Impact of perioperative factors on nadir serum prostate‐specific antigen levels after holmium laser enucleation of prostate

Abstract Objective To investigate the relationship of preoperative prostate size, urinary retention, positive urine culture, and histopathological evidence of prostatitis or incidental prostate cancer on baseline and 3‐month nadir prostate‐specific antigen (PSA) value after Holmium laser enucleation of prostate (HoLEP). Patients and methods Data from 90 patients who underwent a HoLEP by En‐bloc technique were analyzed. PSA values at baseline and at 3‐month follow‐up, preoperative urinary retention and urine culture status, weight of resected tissue, and histopathological evidence of prostatitis or prostate cancer were recorded. We performed univariable and multivariable gamma‐regression analyses to determine the impact of the aforementioned perioperative variables on preoperative PSA, 3‐month postoperative PSA, and change in PSA. Results Serum PSA reduced significantly at 3 months from 6.3 ± 5.9 ng/mL to 0.6 ± 0.6 ng/mL. On both univariable and multivariable analysis, 3‐month nadir level was independent of all preoperative factors examined, except preoperative urinary retention status. Although patients with smaller prostate (resected tissue weight <40 g) had less percentile reduction in PSA when compared with those with larger prostate (resected tissue weight >80 g) (77.67% vs 89.06%; P < .001), patients from both these groups noted a similar PSA nadir level after 3 months (0.54 vs 0.56 ng/dL). The drop in PSA level after HoLEP remained stable up to 1‐year follow‐up. Conclusions PSA nadir 3 months after HoLEP remains relatively consistent across patients, regardless of preoperative prostate size, PSA value, urine culture status, and histopathological evidence of prostatitis or incidental prostate cancer.


| INTRODUC TI ON
Reduction in Prostate-Specific Antigen (PSA) following resection of prostate for benign prostatic hyperplasia (BPH) is directly proportional to the volume of adenoma removed. [1][2][3][4] Since all minimally invasive therapies do not remove the same volume of adenoma, PSA nadir will differ based on the procedure used to treat BPH. Since PSA plays an important role in prostate cancer (Pca) screening, it is necessary to have an adjusted normal PSA nadir for men with a history of adenomectomy for BPH. 5 Holmium laser enucleation of the prostate (HoLEP) has become the standard endoscopic enucleation techniques for surgical treatment of BPH. Although enucleation is well documented to result in dramatic reduction in PSA levels, the nadir level ranges widely from 0.9 to 1.9 ng/dL at 3-6 months post-procedure. [6][7][8] Elmansy HM proposed that if post-HoLEP PSA reduction is <50%, these patients should be followed with frequent PSA measurements to allow earlier detection of Pca. 6 Recent studies also recommend prostatic biopsy for all patients with post-HoLEP PSA above 1 ng/dL. 9 If one attempts to calculate an expected nadir level of PSA based on formula of percent reduction, the nadir level will depend on preoperative baseline PSA. Additionally, it is well known that the baseline PSA is influenced by prostate size, urinary retention status, urinary infection, and presence of prostatitis or incidental Pca. Therefore, we seek to ask whether or not a patient's preoperative characteristics, including prostate size, PSA value, and other factors ultimately influence their post-HoLEP PSA nadir and should we expect a standardized baseline regardless of preoperative variables affecting PSA values?
We investigated the relationship of preoperative prostate size, urinary retention status, positive urine culture, histopathological evidence of prostatitis, and incidental Pca on baseline and 3-month follow-up nadir PSA value after HoLEP. Since knowledge of nadir PSA at 3 months plays a critical role in prostate cancer screening, it is vital to understand factors that might influence this level. To the best of our knowledge, this study is first to evaluate the impact of patient-related perioperative variables on post-HoLEP nadir PSA value. We also reviewed the literature to determine the impact of common surgical techniques: trans-

| Patient selection
This study included patients who underwent En-bloc HoLEP at our institution from July 2017 to June 2019. Patient data were prospectively collected and retrospectively analyzed (Table 1). Institutional Review Board approval was obtained. Elevated PSA was evaluated before HoLEP with imaging, 4K score, and prostate biopsy, as indicated after shared decision making. Since the aim of the present study was to look for a nadir PSA level which may help in prostate cancer screening after HoLEP, we excluded patients with preoperative diagnosis of prostate cancer. Similarly, patients with post-HoLEP symptomatic UTI, and those with missing 3-month PSA data were also excluded (Table 1).

