. Three of these remain BCR-free at a median (range) of 77 (64–90) months. Figure 1 shows Kaplan-Meier analysis for patients with OC tumours. Patients with PSM and negative FS of peripheral margins had a lower BCR-free survival than patients with NSM (P < 0.001). Five- and 10-year BCR-free survival rates were 94.9% and 92.8% for patients with OC margin negative disease, 75.3% and 70.6% for OC disease with PSM but negative FS, and 62.5% and 62.5% for OC disease with PSM and positive FS. In multivariate analysis, for OC tumours the postoperative Gleason score (P= 0.045; hazard ratio 1.727) and NSM (P= 0.012; hazard ratio 0.165) remained independent predictors of BCR, whereas preoperative PSA (P= 0.077; hazard ratio 1.083) and PSM with negative FS (P= 0.618; hazard ratio 0.691) did not, compared with patients with PSM and positive FS.
Figure 2 shows Kaplan-Meier analysis for patients with ECE. Of patients with ECE and PSM, 68.7% (11/16) had negative FS of the peripheral margins. Of those, six remained BCR-free after a median (range) follow-up of 82 (63–113) months. Another three patients with ECE and PSM initially had positive FS of peripheral margins, but negative biopsies on further resection. One of these patients remained BCR-free at a median (range) of 68 (67–80) months. For patients with ECE and PSM but negative FS, BCR-free survival was similar to that for patients with ECE and NSM (P= 0.588).
Adverse prognostic factors of biochemical recurrence after radical prostatectomy include preoperative and postoperative Gleason score, ECE, PSM and their number, location and extension [1–5,12,13]. In contemporary series, PSM most frequently occur at the prostate apex and at the posterolateral aspect of the gland [1,14,15]. However, neither PSM extent, number or location seem to improve the accuracy of prediction of recurrence compared with the existence of a PSM alone .
We hypothesized that systematically taking intraoperative FS of the peripheral resection margins from regions at increased risk for PSM may serve as a surrogate intraoperative parameter for complete tumour excision or presence of residual local disease. This would allow monitoring of complete tumour excision and extended resection if necessary. By this means, a group of patients with PSM at the inked specimen could theoretically be converted into a ‘margin negative’ state and possibly benefit from an improved BCR-free survival. The value of FS biopsies taken from the peripheral resection margins instead of from the specimen itself has not been addressed before, and current literature pertaining to FS usually has a short follow-up.
The efficacy of intraoperative FS to monitor surgical margin status has been evaluated before [7,14–18]. Shah et al.  showed that with repeat excision of the apical soft tissue margin a disease-free status could be achieved. However, a short follow-up period of 3 months in this study does not allow any prognostic conclusions. In one study, apical FS helped to decrease the overall PSM status by 5.1%. However, sensitivity of FS from the apical margin to detect prostate cancer is limited in comparison with permanent section examination . In this study, only 29% of apical PSM were correctly diagnosed with FS. Kübler et al.  found that positive apical soft-tissue biopsies were an independent predictor of biochemical failure compared with apical surgical margin status in patients with apical cancer involvement. The 36-month BCR-free survival rate in this study was 55.9% for patients with positive apical biopsies and 78.7% for those with negative biopsies (P= 0.023).
Goharderakhshan et al.  found that in patients with positive FS analysis of the posterolateral region, 80% of the additional resected tissue including the NVB showed no residual tumour. Similarly, Cangiano et al.  found 18% tumour infiltration in posterolateral FS of 48 patients with suspicious intraoperative findings, prompting wide excision of the corresponding NVB. However, no residual tumour was found in the resected NVB when the FS was positive.
Sensitivity of FS to detect PSM was low in this study, regardless of the location. The positive predictive value of FS for PSM was similarly low, excluding FS at the bladder neck. We acknowledge that taking multiple random FS from the region of the NVB, instead of a whole wedge of tissue from the prostate specimen  may not be representative. Uncertainty exists whether the location of the FS was exactly contiguous to the area of the PSM in the histopathological prostatectomy specimen, that FS samples were too small, or that the FS was indeed truly negative if the PSM had been minimal. However, this study is unique in that only one surgeon systematically obtained an intraoperative detailed analysis of periprostatic margin status from areas at increased risk for PSM. Others have found similarly low sensitivity rates of FS for predicting PSM, providing evidence that a routine of taking FS would not help to substantially reduce the rates of PSM [17,18] while jeopardizing postoperative potency. The prognostic significance of focal PSM remains uncertain [20,21]. Our analysis of intraoperative FS also showed 33% and 36% false-positive rates at the apex and posterolateral region, respectively, representing possible histopathological misinterpretation. This could be explained by the fact that tumour extension in these cases was present only to within a couple of cell layers from the resection margin in the final specimen, representing distances in the micrometer range. Most likely, a discontinuous tumour growth in these areas gave the appearance of a negative margin in the prostatectomy specimen, even if tumour cells were in fact present at the resection margin, yielding positive intraoperative FS biopsies.
