Evaluating Incidence, Location, and Predictors of Positive Surgical Margin Among Chinese Men Undergoing Robot-Assisted Radical Prostatectomy.

PURPOSE: To evaluate the incidence and locations of positive surgical margin (PSM) among Chinese men undergoing RARP and identify the preoperative predictors for PSM.
METHODS: We retrospectively identified 393 patients who underwent RARP according to inclusion criteria by single surgeon in our hospital. PSM was defined as the presence of cancer adjacent to inked surface of the specimen and categorized into four groups based on locations: apex, posterolateral, base, and multifocal. Logistic regression analysis was performed to identify the predictors of overall and location-specific PSM.
RESULTS: The overall PSM rate was 133/393 (34%). The PSM rates for pT2, pT3, and pT4 stage were 63/278 (23%), 50/89 (56%), and 20/26 (77%), respectively. The estimated rates for apical, posterolateral, basal, and multifocal PSM were 8%, 4%, 7%, and 14%, respectively. In univariate analysis, overall PSM related to tPSA, f/tPSA, percentage of positive needles, and Gleason score. Multifocal PSM correlated with smoking history, drinking history, tPSA, f/tPSA, percentage of positive needles, and Gleason score. In multivariate analysis, percentage of positive needles reminded the only independent predictor for overall (OR = 10.5, 95% CI: 2.58-44.4) and basal PSM (OR = 24.0, 95% CI: 3.22-179.4). The f/tPSA (OR = 2.59, 95% CI: 2.18-5.71) and percentage of positive needles (OR = 31.0, 95% CI: 3.17-303) were independent risk factors for multifocal PSM.
CONCLUSION: The multifocal sites were the most common location of positive surgical margin, followed by apical and basal sites among Chinese patients undergoing RARP. The percentage of positive needles was an independent predictor for overall, basal, and multifocal PSM.

Introduction

Prostate cancer (PCa) is the second most diagnosed cancer among men, and the fifth leading cause of cancer death among men worldwide, with over one million cases and 358,989 deaths in 2018.[1,2] Although the incidence of PCa in China is significantly lower than that of the United States and Europe, it has been progressively rising due to the aging population, changes in diet, and widespread implementation of health examination in recent decades.[3,4] Radical prostatectomy (RP) is the standard therapy for clinically localized PCa, and a part of potential multi-model therapy for locally advanced disease.

Robot-assisted RP (RARP) has been routinely performed for RP in developed countries and is now a new choice for most PCa cases in China. With the advantages of enhanced vision and 7 of freedom, RARP is supported to provide efficient oncological control and good functional results. Despite advances in surgical techniques and methodologies, positive surgical margin (PSM) is still inevitable and remains an independent factor of biochemical recurrence, local recurrence, and distant metastasis. Systematic review showed that PSM rates varied from 6.5 to 32%, and the stage-specific rates were 4–23% for pT2, 29–50% for pT3, and 40–75% for pT4 among European and American population undergoing RARP.

In the past decade, several studies have correlated preoperative factors with surgical margin status after RARP.[9-11] However, most studies were based on cohorts of European or American people, and the knowledge about the Chinese population is limited. In our study, we aimed to evaluate incidence and locations of PSM among Chinese population following RARP and identify the predictive factors associated with PSM stratified by locations. This study will be helpful to improve counseling of PSM and provide guidance for clinically decisions, preoperatively and intraoperatively.

Material and Methods

Study Population

This retrospective study was approved by the Ethics Review Board of the First Affiliated Hospital of Zhengzhou University (IRB No. 2021-KY-0118-002), and a waiver of informed consent was obtained. Between October 2014 and December 2019, a total of 425 men underwent RARP through transperitoneal approach by a single surgeon (X. P. Z) in our institution. The 32 patients with incomplete clinical data were excluded from the study, leaving 393 cases available for analysis.

