1 INTRODUCTION

The term benign prostatic hyperplasia (BPH) refers to the non-malignant growth of prostate tissue, predominantly in the prostateʼs transitional zone and is a common cause of male lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction (BPO).1 The prevalence of BPH increases with age: about half of the 50-60-year old male population present with the histological diagnosis of BPH upon autopsy, peaking up to 80% in men above the age of 80 years.1, 2 BPH is a histological diagnosis characterized by an unfavorable balance between stromal and epithelial cell proliferation and cell death in the prostateʼs transitional zone surrounding the urethra.2 Compression of the urethra leads to bladder outlet obstruction (BOO) caused by benign prostatic enlargement (BPE), thus leading to clinically relevant LUTS secondary to BPO. In 2018 about 612 million men worldwide were affected by LUTS/BPO, with annual costs peaking up to five billion US$ for medical treatment.3 Age is a significant predictor of BPH and subsequent LUTS and, by the year 2040, one in four Americans will be above the age of 65, leading to even higher prevalence of LUTS/BPO.4, 5 While prostate size alone may not be an unlimited predictor of LUTS, prostate volume significantly increases with age. Studies have shown that prostate volume increases up to 2.5% per year.5 Typically, the patient seeking urological treatment for LUTS/BPO is 65 years of age or above, bringing with them an increased risk of higher prostate volume and a much more challenging approach when considering the benefits and limitations of medical or surgical treatment.6, 7

With the introduction of holmium laser enucleation of the prostate (HoLEP), a size-independent method for surgical relief of LUTS has constantly challenged transurethral resection of the prostate (TURP) as surgical reference method.8-10 The efficacy of HoLEP is comparable to open prostatectomy (OP), but with shorter catheterization time, hospital stay and less blood loss.9, 11 HoLEP is equally efficient when compared to TURP, and even superior regarding perioperative morbidity.12 HoLEP may therefore be a viable treatment option even in very large prostate glands (≥120 cc).

Considering this, together with the demographic shift in Western countries, the age-dependent progression of prostate size warrants improved understanding of the influence of prostate size on feasibility and functional outcomes of surgical treatment options for LUTS/BPO.

We therefore analyzed the impact of prostate size on preoperative LUTS profile, perioperative morbidity and mortality and postoperative functional outcomes for patients undergoing HoLEP for LUTS/BPO at our tertiary referral center.

2 METHODS 2.1 Patient population and study design

We included 852 patients who underwent HoLEP for LUTS secondary to BPO between 2014 and 2018. A computerized database containing information about patientsʼ prostate sizes, various clinical information, as well as perioperative data and follow-up information, was used for this study. We retrospectively analyzed this database and included patients according to the aforementioned criteria. In total, 852 patients were evaluated, in which all the information was available, and subdivided into three groups. HoLEP for LUTS/BPO was indicated in accordance with the current European Association of Urology guidelines on management of non-neurogenic male LUTS.13 However, patients presenting with an indwelling urinary catheter (ICUD) could not partake in preoperative uroflowmetry. Additionally, patients with a higher-than-expected preoperative prostate-specific antigen (PSA) value (ie, PSA density >0.15 ng/mL/cc) were assessed for prostate malignancy or, if inflammation was the cause of increased PSA, received antibiotics before surgery. The latter, were then re-assessed before definite surgery.

Only two experienced surgeons performed all HoLEPs. We used the VersaPulse® 100 W Holmium Laser (Lumenis Ltd., Yokneam, Israel) with a frequency of 53 Hz and a power setting of 1.2 kJ. Morcellation was performed using a mechanical tissue morcellator (R. Wolf, Piranha, Knittlingen, Germany). According to our standard protocol, a 24 F three-way foley catheter was inserted after surgery and followed by 12 hours of continuous bladder irrigation with normal saline.

Prostate size was assessed with transrectal ultrasound (TRUS) and patients were stratified into three groups. Group 1 included patients with prostate sizes ≤60 cm3 (cc) (n = 157), group 2 included patients with glands from >60 cc to <120 cc (n = 523) and group 3 included only patients with very large prostates ≥120 cc (n = 172). We performed an additional analysis, dividing patients into two clinically very relevant groups: prostate size <80 cc (group 4; n = 410) vs ≥80 cc (group 5; n = 442), that is, where OP is indicated by current guidelines.13

Clinical and pathological information as well as perioperative data were used to describe the patient cohorts. Perioperative complications were analyzed in all groups. They were defined as any adverse event within 30 days of surgery and classified using the modified Clavien-Dindo (CD) scale.14

2.2 Statistical analysis

Statistical analysis was performed using SPSS V26.0 software (IBM SPSS Statistics, Version 26.0. Armonk, NY, USA). Results are given as median and interquartile range (IQR) for continuous variables and as percentage for categorial variables. Univariate analyses were performed using Fisherʼs exact test, t test and Mann-Whitney U test for categorical variables and continuous variables, respectively. All reported P-values were two-sided and considered statistically significant if P < 0.05.

