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ADULT UROLOGYCME ARTICLE

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IS INTRAOPERATIVE FROZEN SECTION ANALYSISAN EFFICIENT WAY TO REDUCE POSITIVE

SURGICAL MARGINS?

TOSHIKI TSUBOI, MAKOTO OHORI, KENTARO KUROIWA, VICTOR E. REUTER,MICHAEL W. KATTAN, JAMES A. EASTHAM, AND PETER T. SCARDINO

ABSTRACTbjectives. To assess the accuracy and efficiency of frozen section analysis to detect positive surgicalargins (�SMs) during radical prostatectomy.ethods. In a consecutive series of 760 patients treated with radical prostatectomy from 1998 to 2002,

reas suspicious for �SMs on the surface of the removed prostate were examined by frozen section analysis.n a subset of 520 patients, the surgeon’s level of suspicion for �SMs was scored and recorded duringadical prostatectomy.esults. Overall, 259 patients underwent frozen section examination. Of these, 55 patients (21%) hadSMs on permanent section examination compared with 50 (10%) of 501 patients with no frozen sectionnalysis (P �0.005). Cancer was present in 23 (8.9%) frozen section specimens, all of which were confirmedn permanent section analysis. Frozen section examination missed 32 �SMs in 236 patients with negativerozen section results. The sensitivity, specificity, and positive and negative predictive value of frozen sectionnalysis to identify �SMs was 42%, 100%, 100%, and 86%, respectively. However, the sensitivity of frozenection analysis was much lower (23 of 105, 22%) when analyzed for the entire population, including thoseho did not have frozen section analysis. Among the subset of 520 patients with the level of suspicion

ecorded, 79 had a �SM on permanent section examination. However, 51 (64%) of these were in patientsith no suspicious area in the prostatectomy specimen.onclusions. Although the positive predictive value of frozen section analysis for �SMs is high, the sensi-ivity is too low to expect that a policy of routine frozen section analysis of suspicious areas will reduce theate of �SMs substantially. UROLOGY 66: 1287–1291, 2005. © 2005 Elsevier Inc.

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he primary objective of radical prostatectomy(RP) is complete excision of the cancer. A pos-

tive surgical margin (�SM) suggests incompleteesection and increases the probability of cancerecurrence.1,2 Patients with a �SM are more likelyo experience biochemical failure and require ad-itional therapy than those whose margins are neg-tive, even when balanced for all other adverserognostic factors.2–4

his study was supported in part by the Leon Lowenstein Foun-ation and an NCI SPORE grant (CA 58204).

From the Departments of Urology, Pathology, and Epidemiol-gy and Biostatistics, Memorial Sloan-Kettering Cancer Center,ew York, New YorkReprint requests: James A. Eastham, M.D., Department of

rology, Memorial Sloan-Kettering Cancer Center, 353 East8th Street, New York, NY 10021. E-mail: easthamj@mskcc.orgSubmitted: January 22, 2005, accepted (with revisions): June

T0, 2005

2005 ELSEVIER INC.LL RIGHTS RESERVED

Because it is difficult to identify the presence andocation of extracapsular extension before surgery,urgeons have tried to detect �SMs with frozenection (FS) analysis during surgery. If the margins positive on FS analysis, additional tissue is oftenesected, until the margins of the complete speci-ens are negative.5,6 The utility of FS analysis has

een questioned; however, it has not been demon-trated that resection of additional tissue favorablylters the prognosis.7 Because many �SMs are inreas not suspected before or during the operation,e questioned the accuracy and sensitivity of FS

nalysis for the detection of �SMs in a contempo-ary RP series.

MATERIAL AND METHODS

ATIENT POPULATIONWe studied 760 consecutive patients with clinical Stage T1-

3NXM0 prostate cancer treated with RP by two surgeons at

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ur institution from 1998 through 2002. Each patient wasssigned a clinical T stage using the 1992 TNM staging system.otal prostate-specific antigen was measured by the Bayer Im-uno 1 prostate-specific antigen system.

