Radical Prostatectomy and Positive Surgical Margins: Relationship with Prostate Cancer Outcome

ARTICLE INFO


INTRODUCTION
The finding of positive surgical margins (PSMs) after radical prostatectomy (RP) implies that cancer resection was not complete leading the surgeon to decide between complementary treatments such as: active surveillance, adjuvant radiotherapy or androgen-deprivation therapy.Many studies report that PSM represents an independent predictor of biochemical recurrence (BCR) after RP.Furthermore, these studies have also shown that most men with PSMs do not develop BCR (1)(2)(3).At multivariate analysis, Gleason score of specimen, pathologic stage, percentage of tumor volume in the surgical specimen and PSMs were all significant risk factors for BCR.Each of these factors has previously been associated with BCR (4).Another study shows that PSM is an independent predictor of BCR after RP, where BCR rates were similar for cases with unifocal and multifocal PSMs, and the risk of BCR was highly dependent on the PSM location.Cases of base and anterior margins of the prostate have a worse prognosis and should be considered candidates for adjuvant treatment due to the very high likelihood of BCR.Although PSMs are more common on the apex, posterior and posterolateral sites, they are associated with lower BCR rates (5).To verify the relationship between PSMs and BCR, we retrospectively analyzed the outcome of a group of patients submitted to RRP, for clinically localized prostate adenocarcinoma with PSMs, and studied the correlations of these results with clinical and pathologic variants.

MATERIALS AND METHODS
From a total of 1250 patients submitted to RRP to cure a clinically localized Prostate Cancer, by the team of the Division of Urology, Pelvic Surgery Department, A.C. Camargo Cancer Center, between March 1991 and June 2008, we retrospectively studied the outcome of 161 patients with PSMs, compared to a control group of 67 patients without PSMs, in a total of 228 cases.Our total number of patients with PSMs was of 298 cases (23.84%).We excluded from the study patients who received hormone therapy or radiotherapy before the surgery, 56 patients who have PSMs and involvement of seminal vesicles and/or inguinal or pelvic lymph nodes or stage T4 disease, and 81 patients who have PSMs with incomplete or missing follow-ups.Based upon their preoperative PSA, rectal digital examination, transrectal ultrasound, pelvic computerized tomography or nuclear magnetic resonance (high risk cases) results and the pathologic study from their prostate biopsies, all patients were considered bearers of organ-confined disease.We recorded patient age, race, preoperative PSA, clinical and pathologic stage, prostate surgical specimen weight, percentage of tumor volume, perineural and/or angiolymphatic invasion, capsular and extracapsular involvement, the number and site (urethral, bladder neck, prostate circumference) of PSMs in the surgical specimens.These were staged according to the 1997 American Joint Committee on Cancer System and graded using the Gleason system.All cases underwent the same protocol for pathologic evaluation, the prostate being analyzed as a whole.After removal of the seminal vesicles, surgical specimens were step sectioned at a constant interval obtaining variable number of transverse sections according to the prostate size.Each transverse section of the prostate was subdivided into 2 anterolateral and 2 posterolateral quadrants.From each quadrant it was obtained one slide unless too large to need a second slide.A visual estimate was used to evaluate tumor extent.After analysis of each quadrant a percentage was reached for the total tumor volume.Extraprostatic extension was evaluated whenever cancer was seen in adipose tissue being considered either focal or extensive.Surgical margins were considered positive when the tumor could be seen on the inked surface of the surgical specimen (6).Serum PSA levels after RRP were measured every 4 months for 2 years and then every 6 months for 2 more years and annually thereafter.BCR was considered when the PSA reached a level ≥ 0.2ng/mL.Thereupon the patient was referred for external pelvic and prostatic bed radiotherapy or radiation plus hormone therapy in selected cases with worse prognosis.CR was determined when clinical evidence of tumor was seen as a metastatic disease, or when PSA rose despite radiotherapy, hormone, or chemotherapy treatments.Minimum follow-up time was of 2 ye-ars after surgery.The time interval to biochemical recurrence was analyzed by the Kaplan-Meier product limit analysis using the log-rank test for comparison between groups.The univariate and multivariate Cox stepwise logistic regression models were used to identify significant predictors of risk of shorter intervals to BCR.The Kaplan-Meier method was used to calculate the curves of biochemical-recurrence free survival (from the date of RRP until date of the first PSA measurement > 0.2ng/mL or to the date of the last follow-up) and clinical-recurrence free survival (from the date of the RRP until the date of detection of local or distant disease or until date of the last follow--up).The Chi-square test was used to correlate clinical and pathologic variables with PSMs.Time interval to biochemical recurrence was analyzed by the Kaplan-Meier product limit analysis using the log-rank test for comparison between groups.Univariate and multivariate Cox stepwise logistic regression models were used to identify significant predictors of risk of shorter intervals to BCR.All statistical tests were performed with p < 0.05 to indicate statistical significance with R free statistical software (www.r-project.org).

