Clinical outcome and safety of holmium laser prostate enucleation after transrectal prostate biopsies for benign prostatic hyperplasia

Prostate cancer is the most common new cancer and the second most deadly malignancy in men in the United States [1]. It is also the most common cancer in men in Europe and Africa [2]. It has been increasing in recent years. US 2022 statistics showed that prostate, lung, and colorectal cancers accounted for nearly half (48%) of all male cancer cases, with prostate cancer alone accounting for 27% of confirmed cases [1]. Currently, early diagnostic tests for prostate cancer mainly include digital rectal examination (DRE), serum prostate-specific antigen (PSA) measurement, and traditional transrectal ultrasound (TRUS) [1]. PSA levels show the risk of prostate cancer with high sensitivity and low specificity [3]. There are two types of prostate cancer imaging studies: magnetic resonance imaging (MRI) and ultrasound. Multiparameter MRI (mpMRI) is currently an important imaging method for the detection and localization of prostate cancer and guidance for a needle biopsy [4, 5]. However, MRI is unsuitable for patients with claustrophobia, pacemakers, or metal pelvic implants [6]. Prostate biopsy remains the mainstay in the diagnosis of prostate cancer. Currently, a 12-core, systematic TRUS-guided prostate biopsy (TR biopsy) for patients with serum PSA values greater than 3.0 ng/mL is the gold standard for diagnosing prostate cancer [7]. However, its sensitivity is low and its detection rate is only 25% to 40% [8]. The false-negative rate of systemic prostate biopsies ranges from 17% to 21% [9, 10]. Moreover, this procedure might be associated with mild or severe adverse events. Hematuria, hematoma, prostatitis, and urinary retention are the most commonly known complications. European Association of Urology (EAU) guidelines give a weak recommendation for the performance of mpMRI in biopsy naïve patients and strongly recommend mpMRI for repeat biopsies [11].

A large number of patients undergoing prostate biopsy often have an enlarged prostate in proportion to an increase in PSA. Therefore, when a prostate biopsy is diagnosed as benign prostatic hyperplasia, secondary surgical treatment such as transurethral resection of the prostate (TURP) or holmium laser enucleation of the prostate (HoLEP) is required. As described above, unexpected biopsy complications may accompany prostate biopsy. Thus, even if TURP or HoLEP is performed after biopsy, these complications might negatively affect surgical outcomes. However, reports on whether HoLEP performed after a TR biopsy will accompany difficulties in the surgical procedure compared to HoLEP performed without a TR biopsy are limited. In addition, there are few reports on how long it takes for TURP or HoLEP to be safely performed after biopsy and how biopsy affects the outcomes of HoLEP. Thus, the objective of this study was to compare and analyze postoperative results of a group that received HoLEP after TR biopsy and a group that received HoLEP without TR biopsy to determine clinical outcomes and safety of TR biopsy after HoLEP for benign prostate hyperplasia (BPH).

The present study protocol was reviewed and approved by the Institutional Review Board (IRB) of Gyeongsang National University Hospital (approval number: 2023-02-003). The waiver of the informed consent requirement was approved by the IRB considering the retrospective study design involving anonymized data.

Using a database approved by the relevant IRB of Gyeongsang National University Hospital, 556 consecutive patients who underwent HoLEP under a single surgeon’s care using the ‘Inverted omega-shaped En-bloc’ HoLEP technique to treat bladder outlet obstructions between 2014 and 2021 were retrospectively analyzed. Patients were divided into two groups according to whether or not prostate biopsy was performed: group 1-total (patients who underwent HoLEP after TR biopsy, n=139) and group 2 (control group, patients who underwent HoLEP without TR biopsy, n=417). Group 1-total was further subdivided into four groups according to the operation time and the number of TR biopsies: group 1-A (patients who underwent HoLEP within four months of TR biopsy, n=45), group 1-B (patients who underwent HoLEP 4 months after TR biopsy, n=94), group 1-C (patients who underwent HoLEP after once systematic TR biopsy, n=120), and group 1-D (patients who underwent HoLEP after twice [n=16] or three times [n=3] of systematic TR biopsies, n=19).

All patients were evaluated for baseline characteristics such as age, body mass index, and comorbid diseases. Preoperative PSA levels, prostate volume, and transitional zone volume were determined using TRUS, the International Prostate Symptom Score (IPSS), International Index of Erectile Function-5 (IIEF-5) score, voided volume (VV), maximum flow rate (Qmax), and postvoid residual volume (PVR). Flexible cystoscopies were routinely performed to evaluate urethral abnormalities, severity of anatomical obstruction, and three-dimensional structures of the prostate. In uroflowmetry results, cases with total urine volume (VV+PVR) less than 150 mL were excluded. Intraoperative data such as enucleation time, morcellation time, enucleated tissue weight, the magnitude of laser energy, and catheterization time were recorded for all patients. Intraoperative and postoperative complications were also recorded. All patients were assessed at one month, three months, six months, and 12 months post-HoLEP using uroflowmetry, PVR, IPSS, and IIEF-5.