S EVALUATIONDuring the surgical procedure, each prostate was carefully

nspected before and after removal. Areas suspicious for �SMsere excised by the surgeon and examined by FS analysis in

he pathology laboratory. If FS analysis showed cancer at theargin, corresponding tissue in the same area was resected.his tissue was submitted separately for histologic analysis.he prostatectomy specimen was then inked to mark thedges of resection and processed as previously described.8

ach FS specimen was serially sectioned at 4-�m intervals. Allositive FS slides were reviewed again by one of us (K.K.) toap the area of cancer. Maps of each RP specimen were pro-

uced. All areas of cancer were measured by a planimetricethod using Image Pro software, version 4.0.0 (Media Cy-

ernetics). The RP specimens were evaluated by departmentalathologists using a standard protocol. Any area of surface ink

n contact with cancer cells was deemed a �SM.8

EVEL OF SUSPICION FOR �SMIn a subset of 520 patients, the surgeon recorded his level of

TABLE I. Clinical and pathologic characteristat radical p

atient Characteristics None* (n � 501)

ge (yr)Median 58Range 36–78

SA (ng/mL)Median 5.8Mean � SD 7.32 � 5.2Range 0.8–41.45

linical T stage (n)T1a 1 (0.2)T1b 2 (0.4)T1c 285 (56.9)T2a 108 (21.6)T2b 65 (13.0)T2c 30 (6.0)T3a 10 (2.0)iopsy Gleason sum (n)3–4 05 1 (0.2)6 358 (71.5)7 (3 � 4) 84 (16.8)7 (4 � 3) 38 (7.6)�8 20 (4.1)

xtent of cancer† (n)Confined to the prostate 404 (80.6)Extracapsular extension 95 (19.0)Seminal vesicle invasion 20 (4.0)Lymph nodes metastases 17 (3.4)SM (n) 50 (10.0)

EY: PSA � prostate-specific antigen; �SM � positive surgical margin.ata in parentheses are percentages.No frozen section analysis performed.Stages not mutually exclusive.In 17 of these patients, additional tissue was resected in area corresponding to loc

uspicion intraoperatively that the margin was positive using a p

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-point scale (1, definitely negative; 2, probably negative; 3,ossibly positive; 4, probably positive; and 5, definitely posi-ive). These judgments were made after careful examination ofhe specimens by the surgeon who was fully aware of thereoperative findings.

TATISTICAL ANALYSISWe calculated the sensitivity, specificity, and positive and

egative predictive values of FS results with reference to theresence of �SMs anywhere in the RP specimens. We thenecalculated the performance of FS analysis with reference onlyo the area of the specimen with a �SM. Finally, we assessed thessociation among a �SM in the RP specimen, the results of FSnalysis, and the surgeon’s assessment of the probability of aSM. When more than one FS was taken in a single patient,

he patient was classified according to the greatest level ofuspicion. If cancer was present in the FS but did not involvehe margin, we considered the FS to be negative (n � 3).tatistical analyses were performed using a commercially avail-ble computer software package (STATA, version 7, College Sta-ion, Tex), with P �0.05 considered statistically significant.

RESULTS

FS analysis of 1 to 3 areas (mean 1.33) of the

f patients according to frozen section resultstatectomy

Frozen Section Results

Positive (n � 23) Negative (n � 236)

59 5849–73 38–74

5.9 6.17.45 � 5.3 7.28 � 4.64.4–30.3 0.4–33.6

0 00 1 (0.4)

10 (43.5) 122 (51.7)4 (17.4) 66 (28.0)4 (17.4) 31 (13.1)5 (21.7) 12 (5.1)

0 4 (1.7)

0 00 1 (0.4)

13 (56.5) 156 (66.1)6 (26.1) 50 (21.2)3 (13.0) 16 (6.8)1 (4.4) 13 (5.5)

13 (56.5) 187 (79.2)9 (39.1) 47 (19.9)2 (8.7) 10 (4.2)

0 9 (3.8)23 (100)‡ 32 (13.6)

f �SM on frozen section; additional tissue was negative for patient treatment.