The surgeon’s ability to discriminate intraoperative findings that could be suspicious of harbouring prostate cancer, such as induration or fibrosis, is not reliable. A study found only 36% PSM in areas deemed as being highly suspicious of prostate cancer by the surgeon . On the contrary, 64% PSM were found in non-suspicious areas. Lepor and Kaci  found only 1.6% prostate cancer infiltration in FS of the lateral pedicle of 63 patients, in whom intraoperative capsular incision was suspected.
The high rates of PSM in this study may be partly because patient selection for nerve-sparing radical prostatectomy was not as stringent as it is in other series, which do not include patients with Gleason score ≥ 7, patients with more than three positive cores, positive lateral and apical cores. Nevertheless, they are comparable with other series [2,12]. A second cause could be the special attention given by the pathologist to searching for the smallest positive margins in this prospective study compared with routine histopathological evaluation. This would explain the overall 5-year and 10-year BCR-free survival rates for OC tumours of 90% and 88%, respectively, which is in the range of BCR-free survival rates of OC tumours with NSM of other series .
A 22.2% lower 10-year BCR-free survival rate was found in patients with OC disease and PSM, who supposedly were converted to a ‘margin negative’ status by FS analysis of peripheral margins and extended resection, compared with patients with OC tumours and NSM. Chuang et al.  compared the survival of patients with PSM with that of those with NSM in OC disease . Actuarial 5-year freedom from BCR was 71.3% and 96.7% (P < 0.0001), respectively, which compares with our findings. Similar results have been presented by Lake et al., who also stratified survival according to the extent of PSM in OC tumours . However, Fesseha et al.  did not find a difference in BCR in 33 patients with isolated PSM at the apex compared with 236 patients with OC margin negative disease, after controlling for other variables.
For patients with ECE, there was no difference in BCR-free survival for PSM but negative peripheral FS compared with that for NSM. However, statistical analysis of these 26 patients is limited.
Recurrence rates of PSA of 64.3% for PSM versus 20.5% for NSM for 406 patients at a median (range) follow-up of 5.2 (0.4–15.8) years were published by Pfitzenmaier et al. . This statistically significant difference was also evident for OC tumours. In a study similar to this one, but with additional margin tissue resection being performed only for suspicious findings or positive FS, Rabbani et al.  found 97.9% and 100% 36-month actuarial BCR-free survival, respectively for NSM and for PSM with negative further resection (P < 0.001) in OC disease . On extended follow-up, Smith et al.  found that for cases with extensive ECE wide excision of the NVB resulted in a sustained BCR-free survival advantage only as long as NSM had been attained. However, the beneficial effect of NSM on survival was observed only in tumours with Gleason scores between 5 and 7.
Our current data show that FS of peripheral resection margins are not reliable in predicting PSM. Also, 5-year and 10-year BCR-free survival was not statistically improved by resecting margins of positive FS. However, BCR rates of patients without tumour after extended resection were somewhat improved compared with histologically incomplete tumour removal. To prove that further tissue resection is actually of no value in improving survival, the presence of a comparative group where, in case of positive FS, no further resection takes place is needed. However, it is inherent that such a comparison is not practicable. Our findings require validation, ideally in a prospective randomized fashion with larger patient numbers, comparing the survival of patients with and without intraoperative FS analysis.
In nerve-sparing prostatectomy of OC disease, negative surgical margins on the prostatectomy specimen and the postoperative Gleason score remain the most powerful predictors of outcome, which was confirmed by multivariate analysis. Based on these findings, we do not recommend a routine of systematically taking intraoperative FS biopsies during nerve-sparing radical prostatectomy. However, it must be stated that following the basic surgical principle of attaining complete tumour resection, regardless of whether improved survival can be achieved, obtaining FS biopsies and relying on further tissue resection is probably warranted in clinically locally advanced disease and in those cases with intraoperative suspicious findings.
We thank Amelie Elsäßer from the Department of Medical Statistics and Biometry for her statistical advice.