Level of invasion into fibromuscular band is an independent factor for positive surgical margin and biochemical recurrence in men with organ confined prostate cancer

All oncologic surgeries aim to completely remove cancers. Therefore, the presence of a positive surgical margin (PSM) after radical prostatectomy (RP) for prostate cancer is considered an adverse event in curing this cancer, with outcome associated with prostate specific antigen (PSA) biochemical recurrence (BCR) and poor outcome [1, 2]. The reported rates of PSMs among pathologically localized prostatectomy specimens vary from 6.5% to 38% in contemporary series of RP [1, 3]. The rate of PSM for pT2 prostate cancers is thought to reflect the surgeon’s experience [4, 5]. However, tumor-behavioral factors might also influence the rate of PSM for organ-confined prostate cancer. A large-volume tumor adjacent to the prostatic capsule may be prone to a PSM if the surgeon rigorously attempts to preserve the nerves and maximize the remaining functioning urethra. The level of prostatic capsular invasion, which focuses on the extra-prostatic extension (EPE), was reported to affect the incidence of BCR [6]. However, recent articles have avoided the term “prostatic capsule” [6‐8], as the prostate does not have a true capsule at the apex, anterior side, and base. Therefore, we instead revisited the level of invasion into fibromuscular band (FMB) as an independent factor for a PSM or BCR in patients with organ-confined prostate cancer. We hypothesized that the level of invasion into FMB would be an independent tumor-behavioral factor that could affect the rates of PSM and BCR in patients with pT2 prostate cancer.

Although the effect of a PSM on long-term cancer-related mortality remains controversial [2, 13], this factor has been proposed as an important predictor of disease progression [14, 15] and one of the strongest determinants of the possibility of benefitting from adjuvant radiotherapy [1]. Among pT2 prostate cancers, a PSM has been considered an iatrogenic factor because these tumors are confined to the prostate; therefore, the surgeons’ experience might be important for reducing the incidence of PSM in a prostate-confined cancer [4, 5]. Previous studies have reported dramatically different rates of PSM according to the surgeons’ clinical experience [16], and found that the learning curves for surgical margins after open or laparoscopic RP plateaued at approximately 200–250 cases [17, 18]. We also reported a similar experience regarding the learning curves for surgical margins in a robotic RP series, wherein we demonstrated that the robotic RP reached a comparable PSM rate for pT3 disease with a surgical experience exceeding 500 cases [19]. However, even after transcending this learning curve for surgical margins, surgeons are among organ-confined prostate disease. Tumor-behavioral factors, such as the extent of EPE, have been identified as risk factors for a PSM, along with the preoperative PSA level and Gleason score [4, 20]. However, it remains unclear whether the tumor-behavioral factor itself is important in terms of the PSM. We previously identified the PTV as an independent risk factor for a PSM (p = 0.035), and both the PTV (p < 0.001) and surgical Gleason score (≥8; p = 0.021) as independent predictors of a BCR of organ-confined prostate cancer [21].

In this study, we hypothesized that the level of invasion into FMB might be another important tumor-behavioral factor associated with the risks of PSM and BCR after a RP of organ-confined disease. Our current results demonstrated that the level of invasion into FMB was an independent risk factor for a PSM (level 2 PCI; p = 0.007), along with the tumor volume (p = 0.013; Table 2). Accordingly, the level of invasion into FMB, tumor volume, and surgical Gleason score are tumor-behavioral factors that might promote a PSM after RP for organ-confined prostate cancer. On the whole, these results agree with those in our previous reports [21]. However, the significance of PTV for BCR was not consistent with our previous study, which included an older cohort (2000–2007) and used specialized method of PTV estimation [21]. The mean PTV was higher in our previous study than in the present study (12.1% vs. 8.7%).

We believe that the level of invasion into FMB has important clinical implications for organ-confined prostate cancer. Although a previous study reported that higher levels of prostatic capsular invasion were associated with a more adverse prognosis among patients with prostate cancer, the authors did not demonstrate whether the level of prostatic capsular invasion was an independent prognostic factor for a BCR of pT2 prostate cancer [6]. In our study, we used the term “fibromuscular band (FMB)” which was commonly accepted instead of “prostatic capsule” [6] and identified the level of invasion into FMB as an independent predictor of a BCR (Table 3). The 5-year BCR-free survival rate among patients with a level 2 FMB and negative surgical margin was similar to that of patients with a level 0–1 FMB group and PSM (86.4% vs. 85.6%; p = 0.578; Fig. 2c). Especially, patients with pT2 disease, a level 2 FMB, PSM, and a surgical Gleason score ≥ 4 + 3 had a worse 5-year BCR-free survival rate, compared to patients with a level 0–1 EPE, PSM, and surgical Gleason score ≥ 4 + 3, although this difference failed to reach statistical significance (53.3% vs. 76.2%; p = 0.225). The recent American Urology Association (AUA)/American Society for Therapeutic Radiology and Oncology (ASTRO) guideline mandated the use of adjuvant radiation therapy for patients with pT3 prostate cancer, based on the results from several randomized controlled trials [22]. Moreover, several studies of non-organ confined prostate cancer demonstrated that adjuvant radiotherapy significantly reduced the risk of BCR and improved metastasis-free and overall survival [23‐25]. Although RP provides decent overall long-term oncologic control and favorable survival rates in patients with organ-confined prostate cancer, we note that the clinical courses might vary depending on the presence of other risk factors. Given the BCR-free survival rates reported for the control arms of previous studies [23‐25], we believe that a certain subgroup of patients with pT2 disease will require adjuvant radiotherapy to reduce the risk of BCR after RP. The group with the worst prognosis in the present study, those with pT2 disease, a level 2 FMB, PSM, and surgical Gleason score ≥ 4 + 3, had a 5-year BCR-free survival rate of 53.3%, similar to that of patients with T3b disease in a previous study [26]. We believe that these patients should therefore be considered candidates for adjuvant radiotherapy after RP.

The present study had a retrospective design and relatively small sample size, and there were other limitations, such as a critical reproducibility of the level of invasion into FMB. Pathologists must re-evaluate the level of invasion into FMB, as well as the levels of all tumors. The highest level of FMB should be used for cases involving multiple tumors in the prostate. Furthermore, the effect of the level of invasion into FMB according to the tumor location remains controversial, and additional studies are needed. Despite these limitations, our study attempted to revisit the concept of the level of invasion into FMB as a tumor-behavioral factor in a contemporary RP cohort. External validation studies with larger cohorts or prospectively designed studies are needed to confirm the clinical implications of our findings.

The level of invasion into FMB is an independent tumor-behavioral factor for PSM and BCR in organ-confined prostate cancer. Patients with a level 2 FMB had a higher risk of BCR after RP. Therefore, the level of invasion into FMB might be used to stratify patients with pT2 disease and a poor prognosis.