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rostate was performed on 259 (34.1%) of 760 pa-

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ients. Table I summarizes the clinical and patho-ogic features of these patients according to thetatus of FS analysis (not performed, positive, oregative).Of the 259 patients with FS analysis, 23 (8.9%)

ad cancer identified on the FSs. All had �SMsonfirmed in the RP specimen (true positive rate00%). FS analysis missed 32 �SMs in 236 pa-ients whose FS results were negative (false-nega-ive rate 13.6%); however, in 18 of these 32, theSM was at a different site from the FS. The sen-

itivity, specificity, and positive and negative pre-ictive value of FS analysis for �SMs in patientsho had this examination was 42%, 100%, 100%,

nd 86%, respectively (Table II).When we reexamined the data comparing the FS

esults to permanent section results in the samerea of the prostate, the sensitivity increased to2%, with 100% specificity. However, the sensitiv-ty of FS analysis was much lower (22% [23 of05]) when the entire patient population was in-luded (ie, the 259 who had FS analysis, as well ashe 501 who did not), because 50 patients amonghose with no FS examination had a �SM (Table II).

Of the 23 patients with a �SM on FS analysis, 1983%) had wide resection of additional tissue inhe area of the �SM and 17 of these (84%) had noancer in this tissue. These patients were includedn our analysis, but for clinical management wereonsidered to have a negative SM. The 2 patients11%) with cancer in the additional tissue wereonsidered to have a �SM for our analysis and forreatment. Thus, the final rate of �SMs in our se-ies was 11.5% (88 of 760).The probability of �SMs on permanent section

TABLE II. Frequency of surgical marginsin radical prostatectomy specimens according

to status of frozen section examination atradical prostatectomy*

rozen Sectionesults

Patients(n)

�SM† in PermanentSection of Radical

ProstatectomySpecimens

Positive(%)

Negative(%)

ositive 23 (100) 23 (100) 0 (0)egative 236 (100) 32 (13.6) 204 (86.4)o frozen section 501 (100) 50 (10.0) 451 (90.0)otal 760 (100) 105 (13.8) 655 (86.2)

EY: �SM � positive surgical margin.ata presented as number of patients, with percentages in parentheses.For patients with frozen section examination: sensitivity 41.8% (23/55), specificity

00% (204/204), positive predictive value 100% (23/23), and negative predictivealue 86.4% (204/259); for entire population: sensitivity 22% (23/105), specificity00% (655/655), positive predictive value 100% (23/23), and negative predictivealue 88.9% (655/737).Any �SMs in radical prostatectomy specimens.

xamination according to the above-mentioned a

ROLOGY 66 (6), 2005

ve levels of suspicion was recorded. For ease ofnalysis, we combined these five levels of suspicionnto three: low, intermediate, and high (Fig. 1).he level of suspicion was high in only 13 patients3%), but 77% had �SMs on permanent sections.leven patients (85%) had FS analysis performed,nd the results of nine (82%) were positive. Only 1atient with a �SM on the permanent section wasissed by FS analysis (false-negative rate 10%); 2

thers did not have FS analysis and were negativen the final specimen. In these high-risk patients,he rate of �SMs on permanent section was 0%0 of 2) when no FS analysis was performed and1% (10 of 11) when FS analysis was performed.The level of suspicion was intermediate in 73 pa-

ients (14%), and 18 (25%) had �SMs on permanentection analysis. FS analysis was performed in8 (79%) of these, but only 6 (10% of those per-ormed) were positive (all true-positive results,ig. 1). However, 10 of 16 patients with a �SM onermanent section examination were missed by FSnalysis (false-negative rate 63%). Two additionalatients had a �SM on permanent sections, but noS analysis had been performed. In this intermedi-te-risk group, the overall rate of �SMs in perma-ent sections when no FS analysis was performedas 13% (2 of 15) compared with 28% (16 of 58)hen FS analysis had been performed.Most (64%) patients with a �SM were in the

ow-risk group. This group constituted 83% of thetudy population, and their overall rate of �SMsas 12% on permanent section examination. FS

nalysis was performed in only 112 or 26% of theseatients (Fig. 1). Of these, 15 patients had �SMsn permanent section examination, and FS analy-is identified only 2 (false-negative rate 87%). An