| Intervention
All procedures were performed by a single, experienced surgeon.
The procedure was performed using a Holmium laser machine at settings of 2 J and 30 Hz for the entire procedure. After an initial cystoscopy, an inverted U-shaped incision was made in the mucosa proximal to the verumontanum. This incision was extended laterally to enter the plane of enucleation. The adenoma was dissected from the pseudo-capsule counter-clockwise from 5 to 9 o'clock using a combination of blunt dissection and holmium laser energy. The vertical fibers near the bladder neck were incised at 12 o'clock anterior to the adenoma to enter the bladder. Thereafter, both lateral lobes were dissected from the bladder neck using laser energy. The right lobe apex was then dissected in a clockwise direction to connect the plane of enucleation that was developed from the anterior aspect of the right lateral lobe. At this point, the entire prostate adenoma typically remains attached to the membranous urethra anteriorly.
This antero-apical mucosal strip was then incised with the aim of safeguarding the sphincter. Finally, the prostate was separated from its posterior capsule, and pushed into the bladder for morcellation.

| Outcomes
The primary outcome was to assess the effect of preoperative urinary retention status, preoperative urine culture status, amount of enucleated tissue, and histopathologic diagnosis (BPH, BPH with prostatitis, and BPH with Pca) on baseline PSA and 3-month post-HoLEP nadir PSA level. PSA data at 6 month and 1 year were also reviewed. Since the preoperative measurement of prostate volume was not standardized, and measurements were done by various modalities that include transrectal ultrasound, CT scan, MRI, transabdominal ultrasound, or estimation on DRE, we did not use that data of preoperative prostate weight for analysis. Instead, we choose to use data of enucleated prostate weight which was measured by a single pathologist in all patients as a surrogate marker of preoperative prostate size.

| Statistics
Descriptive statistics were calculated to summarize the distribution of patient variables. We performed univariable and multivariable analyses to assess the effect of perioperative variables on predicting PSA at baseline, PSA at 3 months after HoLEP, and PSA decrease. The distributions of PSA outcomes did not meet the criteria of normal distribution by the Shapiro-Wilk test. We tested fit of alternative distribution and found that the log-normal and gamma distributions fitted the data similarly well. Therefore, we used paired Student t tests to compare log-transformed PSA baseline and at

| RE SULTS
During the study period, 161 patients underwent HoLEP and 90 patients met inclusion criteria for this study. Patient characteristics are displayed in supplementary Table S1. Mean PSA at baseline and 3 months postoperatively were 6.3 ± 5.9 ng/mL and 0.6 ± 0.6 ng/mL, respectively. This change was statistically significant (P < .0001) and corresponded to a PSA dropped on average by 85.6% (range from 12.3% to 99.7%) from baseline to 3 months post En-bloc HoLEP.
A subset of 25 patients had PSA of 0.82 ± 0.72 ng/dL (baseline PSA = 6.29 ± 4.07 ng/dL) at 6 months follow-up. One-year followup PSA data available from 42 patients revealed that PSA continued to remain low (0.58 + 0.73 ng/dL). (Figure 1).   Upon review of literature, we noted that nadir PSA levels reported post-HoLEP are much lower than most series of TURP and simple prostatectomy (Table 3). In the reported case series following endoscopic prostate enucleation, PSA nadir ranged from 0.5 to 1.9 ng/mL and % PSA decline ranged from 61% to 89%. The overall mean post-procedure PSA value was lower with the En-bloc technique than with the traditional two-lobe or three-lobe techniques (Table 3).