RESULTS
For the 228 patients, follow-up ≥ 5 years was available in 93 patients and ≤ 5 years in 135 patients.Minimum follow-up time after surgery was of 2 years, median follow-up 6.2 years (range 2-15 years).At diagnosis median age of patients was 64.5 years (range 43-81 years ), race was 68.42% white, 19.29% black, and 12.29% mulatto, median preoperative PSA level was 8.47ng/mL (range 1.3-78.8ng/mL).
Prostate specimen weight ranged from 10 to 167g (mean 44.77g), and tumor volume was estimated as ranging from 0.5% to 100% of total prostate volume (mean 12.82%).Prostate capsule invasion (focal and extracapsular) was present in 123 cases and absent in 105, perineural invasion was present in 162 cases and absent in 66, angiolymphatic invasion was present in 18 cases and absent in 210.
Table-1 shows demographic, clinical and pathologic parameters correlated with presence of PSMs, age, preoperative PSA, specimen Gleason score, weight, pathologic stage, percentage of tumor volume, capsular and perineural invasion.Clinical stage and angiolymphatic invasion were not correlated.Patients younger than 50 and older than 70 years of age showed higher incidence of PSMs.Pre-treatment PSA ≥ 10ng/mL, specimen Gleason score ≥ 7, pathologic stage ≥ T2b, tumor volume ≥ 10% of specimen's total volume and presence of capsular and perineural invasion showed statistically significant associations with occurrence of PSMs.
Univariate analysis showed statistically significant (p < 0.001) association between presence of PSMs and BCR, however not with CR (p = 0.06).
Among 161 patients with PSMs, 61 (37.88%) presented BCR, while 100 (62.12%) did not (Table -3).COX univariate analysis of pathologic factors predicting progression-free survival of BCR and CR in 5 years after RRP (Table-4) correlated BCR progression-free survival with pathologic stage, Gleason score, pre-treatment PSA, tumor volume in specimen, capsular and perineural invasion, presence and number of PSMs.
Interestingly, the progression-free survival time for CR was correlated only with angiolymphatic invasion and Gleason score.