3 RESULTS 3.1 Patient characteristics

Table 1 displays demographic parameters of our patient cohorts. In total, 852 patients underwent HoLEP for LUTS secondary to BPO. Patients significantly differed in prostate size, with a median 139 cc (IQR 124-160) in group 3 vs 83 cc (IQR 72-100) and 55 cc (IQR 50-60) in groups 2 and 1, respectively (P < 0.001). Patients also differed in age, with the highest median age of 73 years (IQR 69-77) in group 3 vs 71 years (IQR 65-76) in group 2 (P < 0.02) and 70 years (IQR 62-76) in group 1 (P < 0.003). LUTS profile was significantly different between the patient cohorts (Table 1). Patients in group 3 presented with significantly lower international prostate symptom score (IPSS) of 17 points (IQR 12-22) compared to group 1 with 19 (IQR 14-24) (P < 0.05) with no significant difference to group 2 with 19 points (IQR 14-24). As expected, median PSA was significantly different in all three groups with the highest median of 8.9 ng/mL (IQR 5.6-14.2) in group 3 vs groups 1 and 2 with 3.2 ng/mL (IQR 1.7-5.6) and 5.5 (IQR 3.4-9.6), respectively (P < 0.001). Presenting with an ICUD at time of surgery was significantly more prevalent in group 3 with 40.1% vs 32.5% and 20.4% for groups 2 and 1, respectively (P < 0.002). Apart from that, patient characteristics were comparable between all three cohorts and groups 1, 2 and 3 showed no statistically significant difference in body mass index (BMI), preoperative quality of life (QoL), maximum flow rate (Qmax), post-void residual (PVR), preoperative hemoglobin (Hb) or PSA density prior to surgery.

TABLE 1. Demographic parameters Variables Group 1 (≤60 cc) n = 157 Group 2 (>60 < 120 cc) n = 523 Group 3 (≥120 cc) n = 172 P-value Prostate volume (cc) Median 55 83 139 <0.001 IQR 50-60 72-100 124-160 Age (y) Median 70* 71** 73 *<0.003 IQR 62-76 65-76 69-77 **<0.02 BMI Median 25.6 26.0 26.2 0.540 IQR 23.9-28.3 24.1-27.8 24.0-29.0 IPSS Median 19 19 17 <0.05 IQR 14-24 14-23 12-22 QoL Median 4 4 4 0.722 IQR 2-5 3-5 3-4 Qmax (mL/s) Median 11 11 11 0.941 IQR 8-15 8-15 8-15 PVR (mL) Median 80 100 60 0.154 IQR 30-185 40-170 20-150 Hb (g/dL) Median 15.0 14.7 14.7 0.105 IQR 14.1-15.6 13.8-15.5 13.9-15.4 Total PSA (ng/mL) Median 3.2 5.5 8.9 <0.001 IQR 1.7-5.6 3.4-9.6 5.6-15.2 PSA density (ng/mL/cc) Median 0.06 0.06 0.06 0.277 IQR 0.03-0.11 0.04-0.11 0.04-0.10 ASA score ≥III vs <III 30.6% 31.0% 35.5% 0.509 (%) (48) (162) (61) IDUC 20.4% 32.5% 40.1% <0.002 (%) (32) (170) (69) Note: Bold values indicate statistically significant P-values (P < 0.05). Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index; Hb, hemoglobin; IDUC, indwelling urinary catheter; IPSS, International Prostate Symptom Index; IQR, interquartile range; PSA, prostate specific antigen; PVR, post-void residual urine; Qmax, peak urinary flow rate; QoL, quality of life. * group 1 vs. group 3. ** group 2 vs. group 3. 3.2 Perioperative assessment and functional outcomes