The RARP was performed by transperitoneal approach using the DaVinci system. Limited (obturator) or standard (obturator and external iliac) pelvic lymph node dissection was usually performed among patients with low-risk or intermediate-risk PCa. And extended (obturator, external iliac, and internal iliac) pelvic lymph node dissection was usually performed among patients with suspected lymph node invasion by MRI and/or high-risk PCa.[5,13] Nerve sparing procedure was cautiously performed using interfascial or intrafascial techniques based on clinical stage (≤T2b), Gleason score (GS ≤7), tPSA ≤10ng/mL, erectile function, and patients’ request. Additionally, we adopted the reelpipe approach for hemostasis and protecting nerve. PSM, defined as cancer cells involving the inked surface of the specimen, was categorized into four groups according to the following locations: apex, posterolateral, base, and multifocal sites.

Clinical Parameters Collection

The preoperative parameters including age at surgery, history of smoking, drinking, abdominal surgery and TURP, comorbidities such as hypertension and diabetes mellitus, serum tPSA and fPSA level before biopsy, prostate volume before biopsy, Gleason score determined by biopsy, number and percentage of positive cores in preoperative biopsy, surgical margin status, location of PSM, pathological stage of the cancer, and neoadjuvant ADT were extracted from clinical records. Prostate volume (PV) was measured by 3.0-T MRI system (Siemens, Germany) or ultrasonography scanner (BK Medical, Denmark) using the exact prolate ellipsoid formula. All patients underwent transrectal ultrasound-guided systematic 12-point biopsy according to the same protocol by the same surgeon. If suspected malignant nodules by MRI and/or ultrasound, additional 1–5 needles were performed in regions with cognitive MRI-TRUS fusion and/or abnormal ultrasound echoes. Pathological evaluation of biopsy cores and postoperative specimens were done according to the standards of International Society of Urological Pathology (ISUP).

Statistical Analysis

We described the profile of age, history of smoking, drinking, abdominal surgery and TURP, comorbidities, PSA derivates, prostate volume, and pathological parameters of enrolled participants by surgical margin status. The overall PSM rate was calculated by dividing the number of patients with PSM by the number of enrolled patients. The location-specific PSM rate was estimated using the following formula: location-specific PSM rate ≈ the number of patients with location-specific PSM /the number of patients with location-available PSM * the overall PSM rate. Student’s t test or ANOVA was used to analyze continuous data. The Mann–Whitney U test or Kruskal–Wallis H test was used to analyze ranked data. The χ2 test or Fisher’s exact test was used to analyze categorical data. Bonferroni correction was used for multiple comparisons. Logistic regression analysis was performed to identify predictors for PSM. All tests were two sided with significant level set at .05. All data cleaning and analysis were conducted using R statistical software (version 4.0.2).

Results

Overall and Location-Specific PSM Rates

Between October 2014 and December 2019, 393 (92%) of the total of 425 patients with RARP met study inclusion criteria. The overall PSM rate was 133/393 (34%). In the final pathological evaluation, 278 (71%) patients had pT2 stage, 89 (23%) patients had pT3 stage, and 26 (7%) patients had pT4 stage (Table 1). The PSM rates for pT2, pT3, and pT4 disease were 63/278 (23%), 50/89 (56%), and 20/26 (77%), respectively. Among patients with PSM, 67 (50%) had a solitary PSM, including 29 (18%) with apical PSM, 15 (11%) with posterolateral PSM, 23 (17%) with basal PSM, and 49 (37%) had multiple positive sites. The PSM site was not available among 17 patients (13%). The estimated apical, posterolateral, basal, solitary, and multifocal PSM rates were 8%, 4%, 7%, 20%, and 14%, respectively.

Table 1.

Comparison of Clinical Parameters by Status of Surgical Margin Following Robot-Assisted Radical Prostatectomy.