IGURE 1. Surgeon’s levels of suspicion for �SMsombined into three groups: low (suspicion level 1 and), intermediate (level 3), and high (level 4 and 5). Forach group, graph shows distribution of patients (by per-entages); percentage of each risk group with FS analysiserformed; and percentage of FSs positive for cancer.

dditional 36 patients had a �SM on permanent

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ection analysis, but had had no FS analysis per-ormed. In the low-risk group, the rate of �SMs onermanent section examination was 10% (36 of 322)hen no FS analysis was performed compared with3% (15 of 112) when it had been performed.Among the subset of 520 patients included in the

nalysis of intraoperative level of suspicion for aSM, 79 had a �SM on permanent section analy-

is. However, 51 (64%) of these were in patientshought by the operating surgeon to have a lowrobability of �SMs, and 39 (49%) were in pa-ients who had had no FS analysis performed. Inhis subset, of 41 patients with a �SM who didave FS analysis, 24 (58%) were missed. Thus, 64%51 of 79) of all �SMs were in patients with nouspicious area in the RP specimen; 49% (39 of 79)f the �SMs were in patients who had had no FSnalysis; and 58% (24 of 41) of �SMs were missedn patients who did have FS analysis.

COMMENT

Positive SMs are common, reported in 14% to6% of RP specimens.1,2,8,9 The likelihood of aSM increases with increasing Gleason grade and

athologic stage in the RP specimen and with in-reasing serum prostate-specific antigen levels.1,3,4

he recent decrease in the rate of �SMs4,10 is moreikely related to the favorable shift toward lowertage cancer than toward more effective surgicalechniques. When corrected for pathologic stage,he rate of �SMs in contemporary RP series re-ains high.Although not all patients with a �SM develop

ecurrence after RP, the relative risk of recurrences 1.57 times greater when all other known prog-ostic factors are considered in the analysis.10,11

e recently reported a substantial and statisticallyignificant variation among individual surgeons inhe rate of �SMs adjusted for case mix that wasndependent of the volume of operations per-ormed.10 Except for greater efforts to detect pros-ate cancer earlier and to develop better systemicherapy, developing new techniques to avoidSMs might be the best method to improve the

rognosis of patients with clinically localized pros-ate cancer treated with RP.We began the liberal use of FS analysis to identifySMs during RP so that additional tissue at risk of

arboring malignant cells might be resected.henever preoperative or intraoperative findings

induration, fibrosis) raised a suspicion of cancerear the resection margin, a sample of tissue wasaken for FS analysis. If cancer was present in thisample (as was the case in 23 of the patients), ad-itional tissue was taken (in 19) to reduce thehance that cancer cells would be left in the surgi-

al bed. The results of these efforts were largely p

290

isappointing. The overall rate of �SMs was1.5%. Nearly one half (48%) of all �SMs in thiseries were in patients who did not have a sampleaken for FS analysis. In patients who did have oner more areas examined by FS analysis, 58% of theatients with a �SM were missed. Nearly twohirds of all RP specimens with a �SM on perma-ent section analysis were considered to have norea suspicious for a �SM during RP. The sensitiv-ty of FS examination was low, only 42% in allatients who had an FS analysis and 22% in thentire study population.Our only success was in the small group of pa-

ients considered highly likely to have a �SM. FSsere taken in 85% of these patients, and 82% wereositive. However, this was only 13 patients in thisroup, or 3% of the total.We had less success with FS analysis than others