Displayed in Table 2, the analysis of the perioperative outcomes showed statistically significant differences in enucleation time and morcellation time. We observed a significantly shorter median enucleation time of 27 minutes (IQR 24-38) for patients with smaller prostates in group 1 vs 39 minutes (30-55) and 40 minutes (IQR 33-53) in groups 2 and 3, respectively (P < 0.001). Median morcellation time was significantly shorter for the smaller prostates in group 1 with 6 minutes (IQR 4-9) compared to 13 minutes (IQR 10-18) and 25 minutes (IQR 15-35) for groups 2 and 3, respectively (P < 0.001). However, enucleation speed significantly favored group 3. We observed a median enucleation speed of 2.79 g/min (IQR 2.04-3.77) for group 3 vs 1.60 g/min (IQR 1.10-2.22) for group 2 vs 1.08 g/min (IQR 0.92-1.45) for group 1 with P < 0.001 for all groups, respectively. However, there was no difference in morcellation speed. As anticipated, median total resected tissue was more in group 3 with 115 g (IQR 88-132) vs group 2 with 63 g (IQR 50-75) vs group 1 with 35 g (25-44) with P < 0.001 for all groups, respectively. Also, median tissue retrieval percentage was significantly higher in groups 2 and 3 with 75% (IQR 63-87) and 76% (IQR (65-90), respectively, vs group 1 with 67% (IQR 53-80) (P < 0.001). Table 3 shows perioperative parameters for patients divided into group 4 (<80 cc) and group 5 (≥80 cc). We observed similar results as in groups 1-3 with a median enucleation time of 32 vs 40 minutes, and enucleation speed of 1.25 g/min vs 2.21 g/min for groups 4 and 5 with P < 0.001, respectively. While morcellation time was significantly different between both groups, with 9 and 17 minutes for groups 4 and 5, respectively (P < 0.001), we observed no difference in morcellation speed. As anticipated before, resected tissue was more in group 5, with a median of 82 g vs 48 g in group 4 (P < .001), with a slight – albeit statistically significant – difference in relative tissue retrieval of 73% vs 76% for groups 4 and 5, respectively (P < 0.02). There was no difference in the length of hospital stay or catheterization time.

TABLE 2. 24-h perioperative parameters and clinical outcomes 4 weeks after surgery Variables Group 1 (≤60 cc) n = 157 Group 2 (>60 < 120 cc) n = 523 Group 3 (≥120 cc) n = 172 P-values Enucleation time (min) Median 27 39 40 <0.001 IQR 24-38 30-55 33-53 Enucleation speed (g/min) Median 1.08 1.60 2.79 <0.001 IQR 0.92-1.45 1.10-2.22 2.04-3.77 Morcellation time (min) Median 6 13 25 <0.001 IQR 4-9 10-18 15-35 Morcellation speed (g/min) Median 5.50 5.00 4.57 0.603 IQR 4.00-7.15 3.87-6.06 3.65-5.33 Resected tissue (g) Median 35 63 115 <0.001 IQR 25-44 50-75 88-132 Resected tissue (%) Median 67 75 76 <0.001 IQR 53-80 63-87 65-90 Catheterization time (d) Median 2.0 2.0 2.0 0.147 IQR 2.0-2.0 2.0-3.0 2.0-3.0 Hospitalization time (d) Median 3.0 3.0 3.0 0.104 IQR 3.0-3.0 3.0-4.0 3.0-4.0 Δ Hb (g/dL) Median 0.9* 1.2** 1.8** * < 0.01 IQR 0.3-1.5 0.6-1.8 1.0-2.7 ** < 0.001 Δ IPSS Median 8 8 8 0.613 IQR 4-16 2-16 3-14 Δ QoL Median 2 3 2 0.455 IQR 1-4 1-4 1-4 Δ Qmax (mL/s) Median 10 11 9 0.620 IQR 5-18 6-21 4-19 Δ PVR (mL) Median 77 77 53 0.169 IQR 29-180 30-160 14-150 Note: Bold values indicate statistically significant P-values (P < 0.05). Abbreviations: BMI, body mass index; Hb, hemoglobin; IPSS, International Prostate Symptom Index; IQR, interquartile range; PVR, post-void residual urine; Qmax, peak urinary flow rate; QoL, quality of life. TABLE 3. 24-h perioperative parameters and clinical outcomes 4 weeks after surgery Variables Group 4 (<80 cc) n = 410 Group 5 (≥80 cc) n = 442 P-values Enucleation time (min) Median 32 40 <0.001 IQR 25-45 32-53 Enucleation speed (g/min) Median 1.25 2.21 <0.001 IQR 0.91-1.67 1.48-2.78 Morcellation time (min) Median 9 17 <0.001 IQR 6-12 12-25 Morcellation speed (g/min) Median 5.33 4.71 0.122 IQR 4.00-6.29 3.68-6.07 Resected tissue (g) Median 48 82 <0.001 IQR 36-60 68-107 Resected tissue (%) Median 73 76 0.019 IQR 60-85 62-88 Catheterization time (d) Median 2.0 2.0 0.186 IQR 2.0-2.0 2.0-3.0 Hospitalization time (d) Median 3.0 3.0 .0124 IQR 3.0-3.0 3.0-4.0 Δ Hb (g/dL) Median 1.0 1.5 <0.001 IQR 0.3-1.6 0.8-2.3 Δ IPSS Median 8 8 0.222 IQR 3-16 2-14 Δ QoL Median 3 3 0.322 IQR 1-4 1-4 Δ Qmax (mL/s) Median 10 10 0.960 IQR 6-19 5-20 Δ PVR (mL) Median 73 60 0.108 IQR 24-165 20-150 Note: Bold values indicate statistically significant P-values (P < 0.05). Abbreviations: BMI, body mass index; Hb, hemoglobin; IPSS, International Prostate Symptom Index; IQR, interquartile range; PVR, post-void residual urine; Qmax, peak urinary flow rate; QoL, quality of life.