Parameter	Overall (n = 393)	Surgical Margin Status		P Value
		Negative (n = 260)	Positive (n = 133)
Age (years)	67 (63–72)	67 (63–72)	68 (63–73)	.993
Smoking history (n, %)				.841
No	270 (69)	180 (69)	90 (68)
Yes	123 (31)	80 (31)	43 (32)
Drinking history (n, %)				.683
No	322 (82)	215 (83)	107 (80)
Yes	71 (18)	45 (17)	26 (20)
Hypertension (n, %)				.341
No	265 (67)	180 (69)	85 (64)
Yes	128 (33)	80 (31)	48 (36)
Diabetes mellitus (n, %)				.225
No	330 (84)	223 (86)	107 (89)
Yes	63 (16)	37 (14)	26 (20)
Abdominal surgery (n, %)				.542
No	323 (82)	211 (81)	112 (84)
Yes	70 (18)	49 (29)	21 (16)
TURP (n, %)				.250
No	295 (75)	190 (73)	105 (79)
Yes	98 (25)	70 (27)	28 (21)
tPSA (ng/ml)	26.8 (13.5–65.3)	25.3 (12.4–60.0)	40.7 (16.2–91.9)	.017
f/tPSA	.12 (.08–.17)	.11 (.07–.16)	.14 (.10–.19)	.007
PSAD (ng/ml2)	.34 (.20–.65)	.36 (.20–.69)	.32 (.21–.64)	.747
Prostate volume (ml)	81 (55–125)	74 (52–112)	88 (66–135)	.078
% of positive needles	.59 (.25–1.00)	.59 (.25–1.00)	1.00 (.62–1.00)	<.001
Gleason score (n, %)				<.001
≤3+3	88 (22)	72 (28)	16 (12)
3+4	57 (15)	41 (16)	16 (12)
4+3	97 (25)	64 (25)	33 (25)
≥4+4	151 (38)	83 (32)	68 (51)
Risk category				<.001
low-risk	53 (13)	51 (20)	2 (2)
intermediate-risk	132 (34)	99 (38)	33 (27)
High-risk	208 (53)	110 (42)	98 (74)
Pathological T stage (n, %)				<.001
T2	278 (71)	215 (83)	63 (47)
T3	89 (23)	39 (15)	50 (38)
T4	26 (7)	6 (2)	20 (15)
Nerve-sparing (n, %)				.018
No	366 (93)	236 (91)	130 (97)
Yes	27 (7)	24 (9)	4 (3)

Abbreviations: PSM, positive surgical; TURP, transurethral resection of the prostate; tPSA, total prostate-specific antigen; fPSA, free prostate-specific antigen; f/tPSA, fPSA / tPSA; PSAD, prostate-specific antigen density; NA, not applicable.

Clinicopathological Characteristics of Patients by Surgical Margin Status

The clinicopathological characteristics by status of surgical margin were summarized in Table 1. Patients with PSM had a higher serum tPSA (40.7 vs 25.3, P = .017), f/tPSA (.14 vs .11, P = .007), percentages of positive needles (1.00 vs .59, P<.001), Gleason score (P<.001), and pathological T stage (P<.001), but a lower percentage of nerve-sparing (3% vs 9%, P = .018) compared with negative surgical margin (Table 1). Patients with multifocal PSM had higher proportions of smoking history (P = .042 and .027) and drinking history (P = .049 and <.024), higher tPSA (P = .002 and .030), and f/tPSA (P<.001 and = .032), compared with negative surgical margin and solitary PSM (Supplementary Table 1). Additionally, patients with multifocal PSM had higher percentages of positive needles (P<.001) and Gleason score (P = .003), compared with negative surgical margin. The clinicopathological characteristics but Gleason score (P = .007) were similar between patients with negative surgical margin and solitary PSM (Supplementary Table 1).

Logistic Regression analysis of Predictors for PSM

On univariate analysis, tPSA (OR = 1.01, 95% CI: 1.00–1.02), f/tPSA (OR = 1.59, 95% CI: 1.04–2.43), percentages of positive needles (OR = 6.85, 95% CI: 2.58–18.2), GS (GS = 4+3 vs ≤3+3, OR = 2.32, 95% CI: 1.17–4.61; GS≥4+4 vs ≤3+3, OR = 3.69, 95% CI: 1.96–6.92), and nerve sparing (OR = .23, 95% CI: .07–.77) were significant predictors for overall PSM (Table 2). Regarding multifocal PSM, smoking history (P = .030), drinking history (P = .033), higher tPSA (P = .003), f/tPSA (P = .002), percentage of positive needles (P < .001), and GS (GS≥4+4 vs ≤3+3, P = .004) were risk factors (Table 2). For solitary PSM, GS (GS≥4+4 vs ≤3+3, P = .016) was a significant predictor. And percentage of positive needles was significant predictor for basal PSM. There were no significant predictors for apical and posterolateral PSM (Supplementary Table 2).

Table 2.

Univariate Logistic Regression Analysis of Preoperative Predictive Factors for Overall and Multifocal Positive Surgical Margin.