ave reported.5–7 Cangiano et al.6 evaluated FSnalysis of the posterolateral area of the prostate in8 patients. Nine were positive for cancer, all con-rmed on permanent section examination. How-ver, 9 (24%) of 39 patients with negative FS re-ults had a �SM elsewhere in the specimen. Theensitivity of FS analysis was high (100%) in theosterolateral region in this series, but modest50%) overall. Furthermore, in their study, of 94atients with no FS examination 23 had �SMs, sohat the sensitivity of FS analysis to detect a �SMn the entire population was 22% (9 of 41). In ourtudy, 36 patients (39 FSs) had FS analysis of tissuerom the posterolateral area. Only 3 of these (7.5%)ad a �SM on permanent section examination,nd all of these were detected on FS analysis. How-ver, 20 additional patients had no FS analysis butid have a �SM in the posterolateral region. Thus,ur overall sensitivity for detecting a �SM in theosterolateral area was only 13% (3 of 23).Goharderakhshan et al.5 reported a sensitivity forS analysis of 69% to detect a �SM. Of 15 patientsith positive FS results, 11 (73%) had demonstra-le tumor at the inked margins on the permanentection. Of 81 patients with negative FS results, 5ad tumor at the inked margin on the permanentection, and 7 had a �SM in an area other than thatubmitted for FS analysis. The sensitivity, specific-ty, and positive and negative predictive values was9%, 95%, 73%, and 94%, respectively. Althoughts sensitivity was 69%, this calculation ignored thepatients whose �SMs were in an area other than

hat submitted for FS analysis. If these 7 patientsere included, the sensitivity would decrease to0.7%, similar to the 42% in the present study.Shah et al.7 obtained a circumferential biopsy

rom the apical soft-tissue margin for FS analysisuring RP. Four had a �SM on apical FS analysis,epresenting 25% of 16 �SMs at the apex in the

ermanent sections. The investigators concluded

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hat FS analysis of the apical margin of the prostatead a limited impact on the decision for additionalissue resection. In our study, 8 patients had posi-ive FS results at the apex, and all had �SMs in aermanent section. Of the 91 patients (102 FSs)ith negative FS results at the apex, 4 had a �SM

n an apical section of the permanent sections.herefore, the sensitivity of FS analysis at the apex

n patients with FS examination was high at 67% (8f 12), but this represented only 18% of 45 patientsith apical �SMs in the entire population.

CONCLUSIONS

Although the diagnostic accuracy of FS analysisor a �SM is high (no false-positive results), itsensitivity is low (42% in patients with FS exami-ation and only 22% of all patients). The yield of anS analysis is high in grossly abnormal areas, butost �SMs occur elsewhere in RP specimens.hus, a policy of routine FS analysis of suspiciousreas is not likely to reduce the rate of �SMs sub-tantially.

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ion, prevention and treatment of positive surgical marginsfter radical prostatectomy for prostate cancer. J Urol 160:

99–315, 1998. t

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2. Ohori M, and Scardino PT: Localized prostate cancer.urr Probl Surg 39: 833–957, 2002.

3. Epstein J, Pizov G, and Walsh PC: Correlation of patho-ogic findings with progression after radical retropubic pros-atectomy. Cancer 71: 3582–3593, 1993.

4. Ohori M, Wheeler TM, Kattan MW, et al: Prognosticignificance of positive surgical margins in radical prostatec-omy specimens. J Urol 154: 1818–1824, 1995.

5. Goharderakhshan RZ, Sudilovsky D, Carroll LA, et al:tility of intraoperative FS analysis of surgical margins in re-ion of neurovascular bundles at radical prostatectomy. Urol-gy 59: 709–714, 2002.

6. Cangiano TG, Litwin MS, Naitoh J, et al: IntraoperativeS monitoring of nerve sparing radical retropubic prostatec-omy. J Urol 162: 655–658, 1999.

7. Shah O, Melamed J, and Lepor H: Analysis of apical softissue margins during radical retropubic prostatectomy. J Urol65: 1943–1948, 2001.

8. Rabbani F, Bastar A, and Fair WR: Site specific predic-ors of positive margins at radical prostatectomy: an argumentor risk based modification of technique. J Urol 160: 1727–733, 1998.

9. Epstein JI: Incidence and significance of positive mar-ins in radical prostatectomy specimens. Urol Clin North Am3: 651–663, 1996.10. Eastham JA, Kattan MW, Riedel E, et al: Variations

mong individual surgeons in the rate of positive surgical mar-ins in radical prostatectomy specimens. J Urol 170: 2292–295, 2003.11. Hull GW, Rabbani F, Abbas F, et al: Cancer control

ith radical prostatectomy alone in 1,000 consecutive pa-

ients. J Urol 167: 528–534, 2002.

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