Impact of positive surgical margin length and Gleason grade at the margin on oncologic outcomes in patients with nonorgan‐confined prostate cancer

Positive surgical margins (PSM) represent a poor prognostic factor at radical prostatectomy (RP). To investigate the impact of PSM, its length, the focality and the Gleason grade at the PSM, on the oncologic outcomes in nonorgan‐confined RP patients.

margin status, Gleason at the margin and its length carry important information that should be reported for the specimen. Positive surgical margins (PSM) represent a poor prognostic factor at radical prostatectomy (RP) for prostate cancer (PCa) patients. [1][2][3] Patients with nonorgan confined (pT3) are likely to harbor PSM. Recent studies report rates of PSM ranging from 37% to 61% in pT3 PCa patients. 2,4,5 Specifically, the lowest reported rates (37%) of PSM in pT3 patients derived from a robotically treated cohort by Patel and colleagues within a multi-institutional series. 5 Conversely, higher rates apply for national registries. Wright et al. 2 reported a PSM rate of 44% for pT3a patients within the Surveillance, Epidemiology, and End Results (SEER) database. Similar rates, compared with the one reported by Wright et al., were also recorded by Lightfoot et al. 4 within a robotically treated cohort for pT3a patients (43%) treated by a single high-volume surgeon. However, for patients with seminal vesicle invasion (pT3b) the authors recorded much higher PSM rates (61%). 4 Recently, we reported that PSM negatively impacts survival in patients with non-organ confined PCa within the SEER database. 3 Moreover in organ-confined pT2 PCa the Gleason grade at the PSM and its length are poor risk factors for biochemical recurrence (BCR) after RP. 6 Previously, Ploussard and colleagues reported that the PSM length >3 mm and multifocal PSM in non-organ confined prostate cancer are risk factors for BCR after RP. 7 Similarly, Brimo et al. 8 reported within a small cohort of 108 patients with nonorgan that a higher Gleason grade at the margins is associated with BCR.
However, the predictive value of the Gleason grade at the PSM, its length, and the PSM focality in nonorgan confined pT3 disease on long-term oncologic outcomes remains still debatable.
To address this void, we tested the relationship between PSM and BCR, metastasis, and cancer-specific death. Specifically, we examined the relationship of PSM, the Gleason grade at the PSM, its length and focality, and BCR, metastasis and cancer-specific death after RP, within an institutional high-volume center database of contemporary exclusively nonorgan confined PCa RP patients.

| Study population
After Institutional Review Board approval, 5271 patients that harbored pathologic nonorgan confined PCa (pathologic stage T3) were treated with RP between 2010 and 2016 at a tertiary referral institution (Martini-Klinik Prostate Cancer Center, Hamburg-Eppendorf, Germany) were identified.
Exclusion criteria consisted of lymph node invasion (n = 1459) or unknown margin status (n = 105). These selection criteria yielded 3705 patients, which represent the focus of the current study.

| Surgical approach
Surgery was performed either as an open retropubic or robot-assisted laparoscopic approach as previously described. 9,10 Neurovascular bundle preservation was performed with the intraoperative frozen section (NEUROSAFE) technique as previously described. 10,11 In the case of PSM during the frozen section, a resection of the neurovascular bundle at the corresponding side was performed.

| Surgical margin parameters
Parameters describing the surgical margin status were retrieved from the pathology reports. In cases where a mixed Gleason pattern (i.e., 3 + 4) was recorded for a surgical margin, the predominant Gleason pattern was used for statistical analyses. Time to cancer-specific death was calculated as the time from RP to death or last follow-up. Cancer-specific death was defined as death attributed to PCa.

| Effect of PSM on metastasis
In multivariable Cox models predicting development of metastasis ( In subgroup analysis, focusing on patients with PSM (Table 3) Figure 3D) for <4 mm versus ≥4 mm length of PSM.
Last but not least, in multivariable Cox models predicting cancerspecific death ( Additionally, the site of the PSM may also affect oncologic outcomes after RP, which was unavailable within the current database. Last but not least, our database did not contain information on adjuvant hormone therapy, which may have influenced oncologic outcomes.

| CONCLUSION
PSM represents an independent predictor for worse oncologic outcomes in non-organ-confined PCa at RP. Gleason ≥4 at the margin was associated with the development of BCR, metastasis, and with cancer-specific death after RP. Moreover, the length of PSM was an independent predictor for BCR. Next to margin status, Gleason at the margin and its length carry important information that should be reported for the specimen.