Clinical Parameter	Surgical Margin		Solitary PSM vs Negative		Multifocal PSM vs Negative
	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P
Age (years)	1.00 (.97−1.02)	.737	1.00 (.96−1.03)	.853	1.00 (.96−1.05)	.884
Smoking history (yes vs no)	1.07 (.69−1.68)	.752	.76 (.42−1.41)	.389	1.99 (1.07−3.70)	.030
Drinking history (yes vs no)	1.16 (.68−1.98)	.585	.65 (.29−1.45)	.291	2.11 (1.06−4.19)	.033
Hypertension (yes vs no)	1.27 (.82−1.98)	.287	1.43 (.82−2.49)	.211	1.09 (.57−2.10)	.794
Diabetes mellitus (yes vs no)	1.46 (.84−2.54)	.176	1.59 (.80−3.16)	.183	1.36 (.61−3.03)	.457
Abdominal surgery (yes vs no)	.81 (.46−1.41)	.454	.94 (.47−1.89)	.861	.49 (.18−1.30)	.151
TURP (yes vs no)	.72 (.44−1.19)	.204	.72 (.37−1.37)	.315	.61 (.28−1.32)	.211
tPSA (ng/ml)	1.01 (1.00−1.02)	.011	1.00 (.99−1.01)	.589	1.01 (1.00−1.02)	.003
f/tPSA	1.59 (1.04−2.43)	.032	1.07 (.65−1.77)	.788	2.77 (1.44−5.34)	.002
PSAD (ng/ml2)	.78 (.30−1.99)	.598	.77 (.24−2.48)	.662	1.13 (.31−4.15)	.859
Prostate volume (ml)	1.00 (1.00−1.01)	.146	1.00 (.99−1.01)	.716	1.00 (.99−1.01)	.383
% of positive needles	6.85 (2.58−18.2)	<.001	2.72 (.91−8.13)	.073	38.6 (4.54−327)	<.001
Gleason score (≤3+3 as reference)
3+4	1.76 (.80−3.88)	.163	1.12 (.40−3.11)	.831	2.46 (.73−8.24)	.145
4+3	2.32 (1.17−4.61)	.016	1.74 (.76−3.99)	.191	2.70 (.90−8.08)	.076
≥4+4	3.69 (1.96−6.92)	<.001	2.52 (1.19−5.37)	.016	4.34 (1.58−11.9)	.004
Nerve−spare (yes vs no)	.23 (.07−.77)	.017	1.06 (.54−2.09)	.858	1.54 (.65−3.61)	.325

Abbreviations: PSM, positive surgical margin; TURP, transurethral resection of the prostate; tPSA, total prostate-specific antigen; fPSA, free prostate-specific antigen; f/tPSA, fPSA / tPSA; PSAD, prostate-specific antigen density; ADT, androgen deprivation therapy; NA, not applicable.

On multivariate analysis, percentages of positive needles reminded the only independent predictor for overall (OR = 9.82, 95% CI: 2.38–40.5) and basal PSM (OR = 26.0, 95% CI: 2.02–335). The f/tPSA (OR = 2.90, 95% CI: 1.22–6.88) and percentages of positive needles (OR = 31.0, 95% CI: 3.17–303) were significantly independent risk factors of multiple positive sites (Supplementary Table 3).

Discussion

In our study, we evaluated the incidence and locations of PSM among Chinese patients undergoing RARP, and comprehensively identified the preoperative predictors for PSM stratified by locations. The incidences for overall, apical, posterolateral, basal, and multifocal PSM were 34%, 8%, 4%, 6%, and 13%, respectively. The PSM rates for pT1, pT2, and pT3 stage were 23%, 56%, and 77%, respectively. The percentage of positive needles reminded the only independent predictor for overall and basal PSM. The f/tPSA and percentage of positive needles were significantly independent risk factors of multifocal PSM.