A 12-core systematic TRUS-guided needle biopsies of the prostate were regularly performed in patients with higher preoperative PSA levels (≥4 ng/mL) for diagnosis of prostate cancer. All biopsies were taken under oral antibiotic prophylaxis with fluoroquinolones (levofloxacin 500 mg) in accordance with EAU guidelines [11]. Antibiotic prophylaxis was continued for five days after the biopsy. Glycerin cleansing enemas were done for all patients before biopsy. A transrectal approach using local anesthesia was performed in all prostate biopsies. For local anesthesia, 10 mL bupivacaine was injected through TRUS guidance as a periprostatic block on both sides [11, 12]. In cases of repeat biopsy, two additional core biopsies were performed for each lesion with a PI-RADS (Prostate Imaging Reporting and Data System) score of 3 or higher on MRI, in addition to the 12-core systematic biopsy. Repeat biopsy was followed up for PSA at least four times at 3-month intervals and a second or third biopsy was performed for at least one year.

A single surgeon performed all operations using a 100-watt holmium: yttrium-aluminum-garnet (Ho-YAG) laser device with 550-micron end-firing laser fibers (VersaPulse PowerSuite; Lumenis Medical Systems) and a VersaCut Tissue Morcellator (Lumenis Medical Systems). The laser energy was varied based on prostate volume: 72 W (1.8 J×40 Hz) for greater than 40 mL, 54 W (1.8 J×30 Hz) for 30–40 mL, and 36 W (1.8 J×20 Hz) for smaller than 30 mL. Coagulation power was set at 36 W (1.8 J×20 Hz) or 54 W (1.8 J×30 Hz) for greater than 30 mL and 36 W (1.8 J×20 Hz) for smaller than 30 mL. Metallic sound dilatation up to 30 or 32 Fr was performed before inserting a 26 Fr resectoscope.

All statistical analyses were performed using R software version 4.1.2 (R Foundation for Statistical Computing, 2021). Continuous data are presented as mean±standard deviation and categorical data are represented as number of patients (%). The Shapiro–Wilk test was used to assess the normality of continuous data. When the normality assumption was satisfied, groups were compared using Student’s t-test. Otherwise, the Mann–Whitney U test was conducted. A Pearson’s chi-square test was used when the distribution assumption was met. Otherwise, Fisher’s exact test was used. A linear mixed model was used to analyze operative results over time. Statistical significance was set at p<0.05.

Age, mean body mass index, IPSS, IIEF-5, uroflowmetry, and comorbid diseases (except diabetes mellitus) of group 1-total and group 2 were not significantly different. However, group 1-total had significantly higher PSA levels and large prostate volumes (both p<0.01) (Table 1). There were no significant preoperative differences in IPSS-total score, IPSS-voiding score, IPSS-storage score, IPSS-quality of life (QoL) score, or IIEF-5 score. Results of uroflowmetry (VV, Qmax, and PVR) showed significant differences between group 1-total and group 2.

Table 1
Preoperative characteristics of patients

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The enucleation time of the group 1-total was 59.7±28.2 minutes on average, which was significantly longer than that of group 2 at 41.8±25.0 minutes (p<0.01), and especially group 1-A and group 1-D took significantly longer (p<0.01). Average enucleated tissue weight of group 1-total was 29.2±23.0 mL, which was significantly heavier than that of group 2, 18.8±18.7 mL, and was significantly heavier in group 1-A and group 1-D (p<0.01). Average catheterization duration of group 1-total was 1.9±1.2 days, which was significantly longer than that (1.6±1.2 days) of group 2 (p<0.01) (Table 2). However, there was no significant difference in morcellation time or enucleated tissue ratio between the two groups.

Table 2
Perioperative and postoperative results

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Rates of postoperative complications such as urethral stricture, bladder neck contracture, incontinence of more than three months, and bladder injury by a morcellator did not differ significantly between group 1-total and group 2. They were not significantly different between groups 1-A and 1-B or between groups 1-C and 1-D (p>0.05). Postoperative medications of α-blocker, cholinergics, antidiuretics, and daily PDE-5 (phosphodiesterse 5) inhibitors were not significantly different between the two groups either. However, postoperative medication of anticholinergics or beta-3 agonists was significantly higher in group 2 (p<0.01). (Table 2). Rates of postoperative surgical management such as urethral sounding, endoscopic internal urethrotomy, re-HoLEP for bladder neck contracture, and re-HoLEP for regrowing adenoma were similar in the two groups. Postoperative incidental prostate cancer was similar between group 1-total and group 2, 9 (6.5%) in group 1-total and 25 (6.0%) in group 2 (p=0.357). However, group 1-B had 9 (9.6%) cases of postoperative incidental prostate cancer, which was significantly higher than group 1-A 0 (0.0%) (p<0.01). Significant improvements in IPSS (total, voiding, storage, and QoL), postvoid residual urine, and Qmax were observed in all groups during a follow-up period of one year (Fig. 1) (p<0.05).