Hemoglobin was assessed once preoperatively, and 24 hours after surgery. There was a statistically significant difference in the overall median hemoglobin drop between the three groups with 0.9 g/dL (IQR 0.3-1.5) in group 1 vs 1.2 g/dL (IQR 0.6-1.8) in group 2 (P < 0.01) and 1.8 g/dL (IQR 1.0-2.7) in group 3 (P < 0.001) and between groups 2 and 3 (P < 0.001). After sub-analysis, we report a significant difference between groups <80 cc and ≥80 cc of 1.0 vs 1.5 g/dL (P < 0.001).

Four weeks after surgical treatment LUTS significantly improved in all three patient cohorts. Median IPSS decreased by eight points throughout all patient cohorts (P = 0.613). We observed a relevant improvement in QoL for all three groups with no significant difference between groups. Early functional outcomes 4 weeks after surgery showed no significant difference between all groups, with a difference in Qmax of 10 mL/s (IQR 5-18), 11 mL/s (IQR 6-21) and 9 mL/s (IQR 4-19), respectively (P = 0.620). Median PVR reduction of 77 mL (IQR 29-180), 77 (30-160) and 53 (14-150) were observed for groups 1-3, respectively (P = 0.169). However, we observed no difference between all groups in duration of hospital stay or catheterization time. Furthermore, in groups 4 and 5, postoperative functional outcomes improved in a similar fashion, showing no difference between both groups for improvement of IPSS, QoL, Qmax and PVR (Table 3).

3.3 Perioperative complications

In total, 63 (63/852, 7.4%) patients of the entire cohort experienced at least one perioperative complication. In groups 1, 2 and 3 respectively, nine (5.7%), 41 (7.8%) and 13 (7.6%) patients had at least one perioperative complication. There was no significant difference between all three groups (P = 0.760). The groups also did not differ in the severity of their perioperative complications described by the modified CD score in Table 4. We divided complications into minor (CD I) and major complications (CD II to V) (P = 0.492), requiring an intervention. Complications seen are listed in detail in Table 4. However, when dividing patients into groups 4 and 5, we neither found a difference in number of complications, nor in the severity of complications, defined as CD classification ≥II (P = 0.463; Table 5).

TABLE 4. Perioperative adverse events (AEs) in groups 1-3 according to the Clavien-Dindo classification. The following AEs were identified and consecutive management is given in the table AEs Group 1 (≤60 cc) Group 2 (>60 < 120 cc) Group 3 (≥120c) P-value n = 157 n = 523 n = 172 Overall AEs; n (%) 9 (5.7%) 41 (7.8%) 13 (7.6%) 0.760 Clavien-Dindo I 4 (1.7%) 15 (2.7%) 3 (6.3%) Clavien-Dindo II 1 (0.4%) 1 (0.4%) 1 (0.3%) Clavien-Dindo III 4 (2.0%) 21 (4.5%) 6 (4.5%) Clavien-Dindo IV