In our study, the overall PSM rate was 34%, which was comparable with the reported PSM rates among Chinese (29–42%)[19-21] and Korean (25–34%) population. However, the overall PSM rate was higher than that (mean: 15%, range: 6.5–32%) among Western population. Additionally, the PSM rates stratified by pathological stage were also higher among Chinese population (18–23% for pT2 stage, 44–50% for pT3 stage, and 59–100% for pT4 stage),[19,20] compared with European and American population (9% for pT2 stage, 37% for pT3 stage, and 50% for pT4 stage). This may suggest that Chinese population has a higher PSM rate after adjusting for the pathological stage. Some study found that race was largely independent of adverse pathological features including extracapsular extension, seminal vesical invasion, and PSM after radical prostatectomy.[24,25] The underlying causes of higher PSM rates among Chinese population, including tumor biology, technical aspect, surgeon’s experience, and the reporting pathologist, need to be explored.

The PSM rates significantly increased with pathologic stage, supporting the notion that pathologic stage was a well-recognized predictor of PSM. However, pathologic stage was a postoperative factor. Data on additional preoperative predictors including clinical and pathological characters for PSM had been largely inconclusive. In our study, the percentages of positive needles reminded an independent factor for overall, basal, and multifocal PSM. Tian et al. also found that percentage of positive needles was a strong predictor for PSM in both univariate and multivariate analyses. Yang et al. and Tuliao et al. showed that the number of positive needles in the biopsy specimen reminded an independent predictor of PSM.[11,26] The number and percentages of positive needles reflect the tumor volume and the percentage of tumor, which is directly associated with the tumor aggressiveness and proportion. Additionally, f/tPSA was an independent predictor for multifocal PSM in our study. Tian et al. also reported that f/tPSA was a strong predictor for PSM. However, the impact of f/tPSA on PSM /multifocal PSM was controversial in the two studies. Our previous data found no-linear pattern between f/tPSA and GS. The f/tPSA was smaller among patients with GS≥3+4 compared with patients with GS≤3+3 (.11 vs .15, P<.001). However, the f/tPSA increased with GS among patients with GS≥3+4 (data not shown). One reasonable explanation for the impact of f/tPSA on multifocal PSM was that f/tPSA indirectly reflected the aggressiveness and proportion of tumor tissue.

The multifocal sites were the most common location of PSM in our and Tian et al. ’s study. Our research showed that smoking and drinking history were significant risk factors of multifocal PSM but not independent predictors of multifocal PSM. However, limited study focused on the relationship between history of smoking and drinking and PSM. Previous study suggested that tobacco smoking was associated with high PSA level, high GS, lymph node involvement, overall mortality, PCa specific mortality, and recurrence.[27,28] Additionally, a meta-analysis showed significant dose-response relationship between level of alcohol consumption and risk of PCa. These may suggest that tobacco smoking and alcohol consumption could impact on PCa progression. The biologically plausible mechanisms of smoking promote PCa progression included carcinogens from tobacco smoke impacting tumor promotion, exposure to nicotine deregulating biological process, smoking-related tumor DNA methylation promoting aggression of PCa, and increased plasma levels of testosterone involved in PCa development and progression.[28,30]

The present study was subject to several imitations. First, this study was a single center study and limited by its retrospective design. Second, even though the total number of patients included in this study was satisfactory, the subgroup analysis by PSM location was not feasible and/or underpowered. Third, no central review of pathological results was performed in our study, which may lead to classification errors. However, all the pathological specimens were examined by the pathologists in the same institution according to the same protocol. Therefore, the pathological bias was minimal in our study.

Conclusions

The PSM rate was higher among Chinese population undergoing RARP, compared to Western population. The multifocal sites were the most common location of PSM, followed by apical and basal sites among Chinese patients undergoing RARP. The percentage of positive needles was a strong predictor for overall, basal, and multifocal PSM. The f/tPSA and percentage of positive needles were significantly independent risk factors of multifocal PSM. This study will be helpful to improve counseling of PSM and provide guidance for clinically decisions, such as neoadjuvant therapy, nerve-sparing, or modified surgical method, preoperatively and intraoperatively.

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Supplemental Material, sj-pdf-1-ccx-10.1177_10732748211055265 for Evaluating Incidence, Location, and Predictors of Positive Surgical Margin Among Chinese Men Undergoing Robot-Assisted Radical Prostatectomy by Wugong Qu, Shuanbao Yu, Jin Tao, Biao Dong, Yafeng Fan, Haopeng Du, Haotian Deng, Junxiao Liu and Xuepei Zhang in Cancer Control