Fig. 1
Comparison of International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum urine flow (Qmax), and postvoid residual urine before and after holmium laser enucleation of the prostate (HoLEP) in six groups. Significant improvements in IPSS (total, voiding, storage, and QoL), Qmax, and postvoid residual urine are shown from three months after HoLEP and continued during the 1-year follow-up period in all groups (p<0.01).

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For BPH diagnosis, urine analysis, TRUS, uroflowmetry, and PSA are performed. Patients as candidates for surgical treatment of BPH are usually screened for prostate cancer before treatment to rule out the presence of an incidental tumor that could eventually change the treatment management [13, 14]. Serum PSA level and prostate volume (PV) of patients with BPH have a log-linear relationship that increases proportionally with age [15, 16, 17, 18, 19]. The older the man, the greater the PV. Growth rate of PV increases when PSA level increases. The greater increase in PSA might have resulted from increased PSA secretion from a larger prostate as BPH develops with age. Therefore, many BPH patients require TR biopsy before HoLEP surgery. The increase in BPH patients due to an increase in elderly population requires more TR biopsies.

Transrectal ultrasound-guided needle biopsy can be performed either through a transrectal or a transperineal approach [20, 21, 22]. The PROMIS trial has demonstrated improved detection of clinically significant prostate cancer using transperineal biopsy compared to transrectal biopsy [23]. Transperineal biopsy might have a lower risk of sepsis. Its performance in a clinic setting under local anesthesia has been described. However, extensive perineal template biopsies might increase the rate of urinary retention. Still, many urologists see both approaches as reasonable choices.

In 1998, HoLEP was first used to treat BPH [24]. Until now, a large number of BPH patients are being treated using HoLEP. However, how prostate biopsy affects surgical outcomes of HoLEP is not well known. PSA test as a preoperative test in patients with BPH is performed before surgery in almost all patients. Therefore, for many patients with BPH, a prostate biopsy should be performed before HoLEP to confirm the significance of PSA elevation. In addition to bleeding or hematoma, a prostate biopsy might also be accompanied by prostate inflammation or, in severe cases, urinary obstruction or sepsis [25, 26, 27]. Because prostate biopsy often accompanies these sequelae, it is thought that it might have a particular effect on HoLEP performed later. However, data on the surgical outcomes of HoLEP performed after a prostate biopsy are limited, as the number of preoperative biopsies and HoLEPs performed is not sufficient to accurately predict the results. Yıldız et al. [28] and Etafy et al. [29] have reported no significant difference between the TR and non-TR biopsy groups regarding perioperative complications, postoperative voiding outcomes, or rate of incidental prostate cancer detection. However, Piazza et al. [30] have reported that the time from TR biopsy to HoLEP of ≤6 months is associated with a higher risk of intraoperative complications, lower enucleation efficacy, and longer enucleation time. Patients with a prostate biopsy ≤6 months before HoLEP had significantly worse outcomes than those with a prostate biopsy >6 months before HoLEP.

This study retrospectively analyzed clinical outcomes of 850 cases of HoLEP performed by a single surgeon. We compared and analyzed 556 HoLEP patients for whom data analysis was possible (139 HoLEP with TR biopsy and 417 HoLEP without TR biopsy). HoLEP was performed by a single surgeon and TR biopsy was performed by two urologists (one was the same surgeon who performed HoLEP). This study showed that the mean prostate volume and the level of PSA were larger and higher in the group that had undergone TR biopsy. The reason was that a PSA of 4 ng/mL or more was targeted when performing a prostate biopsy. Since the prostate volume tends to increase in proportion to a high PSA, the group with prostate biopsy performed naturally showed a high PSA and a large prostate.

For this reason, the HoLEP operation time was longer in the group with TR biopsy than in the group without TR biopsy and the postoperative catheterization time was longer in the group that received TR biopsy. However, there was no difference in enucleation ratio when HoLEP was performed between the two groups (with and without TR biopsy). Important implications from results of this study were that there was no significant difference in the rate of incidental prostate cancer detected after HoLEP between the two groups. In group 1-A (TR biopsy ≤4 months), no incidental prostate cancer was found after HoLEP. This might be because HoLEP was performed only on patients without prostate cancer in a short period (≤4 months) after TR biopsy. Moreover, since most biopsies after HoLEP belong to the transitional zone, we do not think it is possible to know whether prostate cancer is present in the peripheral zone. Significant improvements in the IPSS (total, voiding, storage, and QoL), postvoid residual urine, and Qmax were found for all postoperative groups.

PSA was higher and prostate volume was larger in the TR biopsy group. Enucleation time and catheterization duration were significantly longer in the TR biopsy group. However, there were no significant differences in postoperative incidental prostate cancer or postoperative complications between TR biopsy and non-TR biopsy groups. The incidental prostate cancer found after HoLEP was seen only in group 1-B (patients who underwent HoLEP 4 months after prostate biopsy). Significant improvements in IPSS and uroflowmetry were shown in all groups.