DISCUSSION
In contemporary series, PSMs are reported in 11-38% of patients undergoing RP.The prognostic factors pointing at the presence of PSMs are many ranging from pathologic characteristics to the surgeons' expertise and surgical techniques.
Our results correlate younger and older age, pre-treatment PSA higher than 10ng/mL, specimen Gleason score ≥ 7, smaller glands with weight ≤ 40g, pathologic stage ≥ pT2b, percentage of tumor volume higher than 10% of surgical specimen, capsular and perineural invasion with occurrence of PSMs, in accordance with several authors (7)(8)(9).
PSMs point to a greater risk of biochemical progression.D'Amico et al. (8) found that after RP failure rates of 2-year PSA were of 45-55% in patients with PSMs, when compared to 15-25% of those with organ confined disease.Several factors have been assessed to verify whether it is possible to further stratify risk of recurrence in patients with PSMs.In virtually all studies, multiple PSMs have signaled a worse prognosis.Number of PSMs (single vs. multiple) showed that there was a statistically significant higher risk of recurrence in patients with more than one PSM, with a hazard ratio of 2.19 at the 95% CI (9).
A similar result was reported by Obek et al. (10), who showed that at a mean follow-up of 25 months, the recurrence rate in patients with multiple PSMs was of 43% vs. 24% in those with a single focus.Furthermore, patients with two or more PSMs were 2.5 times more likely to have recurrence in a shorter period.
In our study, only 61 (37.88%) out of 161 patients with PSMs presented BCR.As in literature, various PSMs sites, bladder neck and prostate circumference, lead to worse outcome.In our cases with no PSMs, BCR was only found in 7 patients (10.5%).
It is extremely difficult to predict PSM outcome, and as patients with PSMs are at higher risk  of progression, the ability to stratify this risk needs improvement along with other factors that may affect disease progression and survival (11).Focal capsular or extensive extracapsular involvement, were both correlated with BCR in our study.Other studies found that men with PSMs and no extra-capsular spread had a lower rate of recurrence than men with extracapsular disease, but this was contradicted by the SEARCH database study group (12), who found that men with PSMs and no extracapsular spread had a recurrence risk similar to those with extracapsular disease regardless of margin status.
Similar to our results, Stephenson et al. ( 13) noted that 7-year progression-free probability was observed in 60% of patients with positive surgical margins.A positive surgical margin was significantly associated with biochemical recurrence (HR 2.3, p < 0.001) after adjustment of the following factors: age, prostate specific antigen, Gleason score, pathologic stage and year of surgery.An increased risk of biochemical recurrence was associated with multiple vs. single positive surgical margins (adjusted HR 1.4, p = 0.002) and extensive vs. focal positive surgical margins (adjusted HR 1.3, p = 0.004) at multivariate analysis.However, neither parameter improved the predictive accuracy of a nomogram compared to one in which surgical margin status was modeled as positive vs. negative (concordance index 0.851 vs.0.850 vs. 0.850).
In our results, at univariate analysis prostate weight, preoperative PSA, Gleason score, pathologic stage, tumor volume, PSMs, capsular and perineural invasion were correlated with BCR in full agreement with literature.Nevertheless at multivariate analysis only Gleason score and tumor volume were statistically significant independent predictors of BCR (Figure -1).
Guram et al. (14), conclude that patients with vascular invasion in the radical prostatectomy specimen are at high risk of recurrence after surgery, and that adjuvant systemic treatment should be considered for these patients.They further conclude that patients with negative surgical margins and no vascular invasion are likely to be cured by radical prostatectomy.Similarly, our results showed that angiolymphatic invasion and Gleason score were significantly correlated only with CR.
Gleason score reflects tumor aggressiveness, whereas cancer volume illustrates the extent of the lesion, as such it can be hypothesized that high-grade cancer volume and percentage simultaneously reflect cancer invasion ability to spread and their impact on outcome.Our results support the conclusions of other authors (15,16) that high-grade cancer volume had the highest impact on recurrence-free survival in patients with surgically treated and pathologicly organ-confined prostate cancer or that prostate volume has prognostic value in pathology T2 radical prostatectomy specimens (17).These facts highlight the importance of the percentage of tumor volume in the surgical specimen, rather than the presence of PSMs, as important predictor of BCR.Other studies, however, argued that tumor extent does not provide additional information beyond that of Gleason score and surgical margin status (18)(19)(20).

CONCLUSIONS
Our results agree with numerous previous reports that presence, number and site of PSMs have consistent correlation with BCR following RRP within other pathologic factors at univariate analysis.However, not all patients with PSMs will present tumor progression.As confirmed in our study, BCR occurred only in 37.8% of patients with PSMs.Overall, CR was very rare, as it represented 4% of the total number of cases (PSMs and no PSMs).At multivariate analysis, percentage of tumor volume (p = 0.022) and Gleason score (p < 0.005) in the surgical specimen were the independent significant prognostic risk factors for BCR, rather than the presence of PSMs, stressing the importance of these two pathologic factors.Furthermore, angiolymphatic invasion and Gleason score were significantly correlated only with CR.

Figure 1 -
Figure 1 -Probability of biochemical recurrence-free and clinical progression-free survival at 5-10 years according to percentage tumor volume in the specimen.

CaP =
Prostate adenocarcinoma PSMs = Positive surgical margins RRP = Open retropubic radical prostatectomy RP = Radical prostatectomy BCR = Biochemical recurrence CR = Clinical recurrence CONFLICT OF INTEREST None declared.