Cox proportional hazards regression analysis
Higher Ki-67 expression at the margin showed a trend toward significant association with higher risk of BCR (HR:2.06, (0.97–4.43),
P = 0.06). On the other hand, LLOM and number of the margin were not correlated with biochemical recurrence (Table
2).
Table 2
Predictors of biochemical recurrence on multivariable cox regression analysis
Ki 67 in deep tumor |
Group 1 | Reference | | |
Group 2 | 1.41 | (0.57–3.52) | 0.46 |
Group 3 | 4 | (1.64–9.80) | 0.002 |
Ki 67 at margin |
Group 1 | Reference |
Group 2 | 1.12 | (0.55–2.31) | 0.75 |
Group 3 | 2.08 | (0.97–4.43) | 0.06 |
Length of the margin |
< 3 mm | Reference |
> =3 mm | 1.28 | (0.70–2.37) | 0.42 |
Number of margin | |
Single margin | Reference |
Multiple margins | 0.83 | (0.45–1.51) | 0.54 |
High Ki-67 expression in the deep tumor was an independent predictor of biochemical recurrence (HR:4, (1.64–9.80), P = 0.002).
Discussion
In this cohort of patients with positive surgical margin after radical prostatectomy, our results show that high Ki- 67 expression in the deep tumor was a significant predictor of BCR and high Ki-67 expression at the margin showed a trend toward significant association with BCR. We also found that there is no correlation between LLOM and extent of margin on the biochemical recurrence.
PSM is an established adverse pathological feature correlated with biochemical progression [
7]. Indeed, this correlation has impacted urologist practice by utilizing adjuvant treatment in patients with PSM; Grossfeld et al. using the CaPSURE database found that patients with a positive margin were much more likely to receive adjuvant treatment (p 0.0011) [
2].BCR rate in our cohort is in line with previously observed rate in PSM patients (32%–74%) [
8,
9]. In the observation arm of the European Organisation for Research and Treatment of Cancer 22,911, which compared the administration of AT versus patient observation, 41% of the patients were disease-free at five years. Therefore, it is evident that there is overtreatment of patients with positive surgical margin, which might have an adverse impact on patient care, given that the use of AT is not without acute and late gastrointestinal and genitourinary toxicities [
10].
Several studies attempted to classify surgical margins based on different features, such as length of the margin, the extent of the margin, and Gleason score at the margin. Sofer et al. found that there is no correlation between surgical margin site and biochemical progression. Moreover, he demonstrated that there was no statistically significant difference in time to progression between patients with single margin and patients with multiple margins [
11]. Additionally, Epstein et al. failed to demonstrate any difference in the progression between patients with single margin and those with multiple margins [
12]. In the current study, there was no statistically significant difference in prognosis between men with a single site of a positive margin or multiple sites, supporting results from previous studies. However, while LLOM more than 3 mm have been shown to confer a worse prognosis compared to margins < 3 mm, we were unable to validate this finding in our cohort [
13,
14].
Ki-67 is an established marker of cell proliferation, which has been previously studied in prostate cancer and was correlated with biochemical progression, prostate cancer-specific survival and overall survival [
4,
15,
16]. No study to our knowledge has examined the importance of Ki-67 expression in the setting of positive surgical margins.
Mesko et al. demonstrated a significant heterogeneity in intraprostatic and intralesional expression of Ki-67 [
17]. We found that there is high heterogeneity of Ki-67 expression between the index lesion and the margin, with a discordance rate of 37.6%. This has stirred us to measure ki-67 expression at the margin and the index lesion.
Intriguingly, the mean Ki-67 expression in our cohort was 0.5% (±1.32) which is lower than the levels reported in the literature [
17,
18]. There was no significant difference in overall Ki-67 proliferation values when comparing stains performed on old tissue blocks (more than five years old) to stains carried out on more recent blocks. The difference between our results and previously published results is unclear at this point, but could be attributed to the racial differences in the prostate cancer biology [
19‐
22].
In the current study we assessed the significance of Ki-67 at margin accounting for the patients who received AT. Our study has shown that there was a trend towards biochemical recurrence in PSM patients with higher Ki-67 expression at the margin however statistical significance was not attained (HR 2.06, CI 0.97–4.43 P = 0.06). On the other hand, Ki67 expression in the index tumor was an independent predictor of BCR (p = 0.002). This finding may help in the discussion of post-prostatectomy treatment for patients with PSM.
We acknowledge that the present study has some limitations that warrant discussion. First, the data analyzed are retrospective and included patients operated on before the 2005 International Society of Urological Pathology modified Gleason score system. For this reason all pathology slides were reviewed by two expert pathologists and the Gleason score was revised according to the new classification. Second, there are inherent limitations to the reliability and reproducibility of the immunohistochemical techniques.