| D ISCUSS I ON
HoLEP is recommended as a size-independent procedure for the treatment of an enlarged prostate by the American Urology Association. We employed an En-bloc technique for HoLEP in present study and noted an average 3-month postoperative PSA valve of 0.6 ± 0.6 ng/mL, with 85.6 ± 16.7% decrease from baseline. The only other study examining PSA nadir after En-bloc HoLEP reported a similar PSA decrease of 84% with an average 3-month postoperative PSA nadir of 0.75 ng/dL. 10 Kim et al. described a similar "all-inone" En-bloc technique of enucleation using the Thulium laser and found an 81% reduction in PSA from a baseline level from 7.8 ± 15.9 to 0.5 ± 0.4 at 1 month after surgery. 11 However, three other studies that measured nadir PSA at 3-6 months post-HoLEP with the traditional two-lobe or three-lobe techniques found a nadir level ranging from 0.9 to 1.9 ng/dL. 6 Traditionally, it is believed that each gram of tissue removed during TURP causes a reduction in PSA by 0.1-0.3 ng/mL. 12 However, our study indicates that this is no longer applicable following complete enucleation. On sub-group analysis, we also noted that although patients with smaller prostates (resected tissue weight <40 g) had a smaller percentile reduction in PSA when compared with those with larger prostates (resected tissue weight >80 g) (77.67% vs 89.06%; P < .001), patients from both these groups noted a similar PSA nadir level at 3 month (0.54 vs 0.56 ng/dL) (Figure 2). After complete adenomectomy, the residual peripheral zone remains the only source of PSA. It has been shown that both the transition zone and peripheral zone of the prostate grows with age, but once the total prostate volume exceeds 30 g, the size of the peripheral zone becomes attenuated. 13 As most of the patients in our study had prostate sizes >30 gm, we believe that the volume of peripheral zones were equivalent in these patients, resulting in similar PSA values after HoLEP.
PSA nadir is also independent of use of holmium laser, thulium laser, or monopolar energy sources for endoscopic enucleation 14 after complete adenomectomy, dramatic reduction in PSA velocity is also expected. We noted that PSA level remained stable up to 1-year follow-up. Other authors also noted mean PSA level of 0.95 at follow-up of >5 years after HoLEP. 15 At a median follow-up of 12.6 years, the PSA decrease continued to remain at 66.7% from its pre-HoLEP level. 16 PSA velocity is high in patients diagnosed with Pca during follow-up after HoLEP and a threshold of 0.38 ng/mL/y was found to be highly specific for detecting Pca. 6,12 In our study, patients with preoperative urinary retention were We did not detect statistically significant differences in nadir PSA level at 3 months between patients with a histopathological diagnosis of Pca, prostatitis, or benign prostatic hyperplasia. Baseline PSA level in patient with histological evidence of prostatitis was found similar to those without prostatitis (6.03 vs 6.66 P = .157) and both groups had similar mean nadir PSA level at 3-month after surgery (0.70 vs 0.55; P = .520). Similarly, in one study following TURP, there was no significant difference between patients diagnosed with and without prostatitis on postoperative PSA.  We conclude that patients are expected to have a similar PSA nadir at 3 month after HoLEP, regardless of preoperative factors. We found that PSA levels following HoLEP are independent of evidence of indolent Pca or prostatitis on histopathologic examination and remains stable up to 12-months follow-up period. We recommend that Pca surveillance patients should have a PSA measurement at 3 months after any surgical intervention for BPH to evaluate the new PSA nadir.

E THI C S APPROVAL
The study was approved by University of Miami Ethics Committee-Study ID-20,180,511.

CON S ENT TO PARTI CIPATE
Every patient consented to participate in study.

CON S ENT FOR PUB LI C ATI ON
Every patient consented to participate in